Pan-Asian adapted Clinical Practice Guidelines for the management of patients with metastatic non-small-cell lung cancer: a CSCO–ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS

[Audio] Annals of Oncology 30: 171-210, 2019 doi: 10.1093/annonc/mdy554 Published online on December 28, 2018 SPECIAL ARTICLE: Pan Asian Adapted Clinical Practice Guidelines for the Management of Patients with Metastatic Non Small Cell Lung Cancer: A CSCO-ESMO Initiative Endorsed by JSMO, K-S-M-O-, M-O-S--, S-S-O, and T-O-S Authors: Yi Long Wu1*, David Planchard2, Sumin Lu3, Han Sun4, Naoki Yamamoto5, Dong Wan Kim6, Daniel S W Tan7, James C-H. Yang8, Mohd Azrif9, Tony Mitsudomi10, Keunchil Park11, Ross A Soo12, Jin W Chang13, Abdul Alip14, Solange Peters15, and Jean Yves Douillard16 Affiliations: 1Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P R China; 2Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif, France; 3Shanghai Chest Hospital, Shanghai; 4Guangdong Lung Cancer Institute, Guangdong Lung Cancer Institute, Guangdong General Hospital, School of Medicine, South China University of Technology, Guangzhou, P R China; 5Department of Internal Medicine 3, Wakayama Medical University, Wakayama, Japan; 6Seoul National University Hospital, Seoul, Korea; 7Division of Medical Oncology, National Cancer Centre Singapore, Singapore; 8Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; 9Department of Radiotherapy & Oncology, Prince Court Medical Centre, Kuala Lumpur, Malaysia; 10Faculty of Medicine, Department of Thoracic Surgery, Kindai University, Osaka Sayama, Japan; 11Division of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 12Department of Haematology/Oncology, National University Hospital, Singapore, Singapore; 13Division of Haematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung, Taiwan; 14Faculty of Medicine, Department of Clinical Oncology, University of Malaya, Kuala Lumpur, Malaysia; 15Oncology Department, Lausanne University Hospital (C-H-U-V-), Lausanne; 16ESMO, Lugano, Switzerland *Correspondence to: Dr. Yi Long Wu, Guangdong Lung Cancer Institute Guangdong General Hospital and Guangdong Academy of Medical Sciences, located at 106 Zhongshan Er Road in Guangzhou, China, can be contacted at þ86-2083877855 (telephone) or þ86-2083877855 (fax), or via email at [email protected]. The most recent version of the European Society for Medical Oncology (E-S-M-O-) Clinical Practice Guidelines for the diagnosis, treatment, and follow up of metastatic non small cell lung cancer (N-S-C-L-C) was published in 2016. At the E-S-M-O Asia Meeting in November 2017, it was jointly decided by E-S-M-O and the Chinese Society of Clinical Oncology (C-S-C-O-) to hold a special guidelines meeting immediately after the Chinese Thoracic Oncology Group Annual Meeting 2018 in Guangzhou, China. The purpose of this meeting was to modify the 2016 E-S-M-O guidelines to consider ethnic differences in the treatment of metastatic N-S-C-L-C in Asian patients. These guidelines were developed by a consensus of experts from various oncological societies in China (C-S-C-O-), Japan (J-S-M-O-), Korea (K-S-M-O-), Malaysia (M-O-S--), Singapore (S-S-O--), and Taiwan (T-O-S--). The voting was based on scientific evidence and was independent of current treatment practices and drug availability and reimbursement policies in these countries. During the review process, the updated 2018 E-S-M-O Clinical Practice Guidelines for metastatic N-S-C-L-C were also considered in the final stages of developing these Pan Asian adapted guidelines. Key words: metastatic NSCLC, Pan Asian, consensus, guidelines Introduction Worldwide, lung cancer is the leading cause of cancer death, with approximately 1.6 million deaths annually, surpassing all other types of cancer [1]. In both men and women, lung cancer is the most common cause of cancer death worldwide. It is also the most prevalent cancer in Asia and the primary cause of death in Southern Asia. Eastern and South Eastern Asia [2]. Fifty one percent of the world's lung cancer cases occur in Asia [3], and 21% of cancer deaths in Asia are caused by lung cancer [4]. The number of cases and the crude and standardized incidence rates (for both sexes) of lung cancer in five Asian countries per 100000 people in the population are.

[Audio] Special Article: Preparation of the First Pan Asian Adapted E-S-M-O Guidelines for the Management of Patients with Metastatic Colorectal Cancer [25]. Expert Panel Composition: The international panel of experts was selected based on their demonstrated knowledge of the treatment and management of patients with Non Small Cell Lung Cancer (N-S-C-L-C), through their publications and/or participation in the development of national or international treatment guidelines. This included two expert members from Chinese Society of Clinical Oncology (C-S-C-O-), two expert members from European Society for Medical Oncology (E-S-M-O-), and two experts each from the oncological societies of Japan (J-S-M-O-), Korea (K-M-S-O-), Malaysia (M-O-S--), Singapore (S-S-O--), and Taiwan (T-O-S--). Only Asian expert members were allowed to vote on the recommendations. Provisional Statements: Before the meeting, a set of preformulated topics and 24 recommendations for the treatment of metastatic N-S-C-L-C (mNSCLC) were circulated to each of the 12 Asian experts representing the six Asian oncological societies. These recommendations were taken from the latest E-S-M-O Clinical Practice Guidelines [23], and the experts were asked to provide feedback based on the current practice in their countries and available data from Asian patient studies. They were specifically asked whether each recommendation was adaptable for use in their country, and to provide reasoning and relevant references to support their responses. A second survey was also circulated before the face to face meeting to gather the experts' opinions on updates to the recent E-S-M-O Clinical Practice Guidelines for diagnosis, treatment, and follow up, submitted to Annals of Oncology in July 2018 [24]. Voting Process: The panel voted on the final guidelines with a total of 301 million smokers, approximately two thirds of which are young Chinese men. Estimates suggest that half of these smokers will die as a result of smoking if they do not quit [8]. It is estimated that by 2030, yearly deaths from smoking in China will reach approximately 2 million, and by 2050, it will reach 3 million [4, 9]. In Korea, lung cancer is responsible for the highest number of cancer deaths [10], and it is the leading cause of cancer death in men in Japan [11]. In both countries, smoking rates have decreased, but in Korea, the prevalence of lung cancer is expected to continue rising in the next 20-30 years. In Japan, there is also a phenomenon called the Japanese Lung Cancer Smoking Paradox, where the prevalence of cigarette smoking among Japanese men has consistently been higher than in Western counterparts, but the incidence and mortality rates for lung cancer are lower in Japan compared to Western countries [12-14]. There is also a growing interest in understanding the causes of lung cancer in non smokers [15, 16]. Worldwide, an estimated 500000 deaths per year are attributed to lung cancer in individuals who have never smoked [4]. The proportion of non small cell lung cancer (N-S-C-L-C) in never smokers is particularly high in Asian countries [17]. A recent study in Korea, which looked at 5456 cases of lung cancer in a community cancer center, showed that the proportion of cases in non smokers had increased from 19.4% between 2004-2008 to 25.4% between 2009-2012 [18]. Epidemiological data has led to the recognition of non smoking associated lung cancer as a distinct disease entity, where specific molecular and genetic differences have been identified between lung cancers in smokers and those in non smokers [19]. Data from the analysis of six large Western population based cohorts has shown that lung cancers in individuals who have never smoked differ from those of long term smokers in their responses to epidermal growth factor receptor (E-G-F-R-) inhibitors and in the increased prevalence of adenocarcinomas [16]. These findings.

[Audio] The Annals of Oncology published a special article and held a final vote to determine whether to accept or reject a recommendation. Table 1 shows the voting results for the levels of agreement and definitions of evidence and recommendation grades used by a panel of Asian experts who evaluated the E-S-M-O consensus guidelines for managing metastatic non small cell lung cancer in patients of Asian ethnicity. Before the in person meeting, 12 experts from oncology societies in 6 Asian countries and regions (China, Japan, Korea, Malaysia, Singapore, and Taiwan) reported on the applicability of 137 recommendations from the 2016 ESMO NSCLC Clinical Practice Guidelines and the updated 2018 E-S-M-O Clinical Practice Guidelines. These recommendations were organized into 24 categories, with the following levels of agreement: A) complete acceptance, B) acceptance with some reservation, C) acceptance with major reservation, D) rejection with some reservation, and E) complete rejection. The levels of evidence used to support the recommendations were as follows: I) evidence from large, well designed randomized controlled trials or meta analyses, II) small randomized trials or large trials with a suspicion of bias, I-I-I--) prospective cohort studies, IV) retrospective cohort studies or case control studies, and V) studies without a control group, case reports, or expert opinions. The grades of recommendation were categorized as follows: A) strong evidence for efficacy with a substantial clinical benefit, B) strong or moderate evidence for efficacy with a limited clinical benefit, C) insufficient evidence for efficacy or the benefit does not outweigh the risk, and D) moderate evidence against efficacy or for adverse outcomes. Generally, the use of Open Access at E-S-M-O is not recommended due to strong evidence against its effectiveness or for potential negative outcomes. The Asian experts were instructed to base their decisions on the available scientific evidence rather than current practices in their countries, independent of drug approval and reimbursement status. Two experts from E-S-M-O (JYD and DP) were present at the meeting in Guangzhou, China to provide their expert opinions if needed. 1. Diagnosis (1a f) 2. Pathology/molecular biology (2a k) 3. Staging and risk assessment (3a m) 4. Management of advanced metastatic disease (4a c) 5. First line treatment for non small cell lung cancer (N-S-C-L-C) without a treatable mutated gene (5a n) 6. Maintenance (6a d) 7. Treatment for patients with a performance status (P-S---) score of 2 or higher (7a d) 8. Treatment for elderly patients (8a c) 9. Second line treatment for patients with metastatic N-S-C-L-C without a treatable mutated gene (9a k) 10. First line treatment for N-S-C-L-C with an E-G-F-R mutation (10a g) 11. Second line treatment for N-S-C-L-C with an E-G-F-R mutation (11a g) 12. First line treatment for patients with ALK-rearranged N-S-C-L-C (12a d) 13. Second line treatment for patients with ALK-rearranged N-S-C-L-C (13a f) 14. Treatment for patients with ros1-rearranged metastatic N-S-C-L-C (14a d) 15. Treatment for patients with BRAF-mutated N-S-C-L-C (15a b) 16. Treatment for N-S-C-L-C with other treatable mutated genes (16a g) 17. Role of radiotherapy in stage 4 N-S-C-L-C (17a e) 18. Treatment of brain metastases (18a k) 19. Treatment of leptomeningeal carcinomatosis (19a,b,c) 20. Treatment of oligometastatic disease (20a e) 21. Treatment of bone metastases (21a,b,c) 22. Role of minimally invasive procedures in stage 4 N-S-C-L-C (22a,b,c) 23. Palliative care for patients with stage 4 NSCLC 24. Follow up care for patients with stage 4 NSCLC The final consensus statements for evaluation and voting were numbered 1-24 with subcategories assigned a letter code (a, b, etc). B, C, et cetera). An unqualified response of Yes in the pre meeting surveys was considered to be equivalent to accept completely in the final vote, meaning a 100% agreement. However, following the pre meeting surveys, there was disagreement among the six Asian countries on recommendations.

[Audio] Special article: Minimal Morbidity in Annals of Oncology [31-33]. Combining bronchoscopic airway visualization with ultrasound (E-B-U-S) can also be utilized for biopsying large, centrally located lesions [34,35], diagnosing and staging lung cancer, and determining if the disease has spread to the lymph nodes. E-B-U-S-guided transbronchial needle aspiration (T-B-N-A) has been reported to be as accurate as mediastinoscopy but less invasive [36]. Cytological specimens obtained through E-B-U-S-T-B-N-A have been proven to be suitable for molecular testing [37-40]. For lesions located in the periphery, transthoracic percutaneous fine needle aspiration and/or core biopsy, under imaging guidance (typically computed tomography [CT]), is proposed and recommended [41]. This method has shown high diagnostic accuracy [32,42-45], although there is a risk of pneumothorax [44,45]. In cases of pleural effusion, thoracentesis can be used for diagnosis and palliative treatment. If the cytology results from the fluid are negative, an image guided pleural biopsy or surgical thoracoscopy should be performed. If these techniques are unable to provide an accurate diagnosis, more invasive surgical approaches should be considered. The recommendations were voted on again by the panel. In regards to the other recommendations and subcategories, a vote was not necessary as there was complete consensus. All countries voted 'yes' to the question Is this recommendation adaptable for use in your country?, indicating complete acceptance [A=100%]. The final levels of agreement, evidence, and strength of support for each E-S-M-O recommendation by the Asian panel members are provided in the text below for each of the 24 recommendations and their subcategories. Any changes made to the original text, including the addition of new subcategories and revisions to existing recommendations, are also reflected. This information can be found in supplementary Table S-1-3--, available online at Annals of Oncology. These recommendations are highlighted in bold in both the main text of the manuscript and Table 2. Any changes made to the text have also been noted. Additionally, the final voting results from the representatives of each participating region for the E-S-M-O recommendations at the face to face meeting in Guangzhou can be found in supplementary Table S-1-3--, which is available online at Annals of Oncology. Recommendation 1: Diagnosis Recommendation 2: Pathology/Molecular Biology 1a. Bronchoscopy is the preferred technique for central lesions and can be used with bronchial washing, brushing, and transbronchial needle biopsy [A=100% and I, A]. 1b. Endobronchial ultrasound (E-B-U-S-) and/or endoscopic U-S allow for evaluation of regional lymph nodes [A=100% and I, A]. 1c. When dealing with mid to peripheral lesions, transthoracic fine needle aspiration and/or core biopsy are recommended, where a needle is passed through the parenchyma under imaging guidance (typically CT) [A=100% and I, A]. 1d. Thoracentesis can serve as both a diagnostic tool and a palliative treatment when dealing with pleural effusion [A=100% and I, A]. 1e. In cases where the previously mentioned techniques are not effective, more invasive surgical approaches (such as mediastinoscopy, mediastinotomy, thoracoscopy, etc.) may be considered for an accurate diagnosis [A=100% and I, A]. 1f. By working in collaboration and maintaining constant communication between pathologists and those performing the procedures, the diagnostic yields can be significantly improved compared to blind biopsies [A=100% and I, A]. All 12 Asian experts unanimously agreed with and fully accepted the recommendations 1a f above, taken from the ESMO 2018 guidelines for mNSCLC [24]. Evidence from Western studies has shown that multidisciplinary teams can enhance the management and clinical outcomes of patients with NSCLC [27-30]. In most cases, a tissue based diagnosis is necessary for suspected lung cancer, and this often involves challenging tissue sampling. Tissue sampling allows for confirmation of the initial diagnosis, such as distinguishing between non squamous.

[Audio] Annals of Oncology Special Article Table 2. Summary of Final Recommendations by Asian Experts Recommendation 1: Diagnosis 1a. Bronchoscopy is the recommended technique for central lesions and can be used with bronchial washing, brushing, and transbronchial needle biopsy [with a success rate of 100% and a level of evidence and recommendation grade of A]. 1b. Endobronchial ultrasound (E-B-U-S-) and/or endoscopic ultrasound (E-U-S--) can be used to evaluate regional lymph nodes [with a success rate of 100% and a level of evidence and recommendation grade of A]. 1c. For mid to peripheral lesions, transthoracic fine needle aspiration and/or core biopsy or using imaging guidance (usually CT) to pass a needle through the lung tissue is recommended [with a success rate of 100% and a level of evidence and recommendation grade of A]. 1d. In cases where there is a pleural effusion, thoracentesis can be both a diagnostic tool and a palliative treatment [with a success rate of 100% and a level of evidence and recommendation grade of A]. 1e. If the previously mentioned techniques are not adequate for a definitive diagnosis, more invasive approaches such as mediastinoscopy, mediastinotomy, or thoracoscopy may be considered [with a success rate of 100% and a level of evidence and recommendation grade of A]. 1f. Proper collaboration and communication between pathologists and those performing the procedures can significantly improve diagnostic success rates compared to blind biopsies [with a success rate of 100% and a level of evidence and recommendation grade of A]. Recommendation 2: Pathology/Molecular Biology 2a. Sufficient tissue material should be obtained for both histological diagnosis and molecular testing in order to guide individual treatment decisions [with a success rate of 100%]. 2b. Pathological diagnosis should follow the 2015 W-H-O classification of lung tumors [with a success rate of 100%]. 2c. Specific subtyping of all non small cell lung cancers (NSCLCs) is necessary for treatment decision making and should be done whenever possible. Immunohistochemical stains (I-H-C--) should be used to reduce the rate of NSCLC-not otherwise specified (N-O-S--) to less than 10% of cases diagnosed [with a success rate of 100% and a level of evidence and recommendation grade of A and B, respectively]. 2d. E-G-F-R mutation status should be systematically analyzed in advanced non squamous cell carcinomas (NSCCs) [with a success rate of 100% and a level of evidence and recommendation grade of A]. The testing method should cover mutations in exons 18-21, including those associated with resistance to certain therapies [with a success rate of 100% and a level of evidence and recommendation grade of A and C, respectively]. B]. At a minimum, in situations with limited resources or materials, it is necessary to determine the most common activating mutations (exon 19 deletion, exon 21 L-8-5-8-R point mutation) [A=100% and I, A]. 2d-1 The availability of a T790M-mutant effective T-K-I for recurrent disease makes testing for T-7-9-0-M mandatory when first-/second generation EGFR-TKI resistance occurs (added retrospectively). 2e. Testing for A-L-K rearrangement should be systematically performed in advanced non small cell lung cancer [A=100% and I, A]. 2f. Fish remains the standard for detecting A-L-K translocation, but immunohistochemistry (I-H-C--) using high performance A-L-K antibodies and validated assays can be used for screening [A=100% and III, A]. I-H-C has recently been accepted as an equivalent alternative to fish for A-L-K testing. 2g. Testing for ros1 rearrangement should be systematically performed in advanced non small cell lung cancer [A=100% and II, A]. Fish is the standard for detecting ros1 translocation, but a validated RT-PCR test can be used as an alternative. I-H-C can also be used as a screening method [A=100% and IV, A]. 2h. The status of BRAF V600 mutation should be analyzed in all cases of advanced non small cell.

[Audio] Special Article in the Annals of Oncology Table 2. Continued Recommendation 4: Management of Advanced Metastatic Disease 4a. The treatment plan should take into account the patient's histology, molecular pathology, age, performance status, comorbidities, and their preferences [Grade A with 100% certainty]. 4b. Systemic therapy should be offered to all stage 4 patients with a performance status of 0-2 [Grade A with 100% certainty and Class I evidence]. 4c. In all stages of non small cell lung cancer (N-S-C-L-C), smoking cessation should be strongly encouraged as it can improve outcomes [Grade A with 100% certainty and Class 2 evidence]. Recommendation 5: First Line Treatment of N-S-C-L-C without a Druggable Oncogene Driver 5a. Chemotherapy should be considered for all stage 4 N-S-C-L-C patients with E-G-F-R and ALK-negative disease, if there is a contraindication to immunotherapy, and if they do not have significant comorbidities and have a performance status of 0-2 [Grade A with 100% certainty and Class I evidence]. 5b. Single agent pembrolizumab should be considered for eligible patients with a performance status of 0-1, E-G-F-R and ALK-negative NSCLC, and a tumor with PD-L1 expression of at least 50% [Grade A with 100% certainty and Class I evidence]. Chemotherapy should be given in cases where pembrolizumab is contraindicated. 5c. The combination of pembrolizumab and chemotherapy (with pemetrexed and platinum) should be considered for patients with a performance status of 0-1, non squamous N-S-C-L-C without E-G-F-R or A-L-K mutations, if immunotherapy is not contraindicated and if it is approved and available [Grade A with 17% certainty, Grade B with 83% certainty, and Class I evidence] (Figure 2). The survival benefit of combining pembrolizumab with chemotherapy is seen in all levels of PD-L1 expression, but is less significant in PD-L1-negative patients and it is unclear if chemotherapy adds a benefit in patients with PD-L1 levels less than 50%. 5d. The combination of atezolizumab and bevacizumab with carboplatin and paclitaxel should be considered as a treatment option for patients with a performance status of 0-1 and metastatic non squamous NSCLC, if immunotherapy is not contraindicated and if it is approved and available [Grade A with 100% certainty and Class I evidence]. The combination of pembrolizumab and carboplatin and paclitaxel or nab paclitaxel should be considered as the standard option for patients with a performance status of 0-1 and metastatic squamous NSCLC, if immunotherapy is not contraindicated. If approved and available, the use of atezolizumab in combination with carboplatin and nab paclitaxel (Figure 1) is an option for patients with PS 0-1 and metastatic squamous non small cell lung cancer, as long as there are no contraindications to immunotherapy [A=83%, B=17% and I, B] (Figure 1). Nivolumab combined with ipilimumab is a potential treatment choice for patients with PS 0-1, negative E-G-F-R and A-L-K non small cell lung cancer with high T-M-B levels, regardless of their tumor's PD-L1 expression, if approved and available [A=83%, B=17% and I, A]. Platinum based doublet chemotherapy is the recommended option for all stage 4 non small cell lung cancer patients, unless there are contraindications to using platinum compounds [A=100% and I, A]. Four cycles of platinum based doublet chemotherapy followed by maintenance monotherapy with a less toxic drug [I, A], or four to six cycles [A=100% and IV, B] for patients who cannot undergo maintenance monotherapy, are currently recommended. In advanced non small cell lung cancer patients, the use of nab paclitaxel may be considered as a chemotherapy option, especially for those at higher risk of neurotoxicity, with pre existing hypersensitivity to paclitaxel, or contraindications for standard paclitaxel premedication [A=100% and I, B]. For advanced squamous cell carcinoma patients, platinum based doublets with a third generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) are recommended [A=100% and.

[Audio] Annals of Oncology Special Article Table 2. Continued Recommendation 8: Elderly patients 8a. Elderly patients should be considered for immunotherapy based on standard recommendations [Grade A, 100% level of evidence (LoE) and intervention (I)]. 8b. Patients aged 70 years and above with a performance status (P-S---) of 0-2 and adequate organ function should receive carboplatin based doublet chemotherapy [Grade A, 100% LoE and I]. 8c. Single agent chemotherapy remains the standard of care for elderly patients who are not eligible for doublet chemotherapy [Grade A, 100% LoE and B]. Recommendation 9: Second line treatment of patients with non small cell lung cancer (mNSCLC) without a druggable oncogene driver 9a. Patients with a PS of 0-2 who are clinically or radiologically progressing after first line therapy should be offered second line treatment [Grade A, 100% LoE and I]. 9b. Routine PD-L1 testing is recommended at diagnosis [Grade A, 100% LoE and I] to determine the use of pembrolizumab as first or second line treatment. 9c. For patients who have progressed after first line pembrolizumab immunotherapy, platinum based chemotherapy is recommended as the second line treatment option [Grade A, 100% LoE and V, B]. 9d. In general, the phase 3 studies of second line treatment (nivolumab, pembrolizumab, and atezolizumab versus docetaxel) have shown greater efficacy of anti PD1/PDL1 agents in patients with higher PD-L1 expression compared to those with little or no PD-L1 expression. However, unselected patients may still have improved survival and tolerability with anti PD1/PDL1 agents compared to docetaxel [Grade A, 100% LoE and I]. 9e. In most patients with advanced, previously treated, and PD-L1 inhibitor naive NSCLC, anti PD-L1 and PD-1 inhibitors (nivolumab, pembrolizumab, and atezolizumab) are the treatment of choice regardless of PD-L1 expression [Grade A, 100% LoE and I]. 9f. For patients who are not suitable for immunotherapy, second line chemotherapy is recommended. Pemetrexed is the preferred option for non squamous NSCLC, while docetaxel may be a better choice for tolerability [Grade A, 100% LoE and I]. B]. 9g. If the disease is under control and the side effects are acceptable, the treatment may be extended [Grade A=100% and Level II, Grade B]. 9h. In patients with adenocarcinoma, nintedanib/docetaxel is a potential treatment option, particularly for those who have progressed within 9 months of starting first line chemotherapy, with a performance status (P-S---) of 0-2 [Grade A=83%, Grade B=17% and Level II, Grade B]. 9i. Patients with N-S-C-L-C who have progressed after first line chemotherapy and have a PS of 0-2 may be treated with ramucirumab/docetaxel [Grade A=100% and Level I, Grade B]. 9j. Erlotinib is a possible second or third line treatment for patients who are not suitable for immunotherapy or second line chemotherapy and have unknown E-G-F-R status or E-G-F-R wild type tumors [Grade D=66%, Grade E=34% and Level II, Grade C]. 9k. Afatinib may be considered as a potential option for patients with S-C-C who have been pre treated with platinum and are not fit for chemotherapy or immunotherapy, and have unknown E-G-F-R status or are E-G-F-R wild type with a PS of 0-2 [Grade C=100% and Level I, Grade C]. Recommendation 10: First line treatment for EGFR-mutated NSCLC 10a. Patients with a tumor that has a sensitizing E-G-F-R mutation should receive a first line EGFR TKI, such as erlotinib, gefitinib, or afatinib [Level I, Grade A]. There is no consensus on which of the three EGFR TKIs is the preferred option [Level I-I-I--, Grade C]. Dacomitinib will be added to this list when it is approved by regulatory agencies, such as the US FDA and EMA [Grade A=100% and Level I, Grade A]. 10b. First line osimertinib is now considered one of the treatment options for patients with a tumor that has sensitizing.

[Audio] Special Article: Annals of Oncology Table 2. Continued Recommendation 12: First line Treatment of ALK-Rearranged NSCLC 12a. Patients with ALK-rearranged N-S-C-L-C should receive first line treatment with an A-L-K tyrosine kinase inhibitor (T-K-I--), including crizotinib [Grade A with 100% consensus and grade I], ceritinib [Grade A with 100% consensus and grade B], and alectinib [Grade A with 100% consensus and grade I]. 12b. Alectinib is associated with longer progression free survival and lower toxicity compared to crizotinib, and has shown activity against central nervous system (C-N-S--) disease in treatment naive patients with ALK-positive NSCLC [Grade A with 100% consensus and grade I]. 12c. In patients with C-N-S involvement, the use of first line ALK TKIs is effective, and the use of alectinib [Grade 3 and grade A] or ceritinib [Grade 4 and grade B] is recommended [Grade A with 100% consensus]. Ceritinib is a better treatment option than chemotherapy [Grade I and grade B] and possibly crizotinib [Grade 4 and grade B], while alectinib is a better option than crizotinib [Grade I and grade A], and brigatinib is a better option than crizotinib [Grade I and grade B]. 12d. In patients with ALK-rearranged N-S-C-L-C who have localized distant progression and ongoing systemic control, continuation of treatment with an ALK TKI in combination with local treatment of the progressing metastatic sites may be considered [Grade A with 100% consensus and grade III, B]. Recommendation 13: Second line Treatment of ALK-Rearranged NSCLC 13a. Ceritinib and alectinib are recommended for patients with advanced ALK-positive N-S-C-L-C who have progressed on or cannot tolerate crizotinib [Grade A with 100% consensus and grade I, A]. 13b. In patients with ALK-positive N-S-C-L-C who have progressed on crizotinib and have C-N-S involvement, the next generation ALK TKIs such as alectinib or ceritinib should be considered as the next treatment option [Grade A with 100% consensus and grade I, A]. 13c. If available, next generation A-L-K inhibitors such as brigatinib or lorlatinib may be used as an option for patients who progress after a second generation ALK TKI [Grade A with 100% consensus and grade III, C]. If these are not available, pemetrexed and cisplatin should be considered. 13d. Assessment of the molecular mechanisms of resistance may influence treatment decisions [Grade A with 100% consensus after discussion]. 13e. The optimal sequence of ALK-targeted agents is yet to be established. 13f. A combination of atezolizumab and bevacizumab, along with carboplatin and paclitaxel, may be considered as a treatment option for patients with ALK-mutated tumors and performance status of 0-1, if there are no contraindications for using immunotherapy after targeted therapies have been exhausted [Grade A=100% and V, C after discussion]. Recommendation 14: Patients with ros1-rearranged NSCLC 14a. Crizotinib is recommended as first line treatment for stage 4 N-S-C-L-C with ros1 rearrangement, as it has shown a higher response rate and longer duration of response [Grade A=100% and III, A]. 14b. For patients with ros1-positive N-S-C-L-C who did not receive crizotinib as first line treatment, single agent crizotinib may be offered as second line therapy [Grade A=100% and III, A]. 14c. Ceritinib may be considered for crizotinib naive patients, but it is currently not approved by the EMA [Grade A=100% and III, C]. 14d. If patients have received crizotinib as first line treatment, they may be offered platinum based chemotherapy as second line therapy [Grade A=100% and IV, A]. Recommendation 15: Patients with BRAF-mutated NSCLC 15a. Patients with stage 4 N-S-C-L-C and BRAF V600 mutation should be treated with BRAF/MEK inhibitors such as dabrafenib/trametinib in either first or second line [Grade A=100% and III, A]. 15b. If patients have received BRAF/MEK inhibition as first line treatment, they may be offered platinum based chemotherapy as second line therapy [Grade A=100% and IV,.

[Audio] Annals of Oncology Special article Table 2. Continued 17d. For patients previously treated with external beam radiation therapy (E-B-R-T) who are experiencing symptoms from recurrent obstruction in the endobronchial central area, endobronchial brachytherapy (E-B-B) may be considered in selected cases [Grade A with 100% consensus and Grade I-I-I--, Class C]. 17e. Early radiation therapy (R-T---) can alleviate neurological symptoms caused by spinal compression [Grade A with 100% consensus and Grade II, Class B]. Recommendation 18: Brain Metastases 18a. Whole brain radiation therapy (W-B-R-T) should not be offered to patients classified as R-P-A class 3 due to poor prognosis [Grade I, Evidence level E]; only best supportive care (B-S-C) is recommended [Grade A with 100% consensus]. 18b. W-B-R-T may be considered for selected patients, taking into account prognostic factors for better survival [Grade A with 100% consensus and Grade II, Class C]. 18c. At this time, hippocampus avoidance W-B-R-T is not recommended as a standard treatment [Grade A with 100% consensus and Grade I-I-I--, Class C]. 18d. In the case of a single metastasis, stereotactic radiation surgery (S-R-S) alone or resection is the recommended treatment for patients classified as R-P-A class I–II [Grade A with 100% consensus and Grade I-I-I--, Class B]. 18e. After surgical resection, postoperative W-B-R-T or S-R-S is recommended [Grade I, Class A]. 18f. S-R-S alone, without W-B-R-T but with close monitoring of brain imaging via M-R-I--, is an alternative strategy [Grade A with 100% consensus and Grade I-I-I--, Class B]. 18g. For patients with two to four brain metastases and R-P-A class I–II classification, S-R-S alone is recommended [Grade I-I-I--, Class B]. 18h. For symptomatic brain metastases and/or edema, dexamethasone or an equivalent dose of another corticosteroid is recommended [Grade A with 100% consensus and Grade I-I-I--, Class A]. 18i. In patients with previously undetected asymptomatic central nervous system (C-N-S) metastases, systemic therapy with delayed RT may be considered due to similar response rates in both intracranial and extracranial areas [Grade B with 83% consensus, Grade C with 17% consensus, and Grade II, Class C]. 18j. For patients with a treatable oncogene driver (such as E-G-F-R or A-L-K) and clinically asymptomatic brain metastases, tyrosine kinase inhibitors (T-K-I's) may help control brain disease and delay cranial RT [Grade A with 100% consensus and Grade II, Class B]. 18k. Limited data suggests that immune checkpoint inhibitor therapy may be safe for patients with small, untreated C-N-S metastases [Grade A with 100% consensus and Grade I-I-I--, Class -]. B]. Recommendation 19: Treatment of Leptomeningeal Carcinomatosis 19a. It is important to be highly suspicious of leptomeningeal involvement, especially in patients with druggable oncogenic drivers who are undergoing T-K-I treatment [V]. Cerebrospinal fluid (C-S-F--) sampling is the diagnostic method for LM carcinomatosis, but it has low sensitivity and high specificity [IV] [A=100%]. 19b. Patients with druggable oncogenic drivers and LM carcinomatosis can be treated with next generation T-K-I's that are able to penetrate the central nervous system [A=100% and III, B]. 19c. Intra CSF pharmacotherapy may be considered based on clinical factors [A=100% and V, C]. Recommendation 20: Treatment of Oligometastatic Disease 20a. Stage 4 patients with one to three synchronous metastases at diagnosis may have a longer disease free survival with systemic therapy and local consolidative therapy (high dose radiation therapy or surgery) [A=100% and II, B]. Due to limited evidence, these patients should be discussed in a multidisciplinary tumor board [A=100% and II, B], and enrollment in clinical trials is preferred. 20b. While surgery may have a low risk and potential for long term survival, the evidence for its use in oligometastatic disease is limited and the comparative effectiveness of surgery versus radiation therapy as a local treatment has not been established. 20c. Stage 4 patients with limited metachronous metastases may be.

[Audio] Special article Annals of Oncology Table 2. Continued Recommendation 23: palliative care in patients with stage 4 NSCLC 23. It is recommended to provide early palliative care intervention alongside standard oncological care for patients with stage 4 non small cell lung cancer [100% level of agreement and grade A evidence]. Recommendation 24: follow up in patients with stage 4 NSCLC 24. Close follow up every 6-12 weeks is advised for patients with stage 4 N-S-C-L-C to allow for prompt initiation of second line therapy. However, the frequency of follow up should be based on the individual's retreatment options [100% level of agreement and grade 3 evidence]. AJCC, American Joint Committee on Cancer; A-L-K--, anaplastic lymphoma kinase; B-S-C--, best supportive care; C-E-A--, carcinoembryonic antigen; C-N-S--, central nervous system; C-S-F--, cerebrospinal fluid; CT, computed tomography; D-F-S--, disease free survival; E-B-B--, endobronchial brachytherapy; E-B-R-T-, external beam radiotherapy; E-B-U-S-, endobronchial ultrasound; E-G-F-R-, epidermal growth factor receptor; E-M-A--, European Medicines Agency; E-U-S--, endoscopic ultrasound; fish, fluorescent in situ hybridization; Her2, human epidermal growth factor receptor 2; I-H-C--, immunohistochemistry; imRECIST, immune modified recist; iRECIST, immune recist; irRECIST, immune related recist; LM, leptomeningeal; L-M-D--, leptomeningeal disease; M-E-K--, mitogen activated protein kinase; M-R-I--, magnetic resonance imaging; nab paclitaxel, albumin bound paclitaxel; N-T-R-K-, neurotrophic tropomyosin receptor kinase; N-S-C-C-, non squamous cell carcinoma; NSCLC, non small cell lung cancer; NSCLC-NOS, non small cell lung cancer not otherwise specified; OS, overall survival; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; P-E-T--, positron emission tomography; P-F-S--, progression free survival; PS, performance status; QoL, quality of life; recist, Response Evaluation Criteria in Solid Tumors; R-P-A--, recursive partitioning analysis; RT, radiotherapy; S-C-C--, squamous cell carcinoma; S-R-E--, skeletal related event; S-R-S--, stereotactic radiosurgery; T-K-I--, tyrosine kinase inhibitor; T-P-S--, tumor proportion score. Tumour proportion score; U-I-C-C, Union for International Cancer Control; W-B-R-T, whole brain radiotherapy; W-H-O, World Health Organization; WT, wild type. 2h. BRAF V600 mutation status should be systematically analyzed in advanced non small cell lung cancer (N-S-C-L-C) for the prescription of BRAF/MEK inhibitors with a recommendation grade of A (100% agreement) and level of evidence 2. 2i. Molecular testing for E-G-F-R and A-L-K is not recommended in patients with a confirmed diagnosis of squamous cell carcinoma (S-C-C--), except in unusual cases such as those who have never or formerly been light smokers or long time ex smokers, with a recommendation grade of A (100% agreement) and level of evidence 4. 2j. If available, multiplex platforms should be used for molecular testing with a recommendation grade of A (100% agreement) and level of evidence 3. 2k. PD-L1 I-H-C should be systematically determined in advanced NSCLC. This testing is required for treatment with pembrolizumab in all lines of therapy and may also provide important information when using nivolumab or atezolizumab as monotherapy in the second line setting, with a recommendation grade of A (100% agreement) and level of evidence 1. All 12 Asian experts fully agreed with and accepted the recommendations 2a d and 2h k above in the pre meeting surveys with a 100% agreement (A=100%). Two countries (see supplementary Table S1, available at Annals of Oncology online) did not agree, one because in their country fish testing is not used for screening (recommendation 2f) and the other because testing is not reimbursed (it is only done if the drug company pays for the test) (recommendation 2g). After discussion at the face to face meeting, all countries fully accepted the recommendations 2a k based on the available scientific evidence rather than the situation in their countries. A minor revision was made to the wording of recommendation 2g to include the addition of the words a validated reverse transcription polymerase chain reaction (R-T-P-C-R).

[Audio] Annals of Oncology Special article Stage 4 SCC PD-L1 expression Never/former light smoker or long time ex smoker (<15 packs/year)a Any expression of PD-L1b PD-L1 ≥50% PS 0–1 PS 3–4 Molecular test (alk/egfr/ros1/braf) PS 0–1 Pembrolizumab [i, A; Mcbs 5] <70 years and PS 2 or Selected ≥70 years and PS 0–2 Positive Negative High T-M-B (≥10 mutations/Mb) Atezolizumab plus carboplatin plus nab PC (4–6 cycles) followed by atezolizumab [I, B]c Pembrolizumab plus carboplatin/paclitaxel or nab PC (4 cycles) followed by pembrolizumab [I, A] Bsc [ii, B] 4–6 cycles: Carboplatin based doublets: <70 years and PS 2 [II, A] ≥70 years and PS 0–2 [I, A] Single agent chemotherapy: Gemcitabine, vinorelbine or docetaxel [I, B] Targeted therapy Follow recommended treatment depending on PD-L1 expression level 4–6 cycles: Platinum based chemotherapy: Cisplatin/gemcitabine [I, A] Cisplatin/docetaxel [I, A] Cisplatin/paclitaxel [I, A] Cisplatin/vinorelbine [I, A] Carboplatin/gemcitabine [I, A] Carboplatin/docetaxel [I, A] Carboplatin/paclitaxel [I, A] Carboplatin/vinorelbine [I, A] nab PC [I, B] Nivolumab/ipilimumab [I, A]c Disease progression PS 3–4 PS 0–2 Disease progression BSC PS 0–1 Platinum based chemotherapy (see first line treatment for PD-L1 <50%; PS 0–1) Nivolumab [I, A; MCBS 5] Atezolizumab [I, A; MCBS 5] Pembrolizumab if PD-L1 >1% [I, A; MCBS 5] Docetaxel [I, B] Ramucirumab/docetaxel [I, B; MCBS 1] Erlotinib [II, C] Afatinib [I, C; MCBS 2] Figure 1. Treatment algorithm for stage 4 lung squamous cell carcinoma (S-C-C--). aMolecular testing is not recommended in S-C-C--, except in rare cases of never/former light smokers or long time ex smokers (<15 packs/year). bIn the absence of contraindications and depending on the availability of anti PD-L1 combinations with platinum based chemotherapy, this strategy will be favored over platinum based chemotherapy in patients with PS 0–1 and PD-L1 >50%. cDependent on approval status and reimbursement. A-L-K--, anaplastic lymphoma kinase. B-S-C-: Best Supportive Care; E-G-F-R-: Epidermal Growth Factor Receptor; I-H-C--: Immunohistochemistry; Mb: Megabase; M-C-B-S-: Magnitude of Clinical Benefit Scale; nab PC: Albumin Bound Paclitaxel and Carboplatin; PD-L1: Programmed Death Ligand 1; PS: Performance Status; S-C-C--: Squamous Cell Carcinoma; T-M-B--: Tumour Mutation Burden. EGFR [53]. A meta analysis has shown that the overall pooled prevalence of E-G-F-R mutations is 32.3% (95% 101: 30.9% to 33.7%), with a range of 38.4% (95% 101: 36.5% to 40.3%) in China, 36.6% (95% 101: 33.2% to 40.0%) in Japan, and 32.4% (95% 101: 28.0% to 36.8%) in Korea, to 14.1% (95% 101: 12.7% to 15.5%) in Europe [54]. A study in multi ethnic Malaysian patients with N-S-C-L-C showed a similar prevalence of E-G-F-R mutations (36.4%) [55]. Generally, female gender, adenocarcinoma histology, never smoking status, and Asian ethnicity are considered to be the most important factors associated with E-G-F-R mutation positive disease and response to EGFR-TKIs [54, 56]. As previously mentioned [24], the most commonly occurring mutations are deletions in exon 19 and a substitution mutation (L858R) in exon 21, and testing should include these mutations [1, A]. The T-7-9-0-M exon 20 mutation is the most frequent cause of resistance to first and second generation EGFR TKIs, but is rarely found in TKI-naive patients, although patients with germline T-7-9-0-M mutations have been reported [57]. In the case of access to a third generation EGFR-TKI (e.g. osimertinib) that can overcome T790M-mediated resistance [58], testing for T-7-9-0-M mutations should be mandatory [1, A] (see the retrospective addition of recommendation 2d-1 and Table 2). The use of cell free D-N-A (cfDNA) to rule in targetable mutations should be considered when there is insufficient tissue for testing. However, due to the low sensitivity of cfDNA blood testing, all patients who test negative for a T-7-9-0-M mutation at relapse will still require a tissue biopsy [59]. Recent data has revealed that the A-L-K protein (confirmed by positive I-H-C staining) is linked to treatment response [I, A] [60]. I-H-C is now considered a viable alternative to fish testing for A-L-K [50]. A-L-K mutations are a significant contributor to resistance to ALK TKIs,.

[Audio] Special article Annals of Oncology 3d. A CT scan that uses a specialized dye to enhance the images of the chest and upper abdomen, including the liver and adrenal glands, should be performed at the time of diagnosis [A = 100%]. 3e. Imaging of the central nervous system (C-N-S--) should be considered for all patients with metastatic disease at the time of diagnosis [A = 100% and IV, C], and is required for patients with neurological symptoms or signs [A = 100% and IV, A]. Magnetic resonance imaging (M-R-I--) is more sensitive than a CT scan [A = 100% and IV, B]. 3f. If there is suspicion of bone metastases based on clinical findings, imaging of the bones is necessary [A = 100% and IV, B]. 3g. A bone scan or positron emission tomography (P-E-T--), ideally combined with a CT scan, can be used to detect bone metastases [A = 100% and IV, B]. 3h. Non Small Cell Lung Cancer (N-S-C-L-C) is staged according to the AJCC/UICC system (8th edition) and is grouped into stages as shown in Tables 3 and 4. 3i. In cases where there is only one site of metastasis on imaging studies, it is recommended to obtain a cytological or histological confirmation of stage 4 disease [A = 100% and IV, A]. 3j. After 6-9 weeks of systemic therapy, a follow up imaging assessment should be performed using the same radiographic investigation that initially showed the tumor lesions [A = 100% and IV, B]. 3k. Routine follow up with P-E-T is not recommended due to its high sensitivity and relatively low specificity [A = 100% and IV, C]. 3l. Measurements and assessment of response should follow recist criteria version 1.1 [B = 100% and IV, A]. However, the effectiveness of recist in evaluating the response to targeted therapies such as E-G-F-R or ALK TKIs in genetically driven N-S-C-L-C is debatable [B = 100% and IV, B]. 3m. In the case of immune checkpoint inhibitor therapy, recist criteria should be used, although irRECIST, iRECIST, and imRECIST may play a role in overall assessment of treatment effectiveness [A = 100% and IV, B]. The anti programmed cell death protein 1 (PD-1) agent pembrolizumab is now considered the standard first line treatment for selected patients with high programmed death ligand 1 (PD-L1) expression (score of at least 50%). Based on the findings of the keynote-024 trial [64] and subsequent confirmation in the keynote-042 trial [65], PD-L1 immunohistochemistry (I-H-C--) is now mandatory for all patients with advanced non small cell lung cancer (N-S-C-L-C) in the first line setting [1, A]. Although the PD-L1 IHC 22C3 assay is the only validated test in clinical trials for pembrolizumab, comparison studies have shown that commercial kit assays utilizing the PD-L1 I-H-C clones 28-8 and S-P-2-6-3 may serve as alternatives [III, A] [66-70]. If a laboratory developed test is used, thorough validation is essential before clinical use [IV, A]. PD-L1 testing is not required for treatment with nivolumab or atezolizumab in the second line, but may provide useful information. In addition, E-G-F-R mutation status has been found to be inversely correlated with PD-L1 expression [71]. Studies in Asian populations have suggested that E-G-F-R tyrosine kinase inhibitors (TKIs) may indirectly enhance anti tumor immunity [72] and that changes in PD-L1 expression can occur in patients with EGFR-mutant N-S-C-L-C who develop resistance to the T-K-I gefitinib [73]. Patients with E-G-F-R mutations or A-L-K rearrangements have been shown to have lower levels of PD-L1 and C-D-8 co expression in the tumor microenvironment, which may contribute to a poor response to checkpoint inhibitors. Co expression of PD-L1 and C-D-8 in EGFR-mutated or ALK-rearranged lung cancer has been identified as a biomarker.

[Audio] Annals of Oncology Special article Table 3. Clinical classification UICC TNM 8 [85, 86] Primary Tumor (T) TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (in other words not in the main bronchus) T1mi Minimally invasive adenocarcinoma T1a Tumor 1 cm or less in greatest dimension T1b Tumor more than 1 cm but not more than 2 cm in greatest dimension T1c Tumor more than 2 cm but not more than 3 cm in greatest dimension T2 Tumor more than 3 cm but not more than 5 cm or with any of the following features: Involvement of main bronchus regardless of distance to the carina, but without involvement of the carina Invasion of visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region either involving part of or the entire lung T2a Tumor more than 3 cm but not more than 4 cm in greatest dimension T2b Tumor more than 4 cm but not more than 5 cm in greatest dimension T3 Tumor more than 5 cm but not more than 7 cm in greatest dimension or direct invasion of any of the following: Parietal pleura Chest wall (including superior sulcus tumors) Phrenic nerve Parietal pericardium Separate tumor nodule(s) in the same lobe as the primary T4 Tumor more than 7 cm or any size that invades any of the following: Diaphragm Mediastinum Heart Great vessels Trachea Recurrent laryngeal nerve Esophagus Vertebral body Carina Separate tumor nodule(s) in a different ipsilateral lobe to that of the primary Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes This text describes the staging of lung cancer, including details about how the cancer has spread to other areas of the body. This includes involvement of nearby lymph nodes (N2 and N3) as well as distant metastasis (M). Distant metastasis can be further classified as M0 (no distant metastasis) or M1 (with distant metastasis). M1 can be divided into three subcategories: M1a (separate tumor nodules in the opposite lung or in the lining of the lung or heart), M1b (a single extra thoracic metastasis in a single organ), and M1c (multiple extra thoracic metastases in a single or multiple organs). The text also mentions that this information was taken from another source and includes permission from the publishing company. It also clarifies that adenocarcinoma and squamous carcinoma in situ are included, and that a specific type of tumor (superficial spreading tumor) may be classified as T1a. Additionally, the text recommends against using a specific method of imaging (C-E-A-) and suggests performing a contrast enhanced CT scan of the chest and upper abdomen to assess the liver, kidneys, and adrenal glands. Imaging of the central nervous system (C-N-S) may also be necessary for patients with neurological symptoms. All of this information is relevant for determining the stage of the cancer according to the T-N-M system, as laid out by the Union for International Cancer Control (U-I-C-C). A biopsy should be performed, and if possible, an M-R-I of the central nervous system with gadolinium enhancement, or a CT scan of the brain with iodine contrast should be conducted during the initial diagnosis [IV, B]. M-R-I is more sensitive than a CT scan [III, B] [83]. If metastatic disease is detected, further imaging is only necessary if it will.

[Audio] Special Article Annals of Oncology, Table 4: Stages of Lung Cancer according to TNM 8 (Eighth Edition) [85] Non Small Cell Lung Cancer (NNSCLC) stages based on T-classification, N-staging, and M-staging using the irRECIST [88, 89] and more recently the iRECIST [90] and immune modified recist (imRECIST) [91] in an effort to standardize response assessment for immunotherapy clinical trials. However, non conventional responses and pseudo progression are rare in N-S-C-L-C patients receiving treatment (<5% of cases) and it is recommended that the conventional recist 1.1 still be used in routine clinical practice [IV, B] [92-95]. Recommendation 4: Management of advanced metastatic disease. 4a. Treatment decisions should take into consideration the patient's histology, molecular pathology, age, performance status, comorbidities, and preferences [A = 100%]. 4b. Systemic therapy should be offered to all stage 4 patients with a performance status of 0-2 [A = 100% and I, A]. 4c. Smoking cessation should be highly encouraged for all stages of NSCLC, as it has been shown to improve outcomes [A = 100% and II, A]. All 12 of the Asian experts surveyed before the meeting agreed with and fully accepted Recommendations 4a, b, and c. As previously discussed in Recommendation 1, treatment decisions should ideally be made as part of a multidisciplinary team, which is able to evaluate and adjust patient management, including recommending additional investigations and changes in treatment approach [96]. Smoking cessation should be strongly encouraged, as it can improve performance status [97], and continued smoking may affect the efficacy of systemic therapy (for example, smoking reduces the bioavailability of erlotinib [98]). Occult carcinoma TX, N0, M0 Stage 0 Carcinoma in situ Tis, N0, M0 Stage IA T1, N0, M0 Stage I-A-1 T1a (minimally invasive), N0, M0 T1a, N0, M0 Stage I-A-2 T1b, N0, M0 Stage I-A-3 T1c, N0, M0 Stage IB T2a, N0, M0 Stage I-I-A T2b, N0, M0 Stage I-I-B T1a c, N1, M0 Stage IIA-B T2a, N1, M0 T2b, N1, M0 T3, N0, M0 Stage I-I-I-A T1a c, N2, M0 T2a, N2, M0 T2b, N2, M0 T3, N1, M0 Stage I-I-I-B T4, N0, M0 T4, N1, M0 T1a c, N3, M0 Stage I-I-I-C T2a, N3, M0 T2b, N3, M0 T3, N2, M0 Stage I-I-I-C T4, N2, M0 Stage I-I-I-C Any T, Any N, M1 Stage 4 Stage I-V-A Any T, Any N, M1a Stage I-V-B Any T, Any N, M1b Stage I-V-C Any T, Any N, M1c Recommendation 5: The first line treatment for non small cell lung cancer (N-S-C-L-C) without a targetable oncogene driver is T-N-M (tumor, node, and metastasis) staging, with Tis (in situ tumor) and T1a (minimally invasive carcinoma) being part of this classification. The Union for International Cancer Control (U-I-C-C-) and American Joint Committee on Cancer (A-J-C-C-) systems (8th edition) are used to stage N-S-C-L-C, with specific categories listed in Tables 3 and 4. It is recommended that response evaluation be done after two to three cycles of chemotherapy or immunotherapy, using the same radiographic techniques used for the initial diagnosis. For patients undergoing targeted therapy and/or immunotherapy, response evaluation should be done every 6-9 weeks. Lesions should be assessed according to recist v1.1 criteria. However, evaluating response in genetically driven N-S-C-L-C treated with E-G-F-R or ALK TKIs can be challenging, as continued treatment beyond recist progression is common in search of clinical benefits rather than a measurable response. Radiological criteria such as two dimensional immune related response criteria (irRC) and immune related recist (iRECIST) have been developed specifically for immunotherapy. Chemotherapy should be considered for all stage 4 N-S-C-L-C patients with E-G-F-R and ALK-negative disease, in case of immunotherapy contraindications and absence of major comorbidities with an E-C-O-G performance score (P-S---) of 0-2. Single agent pembrolizumab should be considered for eligible patients with.

[Audio] Annals of Oncology has published a special article outlining the recommended treatment for Stage 4 non small cell lung cancer (N-S-C-C) with negative results on molecular tests for ALK, B-R-A-F-, E-G-F-R-, and ros1. Patients with a high expression of PD-L1 (≥50%) and a performance status (P-S---) of 0-1 or 3-4 are eligible for the following treatments: For patients under 70 years old with a PS of 0-2, pembrolizumab is the recommended treatment. This may be combined with other therapies such as carboplatin based chemotherapy for a maximum of 6 cycles. For patients over 70 years old with a PS of 0-2, pembrolizumab is also recommended as a single agent chemotherapy. Other options include gemcitabine, vinorelbine, docetaxel, or pemetrexed. For patients with a high tumor mutation burden (≥10 mutations/Mb), pembrolizumab may be used as a first line treatment. For patients who have not responded to initial treatment, a maintenance treatment such as pemetrexed or gemcitabine can be continued or switched, in combination with bevacizumab if previously given. For patients who have progressed after initial treatment, platinum based chemotherapy is recommended for patients with a PS of 0-2. For patients with a PS of 3-4, nivolumab, atezolizumab, or pembrolizumab may be considered. Other options include docetaxel, pemetrexed, ramucirumab, nintedanib, or erlotinib. Figure 2 provides a clear treatment algorithm for Stage 4 non small cell lung cancer without ALK, B-R-A-F-, E-G-F-R-, or ros1 alterations. In patients with a PS of 0-1 and PD-L1 <50%, anti PD-L1 combinations with platinum based chemotherapy are preferred, if available and not contraindicated. Depending on approval status and reimbursement, A-L-K (anaplastic lymphoma kinase), B-S-C (best supportive care), E-G-F-R (epidermal growth factor receptor), Mb (megabase), M-C-B-S (Magnitude of Clinical Benefit Scale), nab PC (albumin bound paclitaxel and carboplatin), N-S-C-C (non squamous cell carcinoma), PD-L1 (programmed death ligand 1), PS (performance status), and T-M-B (tumor mutation burden) are not suitable for maintenance monotherapy, and are currently recommended. 5i. The nab paclitaxel regimen could be considered as a chemotherapy option for advanced N-S-C-L-C patients, particularly in those with a higher risk of neurotoxicity, preexisting hypersensitivity to paclitaxel, or contraindications for standard paclitaxel premedication [A = 100% and I, B]. 5j. In advanced S-C-C patients, platinum based doublets with a third generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) are recommended [A = 100% and I, A] (Figure 1). 5k. Pemetrexed is preferred over gemcitabine or docetaxel in patients with non squamous tumors [II, A]. The use of pemetrexed is limited to N-S-C-C patients in any line of treatment [A = 100% and I, A]. 5l. Necitumumab/gemcitabine/cisplatin is a treatment option for advanced S-C-C patients expressing E-G-F-R by immunohistochemistry [A = 83%, B = 17% and II, C]. 5m. In patients with N-S-C-C and PS 0-1, bevacizumab improves overall survival when combined with paclitaxel/carboplatin regimens and may be offered in the absence of contraindications (bevacizumab should be given until progression or unacceptable toxicity) [A = 100% and I, A]. The use of immunotherapy is also recommended if approved and available [A = 100% and I, A]. The combination of pembrolizumab plus carboplatin and paclitaxel or nab paclitaxel should be considered a standard choice for patients with PS 0-1 and metastatic squamous N-S-C-L-C in the absence of contraindications for immunotherapy, if approved and available [A = 100% and I, A] (Figure 1). 5e. The combination of atezolizumab with carboplatin and nabpaclitaxel is an option for patients with PS 0-1 and metastatic squamous N-S-C-L-C in the absence of contraindications for immunotherapy [A = 100%]. If approved and available, nivolumab plus ipilimumab is a viable treatment option for patients with PS 0-1, E-G-F-R and A-L-K negative mNSCLC with a high T-M-B--, regardless of tumor PD-L1 expression.

[Audio] Special article Annals of Oncology Article 5n discusses the potential use of Bevacizumab, in addition to platinum based regimens other than paclitaxel/carboplatin, if there are no contraindications. All 12 Asian experts surveyed before the meeting agreed and fully accepted recommendations 5a, b, g, h, i, j, and k. After addressing issues about the approval and reimbursement of new agents in certain countries, they also fully accepted recommendations 5d and m, and partially accepted recommendations 5e, f, and l (83% and 17% acceptance, respectively). Only recommendations 5c and n were discussed during the face to face meeting (see supplementary Table S3, available at Annals of Oncology online). These recommendations involve using standard first line treatments for patients with squamous and non squamous metastatic non small cell lung cancer (mNSCLC) [I, A]. In the IMpower 150 trial, which was the only published trial at the time of the special guidelines meeting in Guangzhou, data was reported on patients with non squamous N-S-C-L-C with E-G-F-R or A-L-K gene changes. The trial showed that adding atezolizumab to bevacizumab plus chemotherapy (either four or six cycles followed by atezolizumab or atezolizumab plus bevacizumab maintenance) significantly improved progression free survival and overall survival (mOS) in patients with non squamous mNSCLC without E-G-F-R or A-L-K mutations (mOS of 19.2 versus 14.7 months, HR 0.78, 95% 101 0.64-0.96, p=0.02). These results were consistent regardless of tumor PD-L1 expression. In the I-T-T patient population, which included patients with N-S-C-L-C with E-G-F-R or A-L-K mutations, P-F-S was also longer for those receiving atezolizumab, bevacizumab, and chemotherapy compared to those receiving only bevacizumab and chemotherapy. These findings support the use of a combination of atezolizumab (anti PD-L1) and bevacizumab (anti VEGF) with carboplatin and paclitaxel as a treatment option for patients with non squamous mNSCLC. In addition, a PS of 0-1, without any contraindications to using immunotherapy, has been investigated. The IMpower 131 study examined the combination of atezolizumab with platinum and taxane chemotherapy (four or six cycles followed by atezolizumab) in patients with squamous mNSCLC, but no improvement in overall survival was found at the first interim analysis (mOS 14.0 vs 13.9 months, HR 0.96, 95% 101 0.76-1.18) [103]. More data is needed to assess the long term benefits, but atezolizumab and carboplatin/nab paclitaxel may be a potential option for patients with squamous mNSCLC (I; B). The combination of carboplatin or cisplatin with pemetrexed and atezolizumab (four or six cycles followed by atezolizumab plus pemetrexed) in the IMpower132 trial was found to be superior to the chemotherapy doublet, although there was no statistically significant difference in overall survival at the time of analysis (mOS 18.1 vs 13.6 months, HR 0.81, 95% 101 0.64-1.03), suggesting another potential treatment opportunity (I, B) [104]. Similarly, in the IMpower130 trial, the combination of carboplatin/nab paclitaxel and atezolizumab (four or six cycles followed by atezolizumab) was found to be superior to the chemotherapy doublet, with improved progression free survival and overall survival (mOS 18.6 vs 13.9 months, HR 0.79, 95% 101 0.64-0.98), indicating another potential treatment option (I, A) [105]. However, no benefit was observed for the addition of atezolizumab to chemotherapy in patients with EGFR/ALK gene alterations (I, B) [105]. While atezolizumab is not approved by the European Medicines Agency (E-M-A) for first line treatment of NSCLC, it has been approved in certain Asian countries. In the keynote189/407 and IMpower130/131/132 trials, the degree of benefit was correlated with tumor PD-L1 expression. As mentioned in the previous recommendation, a pre specified analysis of T-M-B as a biomarker was reported in the phase 3 CheckMate 227 trial, which evaluated the combination of immunotherapy antibodies nivolumab (anti PD-1) and ipilimumab (anti CTLA-4).

Annals of Oncology chemomeravv. Ine seen mvolumno I-INS ror niy01uruao mus It.nnmuruab in Oätjene a tumour simuar benefit was seen oatlents mtn eltner souamous HR 0.63, non HR For now. nlvolurnan Inillmllmnh reoresents nn TMB A i. (oilllm.rmab and Its with ruv6nrmab are not '[he of on the ben•fit of nivolumab was also pianned analysis and showeu Vdtlents with the MB to Overall, the daw ironm 'ne trials above mat immuno, patients With cilaunosed mtNNÄC„ however, the Asian iuon ot oemntonzumao to chemotneraov in patients witn nigh cell I'D-LI ( trial that comnares rhemntheranv rheyko.'int inhibitors ver, 5c; above witn some reservation (A = and First-line treatment in NSCLC patienX with no onco&me driver but with conFadictions for the use ooumer cnemorneu con- dru2gaole oncogene driver witnout maior comorolölnes, is re IS basea on tne venene; for chemotneraov over best Gire ) 106 108 by the survival demonstrated over 1109. 110 No for t ne versus ,tvcles hrst-ltne I— Ill. 112]. four by Plarinum-oaseu panents not sujtz ble for malnrenanC{ recommencied. Several maunum-oased combinanons With and vinordl'ine have shown comoaraole etcjcacv 113- 114 L. ticlllar oatlent Involve the balance the *rid t'u. QI aal For' to QCfiteve atv aer rates. '_v,g was more vomiting nnd • 'In more thrombocytopaenia and wmiSr no 0111erenC{ renal was ooserved 115L Also, toe of peanetrexed [a novel multi-tarsk$.ed aritiielüte that Lidlibits three Volume 30 | Issue21 2019 Special article involved in and ourine end pyrimi- dme svnl_neslsi jepjesents a u-terdpeullc baseci on Qata •r docetaxel Dlaonum cornmnauons 1116, 1171 mat 119; l€wwsz, the aiDum1n-Dound catltlv htøher overall rate JK R) With the no citr:Tenee in or overall I c: WI 1120jD be oon- a opt 1 nn in With Risk 01 for pacn:rzv.el Bl. were d with a larger in;vact on re- sponse in Dauents with 120 0 chemotneraov oot101LS 101' the nrst-nne treatment or oz:Lents between patients With NSLC ana SLC 1070 cvtntnylc agent vlnntelnlne. taxane) are recnm• comorbiclttles A] ( Fivllre.s 1 ona V3cvoevem there are some Irzåtment tlle Of Éli'a!rLSt aoaeu to cisplåtuuvemetrexeo 121 bener[ts in Che 122, 123' ' score 1 i. However: a benefit from the iti011 of necitun?llreah to chemotherapy was not aooarent tne small sungrout' or oauene non- to the umltea osta, the aa(lltlon of necitumumat' to cis- nn'v. It t fiat it nnt as a stullXE;rd option in n'f3St Asian *lid its use NS' sbquld fiåS to in Infth score 2). meta-ana]vses connrnmea 'he ity of Tlz:inurn nnil'lnatlon tneraov alone in NSCLC tranents With no consensus mat revacrzumäD coma De usea 01 commn- with *rid the Asian exnerts anlv -recommenclatlon above With map; Recommendation 6: maintenance Maintenance chemotheraDv should be offered ta nxutfienance nt.svoteev. re- spc,yse to pk,i-knun' and | 187.

[Audio] Special article Annals of Oncology survival [133]. Although a trend towards improved overall survival was observed when analyzing 58% of the 253 patients randomized in this trial [134], the PointBreak trial yielded comparable results in terms of overall survival between two treatment arms. In this trial, patients with non small cell carcinoma (N-S-C-C) were treated with either carboplatin plus paclitaxel plus bevacizumab followed by bevacizumab, or carboplatin plus pemetrexed plus bevacizumab followed by pemetrexed plus bevacizumab (HR, 1.00; 95% 101: 0.86-1.16; P=0.949) [135]. A separate phase 3 trial showed that maintenance treatment with gemcitabine significantly reduced disease progression and potentially improved overall survival in advanced N-S-C-L-C patients who had received four cycles of cisplatin/gemcitabine combination therapy as first line treatment [I, C] [136]. Recommendation 7: In patients with a performance status (P-S---) of 2 and beyond toxicity after first line chemotherapy, PS and patient's preference should be considered [A=83%]. 6b. For patients with N-S-C-C and a PS of 0-1, switch maintenance with pemetrexed should be considered if there is evidence of disease control after four cycles of non pemetrexed containing platinum based chemotherapy [A=100% and I, B]. Pemetrexed continuation maintenance can also be considered for these patients after four cycles of cisplatin/pemetrexed [A=100% and I, A], with or without the addition of bevacizumab. 6c. In N-S-C-L-C patients who have received four cycles of cisplatin/gemcitabine, continuation maintenance with gemcitabine is a potential treatment option [A=100% and I, C]. 6d. Maintenance treatment with erlotinib should only be considered for N-S-C-C patients with an E-G-F-R sensitizing mutation [A=100% and II, B]. 7a. In patients with a PS of 2, chemotherapy has been shown to prolong survival and improve quality of life compared to best supportive care (B-S-C) [A=100% and I, A]. 7b. For eligible patients with a PS of 2, carboplatin based combination therapy should be considered [A=100% and II, A]. 7c. Single agent chemotherapy with gemcitabine, vinorelbine, or docetaxel [A=100% and I, B] may also be an option for these patients. Pemetrexed, restricted to N-S-C-C, can also be considered [A=100% and III]. B] is an alternative treatment choice. Patients with a poor performance status (3-4) should only receive treatment with B-S-C [a 100% acceptance rate and a II, B recommendation], unless a specific genetic abnormality can be targeted with minimal side effects. All 12 Asian experts unanimously agreed with and fully accepted recommendations 6 b, c and d after addressing issues surrounding current practices in certain Asian countries identified in pre meeting surveys (see supplementary Table S4, available at Annals of Oncology online). However, the Japanese experts only accepted recommendation 6a with major reservations. As stated in the E-S-M-O guidelines [24], decisions about maintenance therapy should consider factors such as histology, remaining side effects after first line chemotherapy, response to platinum based treatments, performance status, and patient preference. The above recommendations (6a, b, c, and d) are based on data from multiple trials that have studied the role of maintenance treatment in patients with good performance status (0-1). This includes continuation maintenance (using a medication from the first line treatment) or switch maintenance (using a new medication) after four cycles of platinum based chemotherapy. Phase 3 trials of switch maintenance have shown improved progression free survival and overall survival with pemetrexed [118] and erlotinib [128] compared to placebo, after four cycles of platinum based therapy. This was also seen in a subgroup analysis of Asian patients (from Korea, China, and Malaysia) enrolled in the saturn trial, with both the overall Asian population and patients with EGFR-positive disease showing improved outcomes with erlotinib [129]. For pemetrexed, the benefit was limited to patients with non squamous non small cell lung cancer. Additionally,.

Annals of Oncology comoarzl)le to mat Of 143', Currer1L1b', for the use in YS 2 vaoe11KS. sence or Known mutanons, or rearrangements BRAF VOX,' mutdZion [a(, B]. Recommendation 8: elderly patiene 8a. ImmunotheraDv should be considered according to sta•s dayd in eÉdEiÉy [A li'Jvyo (J—2 and 8'. Por rnose pni-senzs nor aouo:er chemotheraDy. remains the of care All 12 Asian exnerts aøræd with and accented cnmnlete]v the 1141, 1441, and a more recent Of con- troi'ed trials that coruvared non-Vlaonum sitF4e-awnt therapy versus In vents Of caemotneraov to be the orererrea oatjents With ':lztieum- based tneraov is associated Wltn an i the expertetl Comnrehenstve a lor baxd on or iwi'ty I l" , yean'S Old a PS Of and I V : it PS < I anu age years; aro arm the Of CGA (COA caroopmun-oaseå dour.'ler ror fit snowed tsutment on tne basis of CGA to rail patients to irr:: rove -ur _ 3 re011ce treatment-relatH1 L 147 L With Ph anil "late A], arid patient:æ not rhemqtbernpy, single-agent chemotherapy remains the [ i, to nn to p;'tiernts have been eyiaenr-e is a-curnuldone for the use suvvorceo neom second-line Volume 30 | Issue21 2019 Special article dßic«v [148A511 in iavy L 1521. in a sur.:.zrouv andivsis (lie mao oetueen ageo vears ano inose ageu ream 020 trial. there was no öltterence in survival outcomes Detween With '77 L. Cmsmllnothemnv be eonsld- Recommendation 9: second-line treatment of patiene with mNSCLC without a druggable oncogene driver first-une zrwrapy a PS o? V-sz be ojlereu second- 9b. testing ts rourtne?v recommended at diagnosis therapy wun p,iartnum-oaseci chemorner ret r; secönd-,ine trec,iment opcton SW com 9e. PD-LI \ 'fivoiumab, pembroÆzu- "oceraxA, n'ore rozeraouiiy preyue Jor 9g. -irearmenr may.' oe if dispase is controlled 9b. is option patients 9 montns From gne .sxa•z; o' cnemogrwrapy wtrh PS treatment ODtn,'1 ment ongton 'or not sunao,ie tor im snaru5 or EGrK E — 9k. In pretreated with SCC unfit for | 189.

Special article All IL Asian exoerts aureed with and accepted comtrtetely meeMnø survew; i supplementary Table S6. avaH8D:e at Annals of dations anci e', tne aac_lnon or wora InmoLtor to rec- 'recnmmenaation was suhReanentiv Chatwexl with a plementary Table SIY at thc fact three ; bieuzamnb antl Foad and J)rng (YI)A) and the I-'NA tar use In the second-line the treatment uätjents with NSCLC. Witn aavanced Irrespectjye 01 PLEi.1 wnue Sion Ai_'oroval 01 nivolumab was Dased on the data from 149 a 057 148" score 5). In the (.netKMate trial, 272 with NSCLC were to rec:tve ei- n1v6nrm•An nr overall was gnawn to triall, 382 patix:nts NSCLC were tandftll'jsed MVO- Furthermore, a recent uøuate Of these stuaies has shown the 2-vear overall sur- Witn doce'axel) r I, A] and non-squarnous tuvolumab, With of oauents exærlentlnø uracie 5—4 recelwnø clnreqaxel. was beed on the of the KF.å rrAttentR cells to receive Dr receiving docetaxei HR 0.72* C]: with a recently 2-yenr overall survival rates Of 14.3% [I, A1. relatea were less common witn oernbronzurnab than With _ ili:ænt dif- ference in the satetv or oen'Dr01L9-umaD at aoses of g. natlentR novanceo NSA treated Elth ther atezolizumab nr to inmvrove overall su_iNivdl (KR 0.73, CI 0-02—0.87, P < [1511 "Q Iltv With Of a _W toxicity comp-cred with 43% of thüse tremed with docetaxel 11, 1901 Wuetal. Annals of Oncology A1. Thus, based on these trial data anti-PD-I/PP-LI agents should be the truitment Of cholce for most Wilh PO-LI inhibitor-lifiive NSCLC, ilv resuecuve Oi YO-H II, A1. to show anv Denent over le-nent treatments terms ot oven- prove '1tseARe-relatM wmi'tnrns overall Glirvlval *lth in 'finclnt"tseci 155 156' Qnth with II, 11571 158 j, to dncet7:re.l a abie toncitv Otec(Je 159'. a retmsuective analysis Oem- in the erne-acy [overan survival) 01 vernerrexeu Wilh SuS ö.'mont_ns: C.ig: C/ P-—0.0041 L 1191, connrmea seconu-une caemotneraov oonons. comoaranle [L dine uallReii ana ptalanmattnn treatment an option If clisease is combine-a With anttanøiagenic agents has heen Wu_h P FS Vival when Wlth and even in patients. who dio 110t show resuonse to nr-5,:• chernethen- and Of tumour f 160 161' USN (CD score 1 i. Combinänon Of the theraov atone In tne 110 ME-I trial a sluntncant orolcrnuauon :arclnomas i meatan versus montas•. '-iR {rit:_ L, - 163/ Ot results Of 'izunmao mr_nuayeu 164 L . u "ion the Asian exoerts recommenaauon '-31 mat oroooses tnat emoti- nib (an "IRI) re. treltment ootion. particularly for oatlents witn eltner wikL Type turreurs sta- tus not sulltahle immnnotherapv or second-ltne Chernothen- or comoleielv 'On 91; and 011 the Of reports Of the inferiority Of in the of tcwmur; 1165b In a the in 900 vanelll.s, the _EG-Æ•K Inienor to thc: for chemotherapy in par-Lents with EGBI€ :ype tumours Volume 30 Issue 2 2019.

[Audio] Annals of Oncology Special article of treatment with an EGFR TKI in combination with local treatment of progressing metastatic sites may be considered [grade A 100% and level III], based on a study that showed a significant improvement in progression free survival (HR 1.37, 95% 101 1.20–1.56; P < 0.00001) in patients with advanced E-G-F-R wild type non small cell lung cancer [NSCLC] [166]. However, this improvement was not seen when looking at overall survival (HR 1.02, 95% 101 0.87–12; P = 0.81) in a Chinese trial [166]. Another study in Europe showed that second line chemotherapy was more effective in improving both progression free survival [P-F-S] and overall survival [OS] compared to second line EGFR TKI therapy in patients (n = 1278) with previously treated NSCLC [PFS 4.3 versus 2.83 months, HR 0.66, 95% 101 0.57–0.77, OS 8.39 versus 4.99 months, HR 0.7, 95% 101 0.59–0.83; P < 0.0001] [167]. In patients with advanced squamous cell carcinoma [S-C-C], afatinib has been shown to be superior to erlotinib in terms of both P-F-S and OS in the LUX-Lung 8 trial [PFS 2.4 versus 1.9 months, HR 0.82, 95% 101 0.68–1.00; P = 0.041; OS 7.9 versus 6.8 months, HR 0.81, 95% 101 0.69–0.95; P = 0.0077] [168] (ESMO Magnitude of Clinical Benefit Scale [MCBS] score 2). However, the Asian experts have reservations and only partially accept ‘recommendation 9k’ that afatinib may be a therapeutic option for patients with advanced S-C-C [Eastern Cooperative Oncology Group [E-C-O-G] performance status [PS] 0–2] who have progressed after platinum based chemotherapy [grade I, level C]. Based on the ESMO 2018 Clinical Practice Guidelines for diagnosis, treatment, and follow up for metastatic non small cell lung cancer [mNSCLC] [24], patients who experience clinical or radiological progression after first line therapy should be offered second line therapy, regardless of whether or not they received maintenance treatment [grade I, level A]. Currently, there are no prospective trials that have determined the best second line therapy following failure of first line treatment with pembrolizumab, but the preferred recommendation would be platinum based chemotherapy based on results from first line trials [64], as discussed previously. Recommendation 10: first line treatment of EGFR-mutated NSCLC All 12 Asian experts completely agree [grade A 100%] with 'recommendations 10a', which suggest the use of an EGFR TKI as first line treatment in combination with local treatment for progressing metastatic sites. B, D, E, F, and G' were included in the pre meeting surveys (see supplementary Table S7, available at Annals of Oncology online) and subsequently, after discussion, recommendation 10c was made based on the data presented at the end of this section. This decision to accept the E-S-M-O recommendations was based on the recognition that the E-G-F-R mutation status is a well established predictive marker for the treatment of patients with non small cell lung cancer (N-S-C-L-C), as demonstrated by phase 3 trials comparing first generation (erlotinib and gefitinib) (ESMO MCBS score 4 for gefitinib and erlotinib) and second generation (afatinib) EGFR TKIs with standard platinum based chemotherapy regimens (ESMO MCBS score 4) [171-176]. The benefit on progression free survival (P-F-S--) conferred by EGFR-TKI therapy was consistent across all these studies and independent of gender, age, smoking status, and performance status (P-S---). Additionally, this benefit was also observed in Asian patients [171, 175]. However, none of these studies showed a benefit for EGFR TKI therapy over platinum based therapy in terms of overall survival, likely due to high rates of treatment crossover. These data support the use of EGFR TKIs as the standard of care for first line treatment of Asian patients with EGFR-mutated NSCLC [I, A] (Figure 3). Asian.

[Audio] This special article from the Annals of Oncology discusses Stage 4 lung carcinoma with EGFR-activating mutation and performance status scores ranging from 0 to 4. Patients with scores of 3 or 4 may also have the following treatment options: Gefitinib, Erlotinib, or Erlotinib combined with Bevacizumab. In some cases, Afatinib, Dacomitinib, or Osimertinib may also be options. For patients with disease progression, treatment options may include Oligoprogression, Systemic progression, or Local treatment (surgery or RT) in combination with targeted systemic treatment. Exon 20 T-7-9-0-M mutation testing may be done through either re biopsy or cfDNA plasma testing, with a re biopsy being necessary if the plasma test is negative. For patients with a positive exon 20 T-7-9-0-M mutation, Osimertinib may be used as a treatment option, while those who test negative or for whom re biopsy is not feasible may also consider this treatment. In cases of systemic progression, a platinum based doublet or Carboplatin/Paclitaxel/Bevacizumab/Atezolizumab may be used, depending on the patient's performance status. Figure 3 shows a treatment algorithm for patients with Stage 4 lung carcinoma and EGFR-activating mutations, with options for those with Non Small Cell Lung Cancer (N-S-C-L-C). A Japanese trial showed promising results for EGFR-TKI therapy in combination with the antiangiogenic drug Bevacizumab, compared to Erlotinib alone. Another trial in Japan also reported successful interim results for Bevacizumab plus Erlotinib compared to Erlotinib alone, with a significant advantage in terms of P-F-S (progression free survival). Updated data from these trials has also shown that some patients receiving these treatments may require a reduced dosage. Osimertinib, a third generation EGFR TKI, is an effective treatment option for patients with both sensitizing E-G-F-R mutations and the resistant exon 20 T-7-9-0-M mutation. In the phase 3 FLAURA trial [186], osimertinib was compared to standard first generation EGFR TKIs (gefitinib or erlotinib). The results showed that osimertinib had a significantly better progression free survival (P-F-S--) compared to the standard EGFR TKIs (PFS of 18.9 months versus 10.2 months; HR of 0.46, 95% 101 0.37-0.57; P < 0.0001) when used as a first line treatment for advanced N-S-C-L-C with E-G-F-R mutations. The safety profile of osimertinib was similar to that of standard EGFR TKIs, but it had lower rates of serious adverse events. Therefore, osimertinib can be considered as one of the recommended treatments for advanced N-S-C-L-C with E-G-F-R mutations..

[Audio] Annals of Oncology Special article Table 5. Summary of drug approvals and reimbursement in Asian countries according to M-O-S S-S-O T-O-S E-S-M-O MCBS CSCO China J-S-M-O Japan K-S-M-O Korea Malaysia Singapore Taiwan V1.1 [278, 279] Drugs Approval Approval Approval Approval Approval Approval Reimbursement Reimbursement Reimbursement Reimbursement Reimbursement Reimbursement Pemetrexed 1st line 4 Pemetrexed maintenance ND Pemetrexed 2nd line 4 Gemcitabine ND Vinorelbine ND Nab paclitaxel ND Docetaxel ND Cisplatin ND Carboplatin ND Bevacizumab 2 Ramucirumab 1 Nintedanib ND Cetuximab ND Necitumumab 1 Gefitinib 4 Erlotinib 4 Afatinib * * 4 or 2 Osimertinib 4 Crizotinib 4 Alectinib 1st line ND Alectinib 2nd line.

[Audio] Special Article: Annals of Oncology 11f. The standard treatment for patients with negative T-7-9-0-M test results, either in a re biopsy or in a liquid biopsy (if re biopsy is not possible), is a platinum based doublet therapy. [A=100% and I, A] 11g. In patients with EGFR-mutated tumors and a performance status of 0-1, a combination of atezolizumab and bevacizumab with carboplatin and paclitaxel may be considered as a treatment option, as long as there are no contraindications to using immunotherapy after targeted therapies have been utilized. [A=100% and IV, C, after discussion]. Data from a study on patients without an oncogene driver mutation (E-G-F-R or A-L-K) [102] support the use of this combination therapy in patients with non squamous metastatic non small cell lung cancer (mNSCLC) and a performance status of 0-1, as long as there are no contraindications to using immunotherapy. This combination may also be an option for second line treatment. [IV, C] (Figure 3). However, after the meeting in Guangzhou, two publications [192, 193] reported that I-C-T monoclonal antibodies were not effective as single agents for second line treatment in PD-L1-positive, TKI-naive patients with advanced NSCLC, including those with PD-L1 expression of over 50%. These data suggest that using these agents as a treatment option may not be appropriate in this setting. Recommendation 12: First line treatment of ALK-rearranged NSCLC 12a. Patients with ALK-rearranged N-S-C-L-C should receive a first line treatment with an A-L-K tyrosine kinase inhibitor (T-K-I--), such as crizotinib. [A=100% and I, A], ceritinib [A=100% and I, B], or alectinib [A=100% and I, A]. 12b. Alectinib has been shown to have a longer progression free survival and lower toxicity compared to crizotinib, and has also been effective against C-N-S disease in previously untreated patients with ALK-positive NSCLC. [A=100% and I, A]. 12c. In patients with C-N-S involvement, first line use of ALK TKIs has been found to be effective and alectinib [III, A] or ceritinib [IV, B] are recommended as treatment options. [A=100%]. Ceritinib is a more effective treatment strategy than chemotherapy. [I]. B] et vraisemblablement crizotinib [IV, B]; alectinib représente une meilleure option de traitement que crizotinib [I, A]; brigatinib représente une meilleure option de traitement que crizotinib [I, B]. 12d. Chez les patients atteints de L-N-S-C-L-C avec réarrangement de l'ALK et présentant une progression locale lointaine avec un contrôle systémique en cours, la poursuite du traitement avec un T-K-I de l'ALK en combinaison avec un traitement local des sites métastatiques progressifs peut être envisagée [A = 100% et III, B]. Les 12 experts asiatiques ont été unanimement d'accord et ont entièrement accepté les recommandations 11a, b, c, d et f lors du sondage précédant la réunion (Tableau supplémentaire S8, disponible en ligne sur le site Annals of Oncology), ainsi que les recommandations 11e et g après discussion. Dans le cas de la recommandation 11e, le terme hautement a été retiré de l'énoncé osimertinib est hautement actif. Dans le cas de la recommandation 11g, le niveau de preuve a été révisé à IV, C car il n'y avait pas d'essai spécifique évaluant cette approche de traitement en deuxième ligne et le verbe devrait a été remplacé par pourrait (voir le texte en gras ci dessus). Presque tous les patients bénéficiant des T-K-I de l'EGFR développeront une résistance clinique et progresseront après 9 à 12 mois de traitement. Plusieurs mécanismes de résistance aux T-K-I de première génération ont été décrits [164]. Le mécanisme le plus courant de résistance (49%-60% des cas) implique l'acquisition de mutations E-G-F-R exon 20 T-7-9-0-M [191]. Cependant, un certain nombre de T-K-I de l'EGFR de troisième génération sont conçus pour cibler spécifiquement la mutation T-7-9-0-M de l'EGFR [23]. À ce jour,.

[Audio] Annals of Oncology Special article Recommendation 13: Second line treatment of ALK-rearranged non small cell lung cancer (N-S-C-L-C) with alectinib or crizotinib. A clinical trial, known as the alex trial, showed that alectinib had a significantly longer progression free survival (P-F-S--) compared to crizotinib in treatment naive patients with A-L-K rearrangements (PFS 34.8 vs 10.9 months). This superiority was also observed in patients with baseline central nervous system (C-N-S--) metastases (PFS 27.7 months vs 7.4 months). Moreover, alectinib had lower rates of severe adverse events compared to crizotinib. In another phase 3 trial (ALTA 1), alectinib was found to be more effective than crizotinib in patients with ALK-positive advanced N-S-C-L-C who had not previously received an A-L-K inhibitor. The European Medicines Agency (E-M-A--) has approved alectinib for use as a first line treatment for ALK-rearranged NSCLC, and ceritinib as a second line treatment following crizotinib failure. Recently, brigatinib has also received favorable opinion for approval from the E-M-A for use as a second line treatment post crizotinib. Recommendation 13: 13a. Ceritinib and alectinib are recommended for ALK-positive advanced N-S-C-L-C patients who have not responded to or cannot tolerate crizotinib [Grade A recommendation, 100% agreement among experts]. 13b. In patients with ALK-positive N-S-C-L-C that has progressed in the C-N-S while on crizotinib, treatment should be switched to a next generation ALK TKI, such as alectinib or ceritinib [Grade A recommendation, 100% agreement among experts]. 13c. In patients who have progressed after treatment with a second generation ALK TKI, the next generation of A-L-K inhibitors, such as alectinib or ceritinib, should be considered [Grade A recommendation, 100% agreement among experts]. As options, drugs such as brigatinib or lorlatinib should be considered if they are available [with a response rate of 100% and being clinically significant (C)]. If not available, pemetrexed and cisplatin may be considered as an alternative. Assessing the molecular mechanisms of resistance may also play a role in the decision making process [with a response rate of 100% after discussion]. It is still not established which sequence of ALK-targeted drugs is the most effective. The combination of atezolizumab and bevacizumab with carboplatin and paclitaxel could be considered as a treatment option for patients with ALK-mutated tumors and a performance status of 0-1, if there are no contraindications to the use of Stage 4 N-S-C-C [with positive molecular tests for A-L-K--, B-R-A-F-, and ros1 alterations]. If the tumor has a ros1 translocation or a B-R-A-F V-6-0-0 mutation, dabrafenib/trametinib can be used as a treatment option [with a level of evidence 3 and a Magnitude of Clinical Benefit Scale (M-C-B-S-) score of 2]. Crizotinib is also an option for these patients [with a level of evidence 3 and an M-C-B-S score of 3]. For patients who have not received previous treatment with crizotinib, it may be used in combination with platinum based chemotherapy [with a level of evidence 4 and an M-C-B-S score of 4]. For those who have received crizotinib previously, ceritinib may be used alone [with a level of evidence 3 and an M-C-B-S score of 4] or alectinib may be considered [with a level of evidence 3 and an M-C-B-S score of 4]. If the disease progresses, local treatment options such as surgery or radiotherapy may be used in addition to continued targeted systemic treatment [with a level of evidence 4 and a recommendation of C]. Alternatively, platinum based chemotherapy may be used [with a level of evidence 4 and a recommendation of A]. A rebiopsy is recommended to assess the molecular profile of the tumor. Depending on the approval status and reimbursement, ceritinib [with a level of evidence 3 and.

[Audio] A Special article in the Annals of Oncology discusses the use of immunotherapy following targeted therapies in the treatment of certain types of cancer. This approach has been extensively studied (with a success rate of 100% and moderate confidence) and has shown potential in the treatment of tumors with genetic alterations in the E-G-F-R or A-L-K genes. Specifically, the combination of atezolizumab (which targets PD-L1) and bevacizumab with carboplatin and paclitaxel has been shown to be effective as a first line treatment option in patients with non squamous metastatic non small cell lung cancer (mNSCLC) and good performance status (0-1). This approach may also be considered as a second line treatment for patients with ALK-rearranged NSCLC. In terms of recommendations for patients with ros1-rearranged NSCLC, the experts suggest the use of crizotinib as a first line treatment, as it has shown to improve response rates and duration of response. For patients who have not received crizotinib as a first line treatment, it may be offered as a second line therapy. Ceritinib could also be considered in patients who have not received crizotinib before, but it is not currently approved by the European Medicines Agency. If patients have already received crizotinib as a first line treatment, they may be offered platinum based chemotherapy as a second line therapy. All 12 Asian experts unanimously agreed and accepted these recommendations (based on data from the PROFILE 1001 trial which included 50 patients with ros1-rearranged NSCLC) in pre meeting surveys. This trial reported a high overall response rate (O-R-R--) of 72%, a disease control rate (D-C-R--) of 90%, and a median progression free survival (P-F-S--) of 19.2 months. Other studies have also shown promising results for crizotinib in this patient population, with reported O-R-R's of 72-80% and median P-F-S of 9.1-13.4 months. Thus, single agent crizotinib is recommended as a first line or second line treatment for patients with stage 4 non small cell lung cancer (N-S-C-L-C) with a ros1 rearrangement [III, A]. In a Korean phase 2 study, 32 patients with ros1-rearranged advanced N-S-C-L-C were treated with ceritinib [216]. Among patients who had not previously been treated with crizotinib, the overall response rate (O-R-R) was 67%, with a disease control rate of 87%. Ceritinib may be an option for patients who have not received crizotinib, but it is currently not approved by the European Medicines Agency (E-M-A--) [III, C]. Recommendation 15: Patients with BRAF-mutated N-S-C-L-C. All 12 Asian experts fully agreed and accepted recommendations 13a, b, c, and e in the pre meeting survey (see Supplementary Table S9, available at Annals of Oncology online) and subsequently, after discussion, also agreed with recommendations 13d and f. In the case of recommendation 13f, the level of evidence was revised to V, C, as there was no specific trial addressing this second line treatment approach and the word should should be changed to might (see bold text above) (see Supplementary Table S-1-3, available at Annals of Oncology online and Table 2). In the phase 3 PROFILE 1007 trial, crizotinib was shown to be superior to second line chemotherapy (either pemetrexed or docetaxel) in treatment naive patients with previously treated ALK-rearranged N-S-C-L-C, in terms of O-R-R and progression free survival (P-F-S--) [204]. Meanwhile, the ASCEND-5 trial [205] for ceritinib and the alur trial [206] for alectinib have both shown significant improvements in median P-F-S compared to chemotherapy (5.4 months for ceritinib vs 1.6 months for chemotherapy, HR 0.49, p<0.0001; and 9.6 months for alectinib vs 1.4 months for chemotherapy, HR 0.15, p<0.001) in patients with ALK-positive N-S-C-L-C who had previously been treated with crizotinib and chemotherapy. These data support the use.

[Audio] Special Article Annals of Oncology 16e. Crizotinib has shown potential clinical effectiveness for M-E-T exon14 variant N-S-C-L-C, which needs to be verified [A = 100% and III, C]. 16f. Due to the lack of strong evidence, targeting Her2 dysregulation is currently not recommended and participation in ongoing trials is encouraged [A = 100% and III, C]. 16g. Targeting N-R-T-K fusions is currently not recommended and participation in ongoing trials is encouraged [A = 100% and III, C]. All 12 Asian experts agreed and fully accepted 'recommendations 16a g' in the pre meeting surveys [A = 100%]. Recommendation 17: Role of Radiation Therapy (R-T) in Stage 4 NSCLC 17a. RT can provide symptom relief for various clinical scenarios, including hemoptysis, airway obstruction, chest wall pain, bone metastasis, superior vena cava syndrome, and soft tissue or nerve invasion [A = 100% and II, B]. 17b. High dose RT does not result in better palliative effects [A = 100% and II, B]. 17c. External beam radiation therapy (E-B-R-T) alone is more effective for palliation than endobronchial brachytherapy (E-B-B) alone [A = 100% and II, B]. 17d. For patients previously treated with E-B-R-T who experience symptoms from recurrent central airway obstruction, E-B-B may be considered in selected cases [A = 100% and I-I-I-, C]. 17e. Early RT can relieve neurological symptoms from spinal compression [A = 100% and II, B]. All 12 Asian experts agreed and fully accepted 'recommendations 15a and b' in the pre meeting surveys [A = 100%]. The BRAF V600E mutation is observed in 1-2% of lung adenocarcinomas [217-219], particularly in patients with a history of smoking. The effectiveness of B-R-A-F inhibitors vemurafenib, dabrafenib, and sorafenib was confirmed in a European retrospective cohort study of patients with BRAF-mutant lung adenocarcinoma [220]. The overall survival rate for patients receiving first line therapy was 25.3 months for those with V-6-0-0-E mutant disease and 11.8 months for those with non V600E mutant disease. Thirty one patients received one B-R-A-F inhibitor. Additionally, four patients were given a second inhibitor. Out of the patients receiving B-R-A-F therapy, 53% showed a response rate, and 85% showed disease control. In a trial called VE-BASKET, a total of 19 patients with N-S-C-L-C were evaluated for their response. Of these patients, one had not received previous treatment, while 50% and 45% had received one or two or more lines of therapy, respectively, before participating in the study. The response rate (O-R-R) was 42%, the progression free survival (P-F-S) was 7.3 months, and the overall survival had not yet been reached [221]. In a phase 2 study with multiple cohorts, patients with BRAF V600E-mutant metastatic N-S-C-L-C were treated with either dabrafenib alone (cohort A), or in combination with a M-E-K inhibitor (trametinib) (cohort B for second line treatment and cohort C for first line treatment). The response rate for patients receiving dabrafenib monotherapy was 33%, with a median P-F-S of 5.5 months and a median duration of response of 9.6 months [222]. In previously treated patients receiving the combination of dabrafenib and trametinib, the response rate was 66%, and the median P-F-S and duration of response were 10.2 and 9.8 months, respectively [223, 224]. In treatment naive patients receiving the combination therapy, the response rate was 64%, with a median P-F-S of 10.9 months and a median duration of response of 10.4 months [225]. As a result, dabrafenib in combination with trametinib has been approved by the E-M-A and F-D-A for the treatment of patients with advanced or metastatic N-S-C-L-C who have a BRAF V600-mutation. In patients with B-R-A-F inhibitor naive stage 4 N-S-C-L-C with a BRAF V600E mutation, the use of dabrafenib and trametinib is recommended [III, A] (Figure 4). Recommendation 16:.

[Audio] Special article Annals of Oncology Recommendation 18: brain metastases 18a. Whole brain radiation therapy (W-B-R-T) should not be offered to patients in Recursive Positioning Analysis (R-P-A) class 3 due to the poor prognosis [I, E]; only best supportive care (B-S-C) is recommended [A = 100%]. 18b. W-B-R-T may be considered for selected patients if they have good prognostic factors for survival [A = 100% and II, C]. 18c. Avoiding the hippocampus during W-B-R-T is not currently a recommended standard treatment [A = 100% and III, C]. 18d. For patients with a single brain metastasis, stereotactic radiation surgery (S-R-S) alone or surgery is the recommended treatment for those in R-P-A class I-II [A = 100% and III, B]. 18e. Postoperative W-B-R-T or S-R-S is recommended after surgical removal of a brain metastasis [I, A]. 18f. S-R-S alone, without W-B-R-T but with close M-R-I brain imaging follow up, is an alternative treatment option [A = 100% and III, B]. 18g. For patients with two to four brain metastases, S-R-S alone is recommended for those in R-P-A class I-II [III, B]. 18h. For patients with symptomatic brain metastases and/or edema, treatment with dexamethasone or another corticosteroid is recommended [A = 100% and III, A]. 18i. In patients with asymptomatic central nervous system (C-N-S) metastases at diagnosis, systemic therapy with deferred radiotherapy may be considered due to similar responses in the brain and other parts of the body [B = 83%, C = 17% and II, C]. 18j. For patients with a targetable oncogene driver (such as E-G-F-R-, A-L-K) and asymptomatic brain metastases, next generation T-K-I's may effectively control brain metastases and delay radiotherapy [A = 100% and II, B]. 18k. Limited data suggests that immune checkpoint inhibitors may be safe for patients with small, untreated C-N-S metastases [A = 100% and III, B]. All 12 Asian experts fully agreed with and accepted recommendations 18b h and j and k in pre meeting surveys (see supplementary Table S-1-0--, available at Annals of Oncology online), and recommendation 18a after discussion at the face to face meeting. For recommendation 18i, the level of evidence was changed from I-I-B to I-I-C and the word should was changed to can (see bold text above). Ultimately, the recommendation was accepted by five countries with some reservation [B = 83%] and one country with major reservation [C = 17%], due to the limited available data. C-N-S metastases are commonly found in patients with non small cell lung cancer (N-S-C-L-C), particularly in those with adenocarcinomas. Approximately 30%-64% of patients with metastatic N-S-C-L-C have C-N-S metastases. As previously described [23], the treatment for patients with brain metastases and no driver mutations is based on prognosis estimated using the Radiation Therapy Oncology Group Recursive Partitioning Analysis [228]. Radiation therapy is not recommended for R-P-A class 3 patients (who have a Karnofsky index of ≥70%) based on their poor prognosis (median survival is generally <2 months). The role of whole brain radiation therapy (W-B-R-T-) in unselected patients has been questioned based on data from the phase 3 non inferiority QUARTZ trial, in which patients were randomly assigned to receive either best supportive care (B-S-C--) including dexamethasone plus W-B-R-T (20 Gy in five daily fractions) or the same B-S-C without WBRT [229]. This trial showed no difference between the treatment arms in terms of symptom relief, steroid use, overall survival, quality of life (QoL), or quality adjusted life years, confirming no benefit for W-B-R-T in the R-P-A class 3 subset [I, A]. However, a potential benefit for W-B-R-T was seen in younger patients with better Karnofsky indices and either controlled primary disease or no extracranial disease. Therefore, W-B-R-T may be considered for patients with prognostic factors associated with better survival,.

[Audio] Annals of Oncology Special article: The prognosis for patients with non small cell lung cancer (N-S-C-L-C) with leptomeningeal disease (L-M-D--) is poor, and the goal of treatment is to prolong survival while maintaining an acceptable quality of life (QoL). Patients with treatable cancer causing genetic mutations may benefit from a next generation, CNS-penetrating tyrosine kinase inhibitor (T-K-I) as recommended for those with brain metastases [III, B], as previously described for icotinib under 'recommendation 18' [248], and in a recent review [253]. Additionally, a study comparing afatinib and platinum based chemotherapy as first line treatments in E-G-F-R mutation positive patients with N-S-C-L-C and brain metastases showed that afatinib was effective in this setting [254]. The specific and potent C-N-S activity of osimertinib may also suggest its use in this context [53, 186]. Chemotherapy may have activity both inside and outside the brain, and may be effective in the treatment of LMD [IV, C]. Bevacizumab may also have a role [IV, C] [255, 256]. In certain cases, intra cerebrospinal fluid (C-S-F--) pharmacotherapy may be administered through repeated lumbar punctures, a reservoir, or a ventricular device, although patient factors such as performance status, control outside the brain, and potential benefits should be considered [V, C]. There is no randomized data to support the use of radiation therapy for L-M-D--. However, in exceptional cases, focused radiation therapy may be considered for targeted, particularly symptomatic, lesions [V, C]. Recommendation 20: Treatment of oligo metastatic disease (O-M-D--): For patients with asymptomatic brain metastases who have not yet received systemic therapy (such as chemotherapy or TKIs), treatment with systemic therapy as a first line option and delayed radiation therapy should be considered based on trial data that suggest similar response rates inside and outside the brain [II, B] [246, 247]. In a phase 3 trial in Asia involving patients with EGFR-mutant N-S-C-L-C and multiple brain metastases, icotinib (an EGFR-TKI) was shown to have significantly longer progression free survival in the brain compared to whole brain radiation therapy and chemotherapy, suggesting that EGFR TKIs may be a better first line treatment for this patient population [248]. For patients suitable for initial immunotherapy and chemotherapy (I-C-T--) and monoclonal antibody therapy, such as pembrolizumab. C-N-S metastases are typically required to have been treated before beginning therapy in most clinical trials. There is some evidence of positive responses in smaller studies and across different diseases, but there is limited evidence on the safety and effectiveness of immunotherapy for patients with untreated, small volume NSCLC CNS metastases [III, B] [249]. Between 44% and 60% of mNSCLC patients with a treatable oncogene driver (such as E-G-F-R or A-L-K--) develop brain metastases during their illness [250, 251]. For these patients, evidence suggests that using next generation CNS-penetrating tyrosine kinase inhibitors (TKIs) like osimertinib, alectinib, ceritinib, and brigatinib may help control brain disease and potentially delay the need for cranial radiation therapy [II, A] [186, 199, 202]. These T-K-I's may also reduce the occurrence of new C-N-S metastases, significantly postponing the need for C-N-S radiation therapy [184]. Recommendation 19: Leptomeningeal Carcinomatosis (L-M---) 19a. Doctors should be highly suspicious of leptomeningeal involvement in patients with treatable oncogenic drivers who are receiving T-K-I treatment [V]. Testing of cerebrospinal fluid (C-S-F--) can diagnose leptomeningeal disease (also known as LM) but is limited by low sensitivity, although it has high specificity [IV] [A = 100%]. 19b. Patients with treatable oncogenic drivers and LM can be treated with next generation CNS-penetrant TKIs [A= 100% and III, B]. 19c. Intra CSF pharmacotherapy may be considered depending on clinical factors [A= 100% and V, C]. 20a. Stage 4 patients with one to three synchronous metastases at diagnosis may experience.

[Audio] Special article Annals of Oncology: Patients with 3 or more metastases who did not experience progression after initial systemic therapy were studied in a clinical trial (n=49). These patients were divided into two groups: one that received consolidative therapy (chemo or radiation therapy) with or without maintenance treatment, and one that received maintenance treatment alone. Results showed a significant difference in progression free survival (P-F-S--) between the two groups, with 11.9 months in the consolidative therapy group versus 3.9 months in the maintenance group (HR=0.35, p=0.005). A second phase 2 study included patients with 5 or more metastatic sites, and randomized them between receiving maintenance chemotherapy alone or stereotactic ablative radiotherapy (sabr) followed by maintenance chemotherapy (n=29). Currently, there is no published data on the impact of consolidative therapy on overall survival and long term toxicity. Patients with limited metachronous metastases of stage 4 non small cell lung cancer (N-S-C-L-C) may benefit from radical local treatment such as high dose radiation therapy or surgery, as some patients may experience long term disease free survival (D-F-S--) (IV, B). However, this is mainly based on retrospective data and there is a lack of prospective evidence for this treatment approach in patients with driver mutations who have oligoprogression on molecular targeted therapy (IV, C). Additionally, there is limited data on the safety of combining sabr with molecularly targeted agents. The European Organisation for Research and Treatment of Cancer (E-O-R-T-C) imaging group has published recommendations for the use of standard care and advanced imaging modalities in identifying and monitoring patients with oligometastatic disease (O-M-D--) [269]. In cases of synchronous, metachronous, and oligoprogressive disease, inclusion in clinical trials is preferred due to the limited evidence available. Recommendation 21: Bone Metastases 21a. The use of zoledronic acid reduces skeletal related events (S-R-Es) such as pathological fractures, radiation therapy or surgery to bone, and spinal cord compression. It is recommended for stage 4 bone metastatic disease (A=100% and II, B). 21b. In lung cancer patients, denosumab has shown a trend towards being more effective than zoledronic acid in preventing S-R-Es (A=100% and II). 21c. In cases of uncomplicated painful bone metastases, single fraction E-B-R-T is the recommended treatment based on its non inferiority to multiple fraction RT [A = 100% and I, A]. The treatment of distant metastases with surgery or high dose RT [257] is also an option. However, most published clinical trials on local treatment for O-M-D in N-S-C-L-C patients have only included those with 5 or fewer metastases. Furthermore, the majority of these trials have included patients with 3 or fewer metastases, and in an individual patient meta analysis, almost 90% of patients had a single metastasis [257]. Some studies have also limited the number of organs in which these metastases are present [258]. Oligometastases can be either synchronous or metachronous [259], and their biology may differ. It has been suggested that patients with metachronous oligometastases have a better prognosis [257]. In patients receiving systemic therapy (mainly in tumors with driver mutations treated with TKIs), the term oligoprogression can also be used to describe the progression of a limited number of metastatic lesions while all other lesions remain stable. The specific approach to treating oligometastases in the brain has been discussed above (recommendation 18). However, another subgroup that requires discussion is patients with a solitary lesion in the contralateral lung. The International Association for the Study of Lung Cancer (I-A-S-L-C) Staging and Prognostic Factors Committee conducted a systematic literature review to distinguish between a second primary tumor and a metastasis in patients with multiple pulmonary nodules [86]. This review concluded that few features are definitive, with many commonly used factors being.

[Audio] The Annals of Oncology published a special article about one trial, which showed a decrease in aggressive treatment and an improvement in overall survival [277]. Recommendation 24 advises close follow up every 6-12 weeks for patients with stage 4 non small cell lung cancer (N-S-C-L-C), in order to start second line therapy early. However, this recommendation should be based on individual treatment options [A = 100% and III, B]. It is also recommended to consider surgery in patients with N-S-C-L-C who have bone metastases or spinal cord compression [II, B] [272, 291]. In a large phase 3 trial, the medication denosumab was found to be superior to zoledronic acid in preventing skeletal related events (S-R-E) in patients with advanced solid tumors [II, B] [273, 292]. A subgroup analysis of this trial also showed improved overall survival in patients with metastatic N-S-C-L-C who were treated with denosumab [274]. Another phase 3 trial compared denosumab to zoledronic acid in patients with advanced cancers (44% of them had NSCLC) and found that denosumab delayed the occurrence of S-R-E compared to zoledronic acid. In addition, denosumab was also found to improve patients' quality of life by reducing the time period over which pain interfered with daily activities and worsening pain interference [275]. Therefore, denosumab or zoledronic acid are recommended for selected patients with advanced lung cancer and bone metastases, who have a life expectancy of more than 3 months and are at high risk for S-R-Es [I, B]. In a pre meeting survey, all 12 Asian experts agreed with and fully accepted recommendation 24. Due to the aggressive nature of this disease, it is generally recommended to have close follow up every 6-12 weeks after first line therapy in order to start second line therapy early, but this should also depend on individual treatment options [III, B]. In conclusion, recommendation 22 states that minimally invasive procedures, such as endoscopy debulking using laser, cryotherapy, or stent placement, may be beneficial for patients with stage 4 N-S-C-L-C who have symptomatic major airway obstruction or post obstructive infection [A = 100% and III]. 22b. Endoscopy is often used for both diagnosis and treatment in cases of haemoptysis, with the option of endobronchial treatment or the use of endovascular embolization to guide the procedure. This has been proven to be a successful method with a success rate of 100% and is recommended by experts. 22c. In cases of superior vena cava compression caused by non small cell lung cancer (N-S-C-L-C), vascular stenting may be beneficial. Again, this has a success rate of 100% and is recommended by experts at a level of II, B. All 12 Asian experts who were surveyed before the meeting in Guangzhou unanimously agreed and accepted the recommendations 22a c. Endoscopy also has a role in palliative care, specifically in cases where there is obstruction in the major airways causing symptoms or post obstructive infection. In such cases, endoscopic treatment using techniques such as laser, cryotherapy, or stent placement can be helpful. This recommendation is at a level of III, C and is supported by research [23]. Endoscopy is also useful for diagnosing and treating haemoptysis, whether it be through an endobronchial approach or guiding endovascular embolization. This is a level of III, C recommendation. Vascular stenting is also recommended for cases of NSCLC-related superior vena cava compression, with a level of III, B [23]. Recommendation 23: Palliative care for patients with stage 4 non small cell lung cancer. The results of voting by Asian experts before and after the face to face meeting in Guangzhou showed strong agreement (see supplementary Table S1-S13, available online at Annals of Oncology) with the 2016 E-S-M-O Clinical.

[Audio] Special Article: Annals of Oncology Funding All costs associated with this consensus conference were covered by the C-T-O-N-G and C-S-C-O from designated funds, with no grant number applicable. There was no external funding for the event or the production of this manuscript. The following companies have been reported to have interests in the topic of this article: AstraZeneca, Takeda Oncology, Blueprint Medicines, and Hansoh Pharmaceuticals. NY has received consultancy fees from Chugai, AstraZeneca, Boehringer Ingelheim, M-S-D-, Ono, Bristol Myers Squibb, Eli Lilly, Taiho, Takeda, Pfizer, Novartis, and ThermoFisher Scientific, and research funding from Chugai, Boehringer Ingelheim, M-S-D-, Ono, Eli Lilly, Taiho, Takeda, Pfizer, Novartis, and ThermoFisher Scientific. J-W-C-C-, J-Y-D, D-W-K, and HS have declared no conflicts of interest. Disclosure References: 1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65(2): 87–108. 2. Pakzad R, Mohammadian Hafshejani A, Ghoncheh M, et al. The incidence and mortality of lung cancer and their relationship to development in Asia. Transl Lung Cancer Res 2015; 4(6): 763–774. 3. World Cancer Report. iarc2018/wcr.php (accessed November 2018). 4. I-A-R-C. Cancer incidence, mortality and prevalence worldwide. GLOBOCAN 2012. iarc (accessed September 2018). 5. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(16): 394–424. 6. IASLC 2015 Statement on Tobacco Control and Smoking Cessation in Edition; iaslcfiles/wysiwygassets/News/iaslc_2015_tobacco_statement_long.pdf (accessed 7 September 2015). 7. Li Q, Hsia J, Yang G. Prevalence of smoking in China in 2010. N Engl J Med 2011; 364(25): 2469–2470. 8. Koplan J, Eriksen M. Smoking cessation for Chinese men and prevention for women. Lancet 2015; 386(10002): 1422–1423. 9. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2). 115–132. 10. Park JY, Jang SH. Epidemiology of lung cancer in Korea: recent trends. Tuberc Respir Dis (Seoul) 2016; 79(2): 58–69. 11. Foundation for the Promotion of Cancer Research; Cancer Statistics in Japan 2015. ganjoho cancer_statistics_2015.pdf201 (September 2018, date last accessed). 115–132. 10. Park JY, Jang SH. Epidemiology of lung cancer in Korea: recent trends. Tuberculosis and Respiratory Diseases (Seoul) 2016; 79(2): 58–69. 11. Foundation for the Promotion of Cancer Research; Cancer Statistics in Japan 2015. Retrieved from http://ganjoho.or.jp/en/professional/statistics/ cancer_statistics_2015.pdf201 (accessed September 2018). 12. Eldridge L The Japanese lung cancer smoking paradox. Verywell health 2018; verywellhealth.com/smoking paradox-2248990 (accessed November 2018). 13. Funatogawa I, Funatogawa T, Yano E Trends in smoking and lung cancer mortality in Japan, by birth cohort, 1949-2010. Bulletin of the World Health Organization 2013; 91(5): 332–340. 14. Nakaji S, Yoshioka Y, Mashiko T and others Explanations for the smoking paradox in Japan. European Journal of Epidemiology 2003; 18(5): 381–383. 15. Planchard D, Besse B Lung cancer in never smokers. European Respiratory Journal 2015; 45(5): 1214–1217. 16. Wakelee HA, Chang ET, Gomez SL and others Lung cancer incidence in never smokers. Journal of Clinical Oncology 2007; 25(5): 472–478. 17. Toh CK, Gao F, Lim WT and others Never smokers with lung cancer: epidemiologic evidence of a distinct disease entity. Journal of Clinical Oncology 2006; 24(15): 2245–2251. 18. Kang H, Park C-W, Kim W and others Never smoker lung cancer is increasing. Journal of Lung Cancer 2012; 11(2): 89–93. 19. Couraud S, Souquet PJ, Paris C and others BioCAST/IFCT-1002: epidemiological and molecular features of lung cancer in never smokers. European Respiratory Journal 2015; 45(5): 1403–1414. 20. Ha SY, Choi SJ, Cho JH and others Lung cancer in never smoker Asian females is driven by oncogenic mutations, most often involving E-G-F-R (epidermal growth factor receptor). Oncotarget 2015; 6(7): 5465–5474. 21. Society J-L-C-. Lung Cancer Practice Guidelines Version 1.1; www.haigan.gr.jp/modules/guideline/index.php?content_id=3 2017 (accessed October 2018). 22. Zhou Q, Wu YL. Developing China specific lung cancer practice guidelines stratified by resource availability and treatment value. Journal of Global Oncology 2017; 3(4): 285–288. AA reports fees for consultancy from Boehringer.

[Audio] Annals of Oncology Special Article 23. Novello S, Barlesi F, Califano R and others. Metastatic non small cell lung cancer: E-S-M-O Clinical Practice Guidelines for diagnosis, treatment, and follow up. Ann Oncol 2016; 27(Suppl 5): v1-v27. 24. Planchard D, Popat S, Kerr K and others. Metastatic non small cell lung cancer: E-S-M-O clinical practice guidelines for diagnosis, treatment, and follow up. Ann Oncol 2018; 29: iv192-iv237. 25. Yoshino T, Arnold D, Taniguchi H and others. Pan Asian adapted E-S-M-O consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by C-S-C--, kaco, M-O-S--, S-S-O--, and T-O-S--. Ann Oncol 2018; 29(1): 44-70. 26. Dykewicz CA. Centers for Disease Control and Prevention, Infectious Diseases Society of America, American Society of Blood and Marrow Transplantation. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139-144. 27. Forrest LM, McMillan DC, McArdle CS, Dunlop DJ. An evaluation of the impact of a multidisciplinary team, in a single centre, on treatment and survival in patients with inoperable non small cell lung cancer. Br J Cancer 2005; 93(9): 977-978. 28. Freeman RK, Van Woerkom JM, Vyverberg A, Ascioti AJ. The effect of a multidisciplinary thoracic malignancy conference on the treatment of patients with lung cancer. Eur J Cardiothorac Surg 2010; 38(1): 1-5. 29. Protack CD, Blasberg JD, Liu J and others. The impact of decreasing variability in surgical care through a structured multidisciplinary thoracic oncology program. J Clin Pathways 2017; 3: 40-45. 30. Schmidt HM, Roberts JM, Bodnar AM and others. Thoracic multidisciplinary tumor board routinely impacts therapeutic plans in patients with lung and esophageal cancer: a prospective cohort study. Ann Thorac Surg 2015; 99(5): 1719-1724. 31. Ost DE, Ernst A, Lei 10 and others. Diagnostic yield and complications of bronchoscopy for peripheral lung lesions. Results from the AQuIRE Registry were published in the American Journal of Respiratory and Critical Care Medicine in 2016. The study found that bronchial washing during bronchoscopy for pulmonary malignant tumors was both timely and cost effective. Another study compared conventional and endobronchial ultrasound guided transbronchial needle aspiration methods and found that the latter had higher success rates. Endobronchial ultrasound guided biopsy was also found to be effective in the diagnosis of peripheral lung lesions. A systematic review and meta analysis showed that both endobronchial ultrasound and transbronchial needle aspiration were accurate in mediastinal staging for lung cancer patients. The use of an A-L-K inhibitor was successful in treating lung cancer in patients with the fusion gene EML4-ALK, detected through endobronchial ultrasound guided transbronchial needle aspiration. This method was also used for multigene mutation analysis of metastatic lymph nodes in non small cell lung cancer. Thoracic cytology was found to be a suitable method for identifying treatment options for non small cell lung carcinoma, with accurate tumor subtyping and feasibility for molecular testing. The study also assessed the EML4-ALK fusion gene using metastatic lymph node samples obtained through endobronchial ultrasound guided transbronchial needle aspiration. Clin Cancer Res 2010; 16(20): 4938–4945. 41. Chan EY, Gaur P, Ge Y and others. Management of the solitary pulmonary nodule. Arch Pathol Lab Med 2017; 141(7): 927–931. 42. Choi SH, Chae EJ, Kim JE and others. Percutaneous CT-guided aspiration and core biopsy of pulmonary nodules smaller than 1 cm: analysis of outcomes of 305 procedures from a tertiary referral center. A-J-R Am J Roentgenol 2013; 201(5): 964–970. 43. Fontaine Delaruelle C, Souquet PJ, Gamondes D and others. Negative predictive value of transthoracic core needle biopsy: a multicenter study. Chest 2015; 148(2): 472–480. 44. Lee SM, Park CM, Lee KH and others. C-arm cone beam CT-guided percutaneous transthoracic needle biopsy of lung nodules: clinical experience in 1108 patients. Radiology 2014; 271(1): 291–300. 45. Takeshita J, Masago K,.

[Audio] Special Article in Annals of Oncology 59. Mok T, Wu YL, Lee JS, and others. Detection and Dynamic Changes of E-G-F-R Mutations from Circulating Tumor D-N-A as a Predictor of Survival Outcomes in N-S-C-L-C Patients Treated with First line Intercalated Erlotinib and Chemotherapy. Clinical Cancer Research, 2015; 21(14), 3196-3203. 60. van der Wekken AJ, Pelgrim RT, Hart N, and others. Dichotomous ALK-IHC is a Better Predictor for A-L-K Inhibition Outcome than Traditional ALKFISH in Advanced Non Small Cell Lung Cancer. Clinical Cancer Research, 2017; 23(15), 4251-4258. 61. Gainor JF, Dardaei L, Yoda S, and others. Molecular Mechanisms of Resistance to First and Second Generation A-L-K Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discovery, 2016; 6(10), 1118-1133. 62. Chen YF, Hsieh MS, Wu SG, and others. Clinical and Prognostic Characteristics of Lung Adenocarcinoma Patients with ros1 Fusion in Comparison with Other Driver Mutations in East Asian Populations. Journal of Thoracic Oncology, 2014; 9(8), 1171-1179. 63. Wu YL, Yang JC-H, Kim D-W, and others. Phase 2 Study of Crizotinib in East Asian Patients with ros1-Positive Advanced Non Small Cell Lung Cancer. Journal of Clinical Oncology, 2018; 36(14), 1405-1411. 64. Reck M, Rodriguez Abreu D, Robinson AG, and others. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non Small Cell Lung Cancer. New England Journal of Medicine, 2016; 375(19), 1823-1833. 65. Lopes G, Wu Y-L, Kudaba I, and others. Pembrolizumab (pembro) versus Platinum Based Chemotherapy (chemo) as First Line Therapy for Advanced/Metastatic N-S-C-L-C with PD-L1 Tumor Proportion Score (T-P-S--) ≥1%: Open Label, Phase 3 keynote-042 Study. Journal of Clinical Oncology, 2018; 36(Suppl 18), LBA-4. 66. Kerr KM, Hirsch FR. Programmed Death Ligand-1 Immunohistochemistry: Friend or Foe? Archives of Pathology and Laboratory Medicine, 2016; 140(4), 326-331. 67. Hirsch FR, McElhinny A, Stanforth D, and others. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 I-H-C Assay Comparison Project. Journal of Thoracic Oncology, 2017; 12(2), 208-222. 68. Ratcliffe MJ, Sharpe A, Midha A, and others. Agreement between Programmed Cell Death Ligand-1 Diagnostic Assays Across Multiple Protein Expression Cutoffs in Non Small Cell Lung Cancer. Clin Cancer Res 2017; 23(14): 3585-3591. 69. Rimm DL, Han G, Taube JM, and others. A prospective, multi institutional, pathologist based assessment of four immunohistochemistry assays for PD-L1 expression in non small cell lung cancer. jama Oncol 2017; 3(8): 1051-1058. 70. Adam J, Le Stang N, Rouquette I, and others. Multicenter French harmonization study for PD-L1 I-H-C testing in non small cell lung cancer. Ann Oncol 2018; 29(4): 953-958. 71. Soo RA, Lim SM, Syn NL, and others. Immune checkpoint inhibitors in epidermal growth factor receptor mutant non small cell lung cancer: current controversies and future directions. Lung Cancer 2018; 115: 12-20. 72. Chen N, Fang W, Zhan J, and others. Upregulation of PD-L1 by E-G-F-R activation mediates immune escape in EGFR-driven NSCLC: implications for potential immune targeted therapy for N-S-C-L-C patients with E-G-F-R mutation. J Thorac Oncol 2015; 10(6): 910-923. 73. Han JJ, Kim DW, Koh J, and others. Change in PD-L1 expression after acquiring resistance to gefitinib in EGFR-mutant non small cell lung cancer. Clin Lung Cancer 2016; 17: 263-270.e2. 74. Liu SY, Dong ZY, Wu SP, and others. Clinical relevance of PD-L1 expression and CD8+ T cell infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer. Lung Cancer 2018; 125: 86-92. 75. Dong ZY, Zhong WZ, Zhang X, and others. Potential predictive value of T-P-5-3 and K-R-A-S mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res 2017; 23(12): 3012-3024. 76. Hellmann MD, Ciuleanu TE, Pluzanski A, and others. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378(22): 2093-2104. 77. Carbone DP, Reck M, Paz Ares L, and others. First line nivolumab in stage 4 or recurrent non small cell lung cancer. N Engl J Med 2017; 376(25): 2415-2426. 78. Rizvi H, Sanchez Vega.

[Audio] The Annals of Oncology has published a special article regarding the use of pemetrexed and platinum as a first line option for treating advanced non small cell lung cancer. This article, written by Li M, Zhang Q, Fu P, and others, is a meta analysis of randomized controlled trials and was published in PLoS One in 2012. In a phase 3 study conducted by Scagliotti GV, Parikh P, von Pawel J, and others, the effectiveness of cisplatin plus gemcitabine was compared to cisplatin plus pemetrexed in patients with advanced non small cell lung cancer who had not received chemotherapy before. The study, published in the Journal of Clinical Oncology in 2008, showed that both treatments were similarly effective. Another phase 3 study, led by Ciuleanu T, Brodowicz T, Zielinski C, and others, compared maintenance treatment with pemetrexed and best supportive care to placebo and best supportive care in patients with non small cell lung cancer. The study, published in the Lancet in 2009, showed that pemetrexed was more effective in prolonging overall survival. The effectiveness of pemetrexed was also studied in relation to non small cell lung cancer histology. In 2009, Scagliotti G, Hanna N, Fossella F, and others published a review of two phase 3 studies showing that pemetrexed was more effective in treating non small cell lung cancer with certain histologies. In a phase 3 trial published in the Journal of Clinical Oncology in 2012, Socinski MA, Bondarenko I, Karaseva NA, and others compared weekly nab paclitaxel with carboplatin to solvent based paclitaxel plus carboplatin as a first line therapy for advanced non small cell lung cancer. The final results showed that nab paclitaxel was more effective. A randomized, controlled phase 3 study called INSPIRE, led by Paz Ares L, Mezger J, Ciuleanu TE, and others, examined the use of necitumumab in combination with pemetrexed and cisplatin as a first line therapy for stage 4 non squamous non small cell lung cancer. Published in the Lancet Oncology in 2015, the study showed promising results. The correlation between E-G-F-R expression and outcomes was studied in a phase 3 study called SQUIRE, in which patients with stage 4 squamous non small cell lung cancer were treated with either gemcitabine and cisplatin or gemcitabine, cisplatin, and necitumumab. This open label, multicenter study, published in the Annals of Oncology in 2016, showed that E-G-F-R expression was associated with safety and efficacy outcomes. Finally, Thatcher N, Hirsch FR, Luft AV, and others conducted a phase 3 study comparing necitumumab plus gemcitabine and cisplatin to gemcitabine and cisplatin alone as a first line therapy for stage 4 squamous non small cell lung cancer. The results, published in the Annals of Oncology, showed that the addition of necitumumab improved survival rates. An open label, randomized, controlled phase 3 trial was conducted and published in Lancet Oncology in 2015. The study, conducted by Sandler et al, evaluated the effectiveness of paclitaxel carboplatin with or without bevacizumab for treating non small cell lung cancer. This study was followed by a similar study conducted by Zhou et al, which evaluated the use of carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent non squamous non small cell lung cancer. A systematic review and meta analysis conducted by Lima et al in 2011 found that adding bevacizumab to chemotherapy for advanced non small cell lung cancer had positive results. Soria et al conducted a similar review and meta analysis in 2013, which focused on adding bevacizumab to platinum based chemotherapy as first line treatment for advanced non small cell lung cancer. Another maintenance treatment option studied was erlotinib, which was evaluated in a multicenter,.

[Audio] Special article in the Annals of Oncology 132. Paz Ares LG, de Marinis F, Dediu M and others paramount: final overall survival results of the phase 3 study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced non squamous non small cell lung cancer. J-C-O 2013; 31(23): 2895–2902. 133. Barlesi F, Scherpereel A, Rittmeyer A and others: Randomized phase 3 trial of maintenance bevacizumab with or without pemetrexed after first line induction with bevacizumab, cisplatin, and pemetrexed in advanced non squamous non small cell lung cancer: aVAPERL (MO22089). J Clin Oncol 2013; 31(24): 3004–3011. 134. Barlesi F, Scherpereel A, Gorbunova 5 and others: Maintenance bevacizumab pemetrexed after first line cisplatin pemetrexed bevacizumab for advanced non squamous non small cell lung cancer: updated survival analysis of the avaperl (MO22089) randomized phase 3 trial. Ann Oncol 2014; 25(5): 1044–1052. 135. Patel JD, Socinski MA, Garon EB and others: PointBreak: a randomized phase 3 study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage III-B or 4 non squamous non small cell lung cancer. J Clin Oncol 2013; 31(34): 4349–4357. 136. Pe´rol M, Chouaid C, Pe´rol D and others: Randomized, phase 3 study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second line treatment, after cisplatin gemcitabine induction chemotherapy in advanced non small cell lung cancer. J Clin Oncol 2012; 30: 3516–3524. 137. Gridelli C, Ardizzoni A, Le CT and others: Treatment of advanced non small cell lung cancer patients with E-C-O-G performance status 2: results of a European Experts Panel. Ann Oncol 2004; 15(3): 419–426. 138. Quoix E, Zalcman G, Oster JP and others: Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non small cell lung cancer. iFCT-0501 is a randomised, phase 3 trial published in Lancet in 2011. The study (139) by Bronte et al. investigates the potential of platinum based treatment for patients with advanced non small cell lung cancer (P-S-2 N-S-C-L-C) through a systematic review and meta analysis. In 2013, Zukin et al. (140) compare the efficacy of single agent pemetrexed versus combination carboplatin and pemetrexed in patients with advanced non small cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. The results are published in the Journal of Clinical Oncology. The Multicenter Italian Lung Cancer in the Elderly Study (M-I-L-E-S) phase 3 randomized trial by Gridelli et al. (141) in 2003 evaluates chemotherapy for elderly patients with advanced non small cell lung cancer. The study is published in the Journal of the National Cancer Institute. A 2017 study by Spigel et al. (142) in J Thorac Oncol examines the safety and effectiveness of nivolumab in elderly and P-S-2 patients with non small cell lung cancer through the CheckMate 153 trial. Popat et al. (143) presents results from CheckMate 171, a single arm, phase 2 trial in European patients with metastatic squamous non small cell lung cancer, including those aged 70 years and with poor performance status. In 2006, Kudoh et al. (144) publish results from a phase 3 study comparing docetaxel and vinorelbine in elderly patients with advanced non small cell lung cancer through the West Japan Thoracic Oncology Group Trial (WJTOG 9904). A Cochrane systematic review by Santos et al. (145) in 2015 evaluates chemotherapy for advanced non small cell lung cancer in the elderly population. In 2007, Extermann et al. (146) discusses the use of comprehensive geriatric assessment for the management of older patients with cancer. Finally, in their 2017 study (147), Corre et al. examine the use of comprehensive.

[Audio] This text is a compilation of several medical studies and trials related to the treatment of advanced non small cell lung cancer. It includes information on various treatments, such as chemotherapy and epidermal growth factor receptor (E-G-F-R) inhibitors, and their effectiveness in patients with wild type E-G-F-R tumors. The studies referenced in this text include clinical trials comparing different treatments, as well as metaanalyses of multiple trials. The text also touches upon the role of E-G-F-R mutations in determining the response to certain treatments, and includes information on specific drugs, such as gefitinib and erlotinib. Overall, the text provides valuable information for medical professionals working with patients with advanced non small cell lung cancer. 361(10): 947–957. 174. Rosell R, Carcereny E, Gervais R and others conducted a study, known as the EURTAC trial, to compare the effectiveness of erlotinib versus standard chemotherapy as the first line treatment for European patients with advanced non small cell lung cancer (N-S-C-L-C) that have a mutated epidermal growth factor receptor (E-G-F-R-). This multicentre, open label, randomised phase 3 trial was published in the Lancet Oncology journal in 2012 and showed that erlotinib was more effective in this patient population, with a longer progression free survival rate. 175. Another phase 3 study, led by Sequist LV, Yang JC, Yamamoto N and others, compared afatinib versus a combination of cisplatin and pemetrexed in patients with metastatic lung adenocarcinoma also harbouring E-G-F-R mutations. The study, published in the Journal of Clinical Oncology in 2013, showed that afatinib was more effective in terms of progression free survival. 176. Wu YL, Zhou C, Hu CP and others conducted a phase 3 trial, known as the LUX-Lung 6 trial, to compare afatinib versus a combination of cisplatin and gemcitabine as the first line treatment for Asian patients with advanced N-S-C-L-C also harbouring E-G-F-R mutations. This open label, randomised trial was published in the Lancet Oncology journal in 2014 and showed that afatinib was more effective in terms of progression free survival. 177. Inoue A, Kobayashi K, Usui K and others conducted a study in 2009, published in the Journal of Clinical Oncology, which showed that first line treatment with gefitinib is effective for patients with advanced N-S-C-L-C harbouring E-G-F-R mutations who are not eligible for chemotherapy. 178. The ASPIRATION study, published in jama Oncology in 2016, evaluated the effectiveness of first line treatment with erlotinib in Asian patients with EGFR-mutated NSCLC. The study showed that continuous treatment with erlotinib, even beyond the point of disease progression, led to improved outcomes in terms of overall survival. 179. Yang JJ, Chen HJ, Yan HH and others conducted a study on the different patterns of failure in patients treated with E-G-F-R tyrosine kinase inhibitors and the subsequent management strategies for advanced NSCLC. The study, published in Lung Cancer in 2013, showed that different patterns of failure may require different treatment approaches. 180. Lim SW, Park S, Kim Y and others conducted a phase 2 trial to evaluate the effectiveness of continuing treatment with gefitinib beyond disease progression in patients with EGFR-mutated NSCLC. The study, published in Lung Cancer in 2018, showed that this approach may benefit patients by improving their progression free survival. 181. Finally, a phase 3 randomised trial, known as IMPRESS, compared the effectiveness of adding chemotherapy to continued treatment with gefitinib versus placebo in patients with EGFR-mutated N-S-C-L-C after progression on first line gefitinib. The results, published in the Lancet Oncology in 2015, showed that adding chemotherapy did not provide any additional benefits. 16(8): 990–998. 182. Park K, Tan EH, O’Byrne K and others compared the effectiveness of afatinib and gefitinib as first line treatments for patients with E-G-F-R mutation positive non.

[Audio] Special Article: Annals of Oncology 199. Soria JC, Tan D-S-W--, Chiari R, and others. First line ceritinib versus platinum based chemotherapy in advanced ALK-rearranged non small cell lung cancer (ASCEND-4): a randomized, open label, phase 3 study. Lancet, 2017; 389(10072): 917-929. 200. Hida T, Nokihara H, Kondo M, and others. Alectinib versus crizotinib in patients with ALK-positive non small cell lung cancer (J-ALEX): an open label, randomized, phase 3 trial. Lancet, 2017; 390(10089): 29-39. 201. Camidge DR, Peters S, Mok T, and others. Updated efficacy and safety data from the global phase 3 alex study of alectinib (A-L-C--) versus crizotinib (C-Z---) in untreated advanced ALK+ NSCLC. JCO, 2018; 36, Abstr 9043. 202. Peters S, Camidge DR, Shaw AT, and others. Alectinib versus crizotinib in untreated ALK-positive non small cell lung cancer. N Engl J Med, 2017; 377(9): 829-838. 203. Camidge DR, Kim HR, Ahn MJ, and others. Brigatinib versus crizotinib in ALK-positive non small cell lung cancer. N Engl J Med, 2018. 204. Shaw AT, Kim DW, Nakagawa K, and others. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med, 2013; 368(25): 2385-2394. 205. Shaw AT, Kim TM, Crino L, and others. Ceritinib versus chemotherapy in patients with ALK-rearranged non small cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomized, controlled, open label, phase 3 trial. Lancet Oncol, 2017; 18(7): 874-886. 206. Novello S, Mazieres J, Oh IJ, and others. 1299O_PR: Primary results from the phase 3 alur study of alectinib versus chemotherapy in previously treated ALK+ non small cell lung cancer (N-S-C-L-C). Ann Oncol, 2017; 28(Suppl 5): mdx440.058. 207. Kim DW, Tiseo M, Ahn MJ, and others. Brigatinib in patients with crizotinib refractory anaplastic lymphoma kinase positive non small cell lung cancer: a randomized, multicenter, phase 2 trial. JCO, 2017; 35(22): 2490-2498. 208. Shaw AT, Felip E, Bauer TM, and others. Lorlatinib in non small cell lung cancer with A-L-K or ros1 rearrangement. An international phase 1 trial, with multiple centers, open label, single arm, is the first to be conducted on humans. Published in Lancet Oncology 2017; 18(12): 1590–1599. 209. Lin JJ, Zhu VW, Schoenfeld AJ and others studied the effects of Brigatinib on patients with ALK-positive N-S-C-L-C who were resistant to alectinib treatment. Their findings were published in the Journal of Thoracic Oncology 2018; 13(10): 1530–1538. 210. Shaw A, Martini JF, Bauer T and others presented data on the effectiveness of lorlatinib in patients with advanced ALK-positive N-S-C-L-C with A-L-K kinase domain mutations at the American Association for Cancer Research Meeting, Chicago, U.S.A. The results were published in Cancer Research 2018; 78(13) (Suppl). 211. Yoda S, Lin JJ, Lawrence MS and others conducted a study on the sequential use of A-L-K inhibitors which showed that it can lead to the development of lorlatinib resistant mutations in ALK-positive lung cancer. Their findings were published in Cancer Discovery 2018; 8(6): 714–729. 212. Shaw AT, Ou SH, Bang YJ and others conducted a study on the use of crizotinib in patients with ros1-rearranged NSCLC. The results were published in the New England Journal of Medicine 2014; 371(21): 1963–1971. 213. Moro Sibilot D, Faivre L, Zalcman G and others conducted a phase 2 trial on crizotinib in patients with advanced ros1-rearranged NSCLC. Their preliminary results were published in the Journal of Clinical Oncology 2015; 33: 8065–8065. 214. Mazieres J, Zalcman G, Crino L and others studied the use of crizotinib in patients with advanced lung adenocarcinoma and a ros1 rearrangement. Their results were published in the EUROS1 cohort in the Journal of Clinical Oncology 2015; 33(9): 992–999. 215. Goto K, Yang JC-H, Kim D-W and others conducted a phase 2 study on crizotinib in East Asian patients with ros1-positive advanced NSCLC. The results were published.

[Audio] Annals of Oncology publishes a special article on the treatment of brain metastases. The article discusses the results of various clinical trials, including a randomized trial comparing postoperative radiotherapy with and without whole brain radiation therapy, a controlled trial comparing stereotactic radiosurgery plus whole brain radiation therapy to stereotactic radiosurgery alone, and a study comparing adjuvant whole brain radiotherapy to observation. Other studies reviewed in this article include a meta analysis of phase 3 trials on stereotactic radiosurgery with or without whole brain radiation therapy, a phase 2 trial on hypofractionated stereotactic radiotherapy, and a Cochrane database review on whole brain radiation therapy versus both whole brain radiation therapy and radiosurgery. Additionally, the article discusses the results of a single center, randomized, controlled, phase 3 trial comparing post operative stereotactic radiosurgery to observation, and a multi institutional observational study on stereotactic radiosurgery for patients with multiple brain metastases. Another trial discussed in the article compares stereotactic radiosurgery to observation for patients with asymptomatic cerebral oligo metastases in non small cell lung cancer. Annals of Oncology 2015; 26(4): 762–768. 247. Robinet G, Thomas P, Breton JL, and others. Results of a phase 3 study comparing early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastases of non small cell lung cancer: Groupe Francais de Pneumo Cancerologie (G-F-P-C-) Protocol 95-1. Annals of Oncology 2001; 12(1): 59–67. 248. Yang JJ, Zhou C, Huang Y, and others. Icotinib versus whole brain irradiation in patients with EGFR-mutant non small cell lung cancer and multiple brain metastases (B-R-A-I-N): a multicentre, phase 3, open label, parallel, randomized controlled trial. Lancet Respiratory Medicine 2017; 5(9): 707–716. 249. Goldberg SB, Gettinger SN, Mahajan A, and others. Pembrolizumab for patients with melanoma or non small cell lung cancer and untreated brain metastases: early analysis of a non randomized, open label, phase 2 trial. Lancet Oncology 2016; 17(7): 976–983. 250. Baik CS, Chamberlain MC, Chow LQ. Targeted therapy for brain metastases in EGFR-mutated and ALK-rearranged non small cell lung cancer. Journal of Thoracic Oncology 2015; 10(9): 1268–1278. 251. Rangachari D, Yamaguchi N, VanderLaan PA, and others. Brain metastases in patients with EGFR-mutated or ALK-rearranged non small cell lung cancers. Lung Cancer 2015; 88(1): 108–111. 252. Nayar G, Ejikeme T, Chongsathidkiet P, and others. Leptomeningeal disease: current diagnostic and therapeutic strategies. Oncotarget 2017; 8(73312–73328). 253. Morin Ben Abdallah S, Wong A. Brain metastases in non small cell lung cancer: are tyrosine kinase inhibitors and checkpoint inhibitors now viable options? Current Oncology 2018; 25: 103–S114. 254. Schuler M, Wu YL, Hirsh S, and others. First line afatinib versus chemotherapy in patients with non small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. Journal of Thoracic Oncology 2016; 11(3): 380–390. 255. Besse B, Le Moulec S, Mazieres J, and others. Bevacizumab in patients with non squamous non small cell lung cancer and asymptomatic brain metastases: a phase 2 trial. Annals of Oncology 2010; 21(11): 2335–2342. Untreated brain metastases (B-R-A-I-N): a non randomized, phase 2 study. Clinical Cancer Research 2015; 21(8): 1896–1903. 256. Zimmermann S, Dziadziuszko R, Peters S. Indications and limitations of chemotherapy and targeted agents in non small cell lung cancer brain metastases. Cancer Treatment Reviews 2014; 40(6): 716–722. 257. Ashworth AB, Senan S, Palma DA and others. An individual patient data meta analysis of outcomes and prognostic factors after treatment of oligometastatic non small cell lung cancer. Clinical Lung Cancer 2014; 15(5): 346–355. 258. Hellman S, Weichselbaum RR. Oligometastases. Journal of Clinical Oncology 1995; 13(1): 8–10. 259. Kozower BD, Larner JM, Detterbeck FC, Jones DR. Special treatment issues in non small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of.

[Audio] Specially Featured Article: Annals of Oncology 277. Temel JS, Greer JA, El Jawahri A and others' Effects of early integrated palliative care on patients with lung and gastrointestinal cancer: a randomized clinical trial. JCO 2017; 35(8): 834–841. 278. Cherny NI, Dafni U, Bogaerts J and others' ESMO-Magnitude of Clinical Benefit Scale version 1.1. Ann Oncol 2017; 28(10): 2340–2366. 279. Dafni U, Karlis D, Pedeli 10 and others' Detailed statistical assessment of the characteristics of the E-S-M-O Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules. E-S-M-O Open 2017; 2(4): e000216. versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 2012; 7(12): 1823–1829. 275. Henry D, Vadhan Raj S, Hirsh 5 and others' Delaying skeletal related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer 2014; 22(3): 679–687. 276. Temel JS, Greer JA, Muzikansky A and others' Early palliative care for patients with metastatic non small cell lung cancer. N Engl J Med 2010; 363(8): 733–742. 210 | Wu and others Volume 30 | Issue 2 | 2019.