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Objectives: Canakinumab, an interleukin-1 beta inhibitor, previously showed reduced lung cancer incidence and mortality (CANTOS). Here, we compare the efficacy/safety of canakinumab versus placebo in patients with advanced non-small cell lung cancer (NSCLC) who had progressed after platinum-based doublet chemotherapy (PDC) and immunotherapy., Materials and Methods: CANOPY-2, a randomized, double-blind, phase 3 trial, enrolled adult patients with stage IIIB/IV NSCLC, without EGFR or ALK alterations, who had received one prior PDC regimen and one prior programmed death-1/programmed death-ligand 1 inhibitor and experienced subsequent disease progression. Patients were randomized to canakinumab plus docetaxel or placebo plus docetaxel., Results: A total of 237 patients were randomly allocated: 120 (51 %) to canakinumab and 117 (49 %) to placebo, stratified by histology and prior lines of therapy. Three patients in the placebo arm did not receive study treatment. The trial did not meet its primary endpoint of overall survival: median 10.6 months (95 % confidence interval [CI], 8.2-12.4) for the canakinumab arm and 11.3 months (95 % CI, 8.5-13.8) for the placebo arm (hazard ratio, 1.06 [95 % CI, 0.76-1.48]; one-sided P-value = 0.633). AEs (any grade) were reported in 95 % of patients in the canakinumab group and in 98 % of patients in the placebo group. Grade 3-4 AEs were experienced by 62 % and 64 % of patients in the canakinumab and placebo groups, respectively, and grade 5 AEs were experienced by 8 % and 5 %. Prespecified, post-hoc subgroup analyses showed that patients with undetected circulating tumor DNA (ctDNA) and/or lower levels (< 10 mg/L) of C-reactive protein (CRP) achieved longer progression-free and overall survival than those with detected ctDNA or higher (≥ 10 mg/L) CRP levels. There was no association with treatment arm., Conclusion: Adding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy., Clinical Registration: NCT03626545., Competing Interests: Declaration of competing interest Luis Paz-Ares reports grants from AstraZeneca, Bristol Myers Squibb, Merck, and Pfizer; consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Janssen, Lilly, Merck, Mirati, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, and Takeda; speaker honoraria from AstraZeneca, Janssen, Merck, and Mirati; leadership roles in Altum Sequencing and Genomica, all outside the submitted work. Yasushi Goto reports clinical trial grants from AZK and Pfizer; institutional grants from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Kyorin, Novartis, Ono Pharmaceutical, and Pfizer; speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, Merck, Novartis, Ono Pharmaceutical, Pfizer, and Taiho; leadership roles in Cancer Net Japan and JAMT, all outside the submitted work. Darren Lim reports grants from Bristol Myers Squibb; speaker honoraria from Boehringer Ingelheim, Merck, and Roche; and support for attending meetings from AstraZeneca and Taiho Pharmaceuticals, all outside the submitted work. Balazs Halmos reports research funding and honoraria for steering committee work from Novartis during the conduct of the study; reports grants from AbbVie, Advaxis, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Merck, and Pfizer; consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genentech, Janssen, Merck, Pfizer, Takeda, and Veracyte; and participation in advisory board meetings for Apollomics and TPT, all outside the submitted work. Byoung Chul Cho reports research funding from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, GI Innovation, Interpark Bio Convergence Corp., Janssen, MedPacto, Merck, MOGAN Institute, Novartis, Ono Pharmaceutical, and Yuhan; royalties from Champions Oncology; consulting fees from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, MedPacto, Merck, Novartis, Ono Pharmaceutical, Pfizer, Roche, Takeda, and Yuhan; participation in advisory board meetings for Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Joseah BIO, and KANAPH Therapeutics Inc.; stock ownership of Bridgebio Therapeutics, Cyrus Therapeutics, Gencurix Inc., Interpark Bio Convergence Corp., KANAPH Therapeutics Inc., and TheraCanVac Inc.; is a board of director for Gencurix Inc. and Interpark Bio Convergence Corp.; and is a founder of DAAN Biotherapeutics, all outside the submitted work. José Luis González Larriba reports consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Janssen, and Merck; speaker honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, and Roche; and support for attending meetings from Bristol Myers Squibb, Janssen, Merck, Pfizer, Roche, and Takeda, all outside the submitted work. Caicun Zhou reports speaker honoraria from Amoy Diagnostics, Boehringer Ingelheim, C-stone, Eli Lilly, LUYE Pharma, Merck, Qilu, Roche, and Sanofi; and speaker and advisor fees from Hengrui, Innovent Biologics and TopAlliance Biosciences Inc., all outside the submitted work. Ingel Demedts reports consultancy and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck, and Roche, outside the submitted work. Jincheng Wu, David Demanse, and Bharani Dharan are Novartis employees. Bijoyesh Mookerjee, Socorro Portella, and Zewen Zhu were Novartis employees at the time the study was conducted. Martin Reck reports consulting fees, speaker honoraria and support for attending meetings from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Sanofi, and Roche; and participation in advisory board meetings for Sanofi, all outside of submitted work. Manuel Cobo, Akin Atmaca, and Sofia Baka declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival., Materials and Methods: Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS., Results: More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm., Conclusion: These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen., Clinicaltrial: gov Identifier: NCT02763579., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.V.L. declares grants or contracts from Alkermes, Bayer, Blueprint, Bristol Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics; consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/Merck Sharpe & Dohme, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; and participation on a Data Safety Monitoring or Advisory Board for Candel Therapeutics. T.S.K.M. declares consulting and advisory personal fees from AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd., geneDecode (uncompensated), Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics, Ignyta Inc., IQVIA, Incyte Corporation, Janssen, Lilly, Loxo-Oncology, Lunit USA, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., Novartis, OrigiMed, Pfizer, Inc., Puma Biotechnology Inc., Roche, Sanofi-Aventis R&D, Takeda, Yuhan Corporation, SFJ Pharmaceuticals, Curio Science, Inivata, Berry Oncology, Qiming Development (HK) Ltd., Gilead Sciences, Inc., Vertex Pharmaceuticals, and Covidien LP; lecture personal fees from ACEA Pharmaceuticals, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Fishawack Facilitate Ltd., geneDecode, (uncompensated), InMed Medical Communication, Janssen, Lilly, Lunit USA, Inc., MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharpe & Dohme, Novartis, OrigiMed, PeerVoice, Physicians’ Education Resource, P. Permanyer SL, Pfizer, Inc., PrIME Oncology, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Daz Group, Lucence Health Inc., Merck Pharmaceuticals HK Ltd., Shanghai BeBirds Translation & Consulting Co. Ltd., Liangyihui Network Technology Co. Ltd., and Taiho; grants from AstraZeneca, Bristol Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Inc., Roche, Takeda, Clovis Oncology, SFJ Pharmaceuticals, XCovery, and G1 Therapeutics Inc.; personal fees for supporting an advisory board for Inivata, Berry Therapeutics Inc., and G1 Therapeutics Inc.; shareholding for Aurora, Sanomics Ltd., Hutchison ChiMed; and a role on the Board of Directors for Lunit USA, Inc., AstraZeneca PLC, Hutchison ChiMed, Sanomics Ltd., Aurora. B.Y.N declares employment by Genentech and stockholding in Roche. A.S.M declares grants or contracts from NIH/NCI, Verily, Novartis, Department of Defense, and Mark Foundation; payment or honoraria to institution for lecture, presentations, speakers bureaus, manuscript writing or education events from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech; support for attending meetings and/or travel from Shanghai Roche Pharmaceuticals; patents planned, issues, or pending for patents submitted unrelated to this work; and other financial or non-financial interests from non-remunerated director of the Mesothelioma Applied Research Foundation. R. De Boer declares payment of honoraria from Novartis, AstraZeneca, and Gilead; and support for attending meetings and/or travel from Amgen, Novartis, and Roche. S.S. declares payment or honoraria for lectures, presentation, speakers bureaus, manuscript writing, or educations events from Chugai Pharma, AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Merck Sharpe & Dohme, Nippon Boehringer-Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, and Company, Novartis, Kyowa Kirin, Yakult Honsha, and Towa Pharmaceutical. R. Dziadziuszko declares consulting fees from Roche, Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Foundation Medicine, Novartis, and Karyopharm; and payment or honoraria from Roche, Novartis, AstraZeneca, and Pfizer. A.S. declares payment or honoraria from AstraZeneca, Bristol Myers Squibb, Roche, Merck Sharpe & Dohme, Novartis, and Pfizer; support for attending meetings and/or travel from Bristol Myers Squibb, Roche, Boehringer-Ingelheim, and AstraZeneca; and participation on data safety monitoring or advisory boards for Bristol Myers Squibb, Roche, Takeda, AstraZeneca, BIOCAD, and Boehringer-Ingelheim. M.J.H declares payment or honoraria from Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Merck Sharpe & Dohme, and Roche; and participation on data safety monitoring or advisory boards for Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Merck Sharpe & Dohme, and Roche. M.C.G. declares grants from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Amgen, GSK, Sanofi; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Janssen, Lilly, Yuhan, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Amgen, Libbs, and Sanofi; payment of honoraria from Boehringer-Ingelheim, Pfizer, Bayer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, Merck Serono, Janssen, and Amgen; support for attending meetings and/or travel from Boehringer-Ingelheim, Pfizer, Bayer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, and Merck Serono; participation on data safety monitoring or advisory boards for TEVA, Boehringer-Ingelheim, Bayer, Pfizer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Yuhan, Janssen, Merck Serono, Novartis, Amgen; and payment of honoraria for promotional activities from Boehringer-Ingelheim, Pfizer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, TEVA, Amgen, and Janssen. C.M.G. declares research grants/funding to self from AstraZeneca; advisory/consultancy to AstraZeneca, Kisoji Biotechnology, Jazz Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau/expert testimony for AstraZeneca and BeiGene. J.V.H declares advisory/consultancy for Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, and Mirati Therapeutics; research support to AstraZeneca, GlaxoSmithKline, and Spectrum; and royalties/licensing fees from Spectrum. L.A.B. declares an advisory role/consultancy for AstraZeneca, AbbVie, Bristol Myers Squibb, and Merck; and research funding from AstraZeneca and AbbVie. S.L. declares employment by Genentech and stockholding in Roche. A.C. declares employment by Roche and stockholding in Roche. S.M. declares employment by Roche and stockholding in Roche. L.A. declares employment by Roche and stockholding in Roche. D.S.S. declares employment by Genentech and stockholding in Roche. M.R. declares consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; payment of honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; support for attending meetings and/or travel from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; and participation on data safety monitoring or advisory boards for DSMB Sanofi. G.L. and M.K. declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

The implementation of immune checkpoint inhibitors (ICIs), with or without chemotherapy, as first-line treatment for patients who do not have actionable mutations has proved to be a major paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). However, the transition of ICIs, such as pembrolizumab and nivolumab, to a first-line setting has left an unmet need for effective second-line treatment options, which is an area of intense research. In 2020, we reviewed the biological and mechanistic rationale for anti-angiogenic agents in combination with, or following, immunotherapy with the aim of eliciting a so called 'angio-immunogenic' switch in the tumor microenvironment. Here, we review the latest clinical evidence of the benefits of incorporating anti-angiogenic agents into treatment regimens. While there is a paucity of prospective data, several recent observational studies indicate that the marketed anti-angiogenic drugs, nintedanib or ramucirumab, are effective in combination with docetaxel following immuno-chemotherapy. Addition of anti-angiogenics, like bevacizumab, have also demonstrated clinical benefit when combined with first-line immuno-chemotherapy regimens. Ongoing clinical trials are assessing these agents in combination with ICIs, with encouraging early results (e.g., ramucirumab plus pembrolizumab in LUNG-MAP S1800A). Also, several emerging anti-angiogenic agents combined with ICIs are currently being assessed in phase III trials following immunotherapy, including lenvatinib (LEAP-008), and sitravatinib (SAPPHIRE) It is hoped that these trials will help expand second-line treatment options in patients with NSCLC. Areas of focus in the future will include further molecular dissection of the mechanisms of resistance to immunotherapy and the various response-progression profiles to immunotherapy observed in the clinic and the monitoring of the dynamics of immunomodulation over the course of treatment. Improved understanding of these phenomena may help identify clinical biomarkers and inform the optimal use of anti-angiogenics in the treatment of individual patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Reck received fees for honoraria, consulting/advisory roles and speaker’s bureau from Boehringer Ingelheim. Sanjay Popat received personal fees from Bristol Myers Squibb, Roche, Takeda, AstraZeneca, Pfizer, Merck Sharp & Dohme, EMD Serono, Guardant Health, AbbVie, Boehringer Ingelheim, Tesaro, OncLive, Medscape. Christian Grohé has received sponsorship or research funding and payment or other financial remuneration from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, F. Hoffmann-La Roche; and payment or other financial remuneration from Lilly. Silvia Novello received personal fees for advisor/speaker’s bureaus from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, Pfizer, Roche, Merck Sharp & Dohme, Eli Lilly, AbbVie. Wolfgang M. Brueckl received lecture and educational event (personal) fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, Merck Sharp & Dohme, Pfizer, Roche Pharmaceuticals, Takeda; congress (personal) fees from Boehringer Ingelheim, AstraZeneca, Roche Pharmaceuticals; and advisory board fees (personal) from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharp & Dohme, Lilly Pharma, Bristol Myers Squibb, Roche. Dejan Radonjic and Rolf Kaiser are employees of Boehringer Ingelheim. Rolf Kaiser also has a patent EP 2994125 issued. John Heymach received fees for advisory roles from AstraZeneca, EMD Serono, Boehringer Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Eli Lilly, Spectrum, Sanofi, Takeda, Mirati Therapeutics, Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, RefleXion, Chugai Pharmaceuticals; fees for a Board of Directors role from Rexanna Foundation; corporate-sponsored research fees from AstraZeneca, Boehringer Ingelheim, Spectrum, Takeda; and royalties and licensing fees from Spectrum. Jesus Corral and Maya Gottfried report no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: For refractory NSCLC patients with EGFR mutations, recent studies have demonstrated a favorable response to the combination of anti-angiogenic therapy and checkpoint inhibition but included only very few patients with uncommon EGFR mutations for which treatment options are still limited despite new targeted treatments., Materials and Methods: Sixteen stage IV NSCLC patients with uncommon EGFR mutations from 9 different German centers were treated in first or further line with Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel (ABCP). PFS was evaluated from start of ABCP and OS from time of initial diagnosis of stage IV., Results: Patients with either an Exon 20 insertion (n = 9) or other uncommon EGFR mutations (n = 7) received ABCP in first, second or further line. Nine patients had received a TKI therapy in first line with an ORR of 66.7 % and a median time-to-next-treatment of 6.7 months. After a median number of 4 ABCP cycles, 4 patients (25.0 %) required a dose reduction of chemotherapy and 5 patients (31.3 %) suffered from grade 3 or 4 toxicity. Overall response rate was 81.3 % and disease control rate 87.5 %. 14 patients (87.5 %) received a maintenance with AB and the median follow-up after initial diagnosis was 24.3 months. Median PFS was 13.6 months for both the entire cohort and for Exon 20 insertions. Corresponding median OS was either not reached or 30.7 months. Landmark analysis at 12 months gave a PFS of 42.8 % and an OS of 93.3 %. Four patients were rechallenged with ABCP while progressing under maintenance and responded again. In further line therapy, clinical benefit was achieved in all of 3 patients receiving Amivantamab, but in only one of four patients receiving mobocertinib., Conclusion: In this retrospective analysis, ABCP achieves an encouraging outcome for patients with uncommon EGFR mutations and is a valuable option in the early treatment course., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AT, ND, ID, PH, TO, CW and MR have received honoraria or travel expenses from Roche/Genentech. MR is part of the Speakers Bureau of Roche/Genentech., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Exercise has been reported to alleviate disease as well as treatment impact in patients with lung cancer. Nevertheless, there is limited information available regarding the perception of lung cancer dedicated healthcare professionals' and their advice on exercise., Materials and Methods: An online survey exploring healthcare professionals' practice patterns, perceptions, barriers, and facilitators of exercise in patients with lung cancer was conducted within members of the EORTC Lung Cancer Group (LCG)., Results: One hundred forty-one healthcare providers completed the survey, mainly medical and radiation oncologists. Overall, 63% of the study participants declared that they frequently assessed exercise level in their patients, and 43% of them reinforced the importance of exercise. However, only 10% referred patients to an exercise program or specialist. Although the majority of the respondents had a positive perception regarding the benefits and safety of exercise (even in patients with advanced disease and/or bone metastasis), two-thirds of clinicians reported not having adequate training about exercise counselling. Moreover, 53% reported to lack of knowledge of guidelines referring to exercise in patients with cancer. Several obstacles and facilitators to improve exercise promotion in lung cancer care were identified., Conclusion: Healthcare providers recognize the relevance and feasibility of exercise as part of cancer treatment intervention, but specific pathways to do the referral are frequently missing. Future structured and well-designed strategies and initiatives are needed to support an effective referral in order to implement exercise interventions routinely in clinical practice., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The transcription factor NRF2 (nuclear factor E2-related factor 2) (also known as nuclear factor, erythroid 2 like 2 [NFE2L2]) is the master regulator of cellular antioxidant responses. NRF2 is repressed by interaction with a redox-sensitive protein KEAP1 (Kelch-like ECH-associated protein 1). Dysregulation of KEAP1/NRF2 transcriptional activity has been associated with the pathogenesis of multiple diseases, and the KEAP1/NRF2 axis has emerged to be the most important modulator of cellular homeostasis. Oxidative stress plays an important role in the initiation and progression of many chronic diseases, including diabetes, cancer, and neurodegenerative diseases. Although its role in immunotherapy is still somewhat controversial, it is well documented from clinical studies that KEAP1/NRF2 mutations in NSCLCs are associated with resistance to various cancer treatments including chemotherapy, X-irradiation, TKI treatment, and a shorter OS and currently available results from clinical trials suggest that KEAP1/NRF2 mutations can be used as a prognostic biomarker (poorer prognosis) for determining prognosis following immunotherapy and a predictive marker for chemo-, radio-, immunotherapy- and TKI-resistance. Despite overwhelming enthusiasm about the various KEAP1/NRF2 inhibitors that have been described during the last decades, none of these inhibitors are currently explored in clinical trials or in clinical applications which clearly add weight to the proposal that the development of these inhibitors remains challenging, but will be beneficial for novel treatment approaches in NSCLC in the near future. In this review we highlight the molecular features, the key components, and possible inhibitors of the KEAP1/NRF2 pathway, its role as prognostic and predictive biomarker, and the resulting clinical implications in NSCLC patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the "real-world" setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany., Patients and Methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1., Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4-10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9-9.2) with druggable ALK alterations., Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the effectiveness and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) previously treated with both chemo- and immunotherapy., Materials and Methods: LUME-BioNIS is a European, prospective, multicenter, non-interventional study of patients with advanced adenocarcinoma NSCLC, who initiated nintedanib plus docetaxel after first-line chemotherapy in routine practice according to the approved nintedanib EU label. The primary objective is to explore whether molecular biomarkers can predict overall survival (OS). Information on clinical or radiologic progression and death, and adverse drug reactions (ADRs)/fatal adverse events (AEs) was collected during follow-up. Here, we report a subgroup analysis evaluating outcomes in immunotherapy-pretreated patients., Results: Of 260 enrolled patients, 67 (25.8%) had prior immunotherapy and were included in this subgroup analysis. Prior immunotherapy was administered in first-line in 20 patients (29.9%; combined with chemotherapy in 4 patients [6.0%]) and later-lines in 47 patients (70.1%), and most commonly comprised nivolumab (39 patients; 58.2%), atezolizumab (14 patients; 20.9%) and pembrolizumab (11 patients; 16.4%). Nintedanib plus docetaxel was given in second-line in 10 patients (14.9%) and in later-lines in 57 patients (85.1%). Median OS was 8.8 months (95% confidence interval [CI]: 7.0-11.5) and median progression-free survival (PFS) was 4.6 months (95% CI: 3.5-5.7). Among 55 patients with available data, rates of objective response and disease control were 18.2% and 78.2%, respectively. In 65 patients evaluable for safety, the most common on-treatment ADRs/AEs were malignant neoplasm progression (19 patients; 29.2%), diarrhea (21 patients; 32.3%) and nausea (10 patients; 15.4%)., Conclusions: Used according to the approved nintedanib label in routine practice, nintedanib plus docetaxel demonstrated clinical effectiveness, with no unexpected safety findings, in patients with prior chemotherapy and first- or later-line immunotherapy. These data add to the real-world evidence that can inform clinical decisions in the changing therapeutic landscape., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Efficacy, safety, pharmacokinetics (PK), and immunogenicity of the biosimilar candidate SB8 was compared to its reference product bevacizumab (BEV) in patients with metastatic or recurrent nonsquamous non-small cell lung cancer., Methods: Patients were randomized (1:1) in a phase III, double-blind study to receive intravenous SB8 or BEV 15 mg/kg with paclitaxel/carboplatin every 3 weeks for 24 weeks, followed by SB8 or BEV maintenance monotherapy. The primary endpoint was best overall response rate (ORR) by 24 weeks. Secondary endpoints included survival outcomes, safety, PK, and immunogenicity., Results: 763 patients (SB8, n = 379; BEV, n = 384) were randomized; baseline characteristics were well balanced. Best ORR in the FAS was 47.6% and 42.8%, and best ORR in the PPS was 50.1% and 44.8% for SB8 and BEV, respectively. The risk ratio of best ORR was 1.11 (90% CI, 0.975-1.269), and the risk difference in best ORR was 5.3% (95% CI, -2.2%-12.9%). Median survival outcomes were comparable between SB8 and BEV: progression-free survival was 8.50 vs 7.90 months, respectively (HR [95% CI], 0.99 [0.83-1.18]; p = 0.9338); overall survival was 14.90 vs 15.80 months, respectively (HR [95% CI], 1.03 [0.83-1.28]; p = 0.7713); and duration of response was 7.70 vs 7.00 months, respectively (HR [95% CI], 1.05 [0.81-1.37]; p = 0.6928). Severity and incidence of treatment-emergent adverse events, PK, and immunogenicity were comparable between SB8 and BEV., Conclusion: This study demonstrated equivalence between SB8 and BEV in terms of best ORR risk ratio, with comparable safety, PK, and immunogenicity., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology., Methods: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus., Results and Conclusion: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: Stage IV small cell lung cancer (SCLC) is associated with short survival and progression after first-line systemic therapy frequently occurs within months. Although topotecan is approved for second-line treatment, its efficacy is limited, and treatment heterogeneity exists., Material and Methods: The decision-making patterns for second line treatment of 13 European medical oncologists with expertise in SCLC were analyzed., Results: The two criteria most relevant to decision-making were the performance status and the interval of recurrence since first-line treatment. With an interval of less than 3 months since the end of first-line chemotherapy, 62 % of the experts recommended cyclophosphamide, doxorubicin and vincristine (CAV) for fit patients and 54 % recommended topotecan for unfit patients. For an interval of more than 6 months, a clear consensus for a re-challenge with a platinum doublet was achieved (92 %). However, there was no consensus on the second-line therapy with an interval of 3-6 months since the end of first-line therapy., Conclusion: Real world practice may differ from recommendations in general guidelines and cannot always be directly derived from trial results as other factor such as habits, patient's preference, convenience or costs have to be factored in., Competing Interests: Declaration of Competing Interest MF reports advisor fees (paid to institution) from BMS, MSD, AstraZeneca, Boehringer Ingelheim, Roche, Takeda and institutional research grants from BMS and AstraZeneca CP: none MR reports honoraria for lectures and consultancy from Abbvie, Amgen, AstraZenece, BMS, Boehringer-Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung. FB: none RC reports honoraria and consultancy fees from AstraZeneca, Boeringer Ingelheim, Lilly Oncology, Roche, Pfizer, MSD, Bristol Myers Squibb, Takeda and Novartis; institutional grands for conduct of clinical trials or contracted research from Roche, AstraZeneca, Pfizer, Clovis, Lilly Oncology, MSD, BMS, Abbvie, Takeda and Novartis; stock ownership of The Christie Private Care. FC reports consultation and participation in advisory boards and lectures for Roche, AstraZeneca, Pfizer, BMS, Takeda, Lilly, MSD, Bayer. BB reports institutional grants from Abbvie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfizer, Pharma Mar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma, Tolero Pharmaceuticals. PG reports speaker and/or advisory fees for Roche, AstraZeneca, BMS, Guardant Health, MSD, Pfizer, Janssen, Boehringer Ingelheim, Novartis, Gilead, Rovi, Abbvie, Lilly, Takeda, Sysmex, Blueprint Medicines, and Bayer. EF reports personal fees from Abbvie, AstraZeneca, Blue Print Medicines, Boehringer Ingelheim, BMS, Eli Lilly, Guardant Health, Jannsen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Prime Oncology, Roche, Samsung, Takeda, Touchtime, GSK, Bayer; grants from Grant for Oncology Innovation (GOI), Fundacion Merck Salud, outside the submitted work; and Grifols: Independent Member of the Board. MOB reports advisory board work for MSD, BMS, BI and Pierre Fabre. LP-A is a board member of Genomica and Altum Sequencing, and has received honoraria from Roche/Genentech, Eli Lilly, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Merck Serono, Pharmamar, Novartis, Celgene, Sysmex, Amgen, Blueprint and Incyte; and travel, accommodations or expenses from Roche, AstraZeneca, AstraZeneca Spain, Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly and Pfizer. FdM reports fees as consultant/advisor role for AstraZeneca, Bristol Myers Squibb, Roche, Genentech, Pfizer and MSD VW reports personal fees and other from Roche, personal fees and other from BMS, personal fees and other from Astra Zeneca, personal fees from MSD, personal fees from Takeda, other from Pfizer, personal fees and other from Boehringer Ingelheim, personal fees from Lilly, outside the submitted work. DDR reports outside of this project advisor fees from Bristol-Myers Squibb, Celgene, Merck/Pfizer, Roche/Genentech, AstraZeneca, MSD, Seattle genetics; institutional research funding from Boehringer Ingelheim, Bristol-Myers Squibb, AstraZeneca, Philips, Olink. PMP reports speaker fees from Janssen and institutional educational grants from AstraZeneca and Celgene., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The introduction of licensed front-line immunotherapies has heralded a new era for the treatment of non-oncogene-addicted, advanced non-small cell lung cancer (NSCLC). Yet as with all evolutions in clinical management, changes in practice can outpace the availability of the clinical evidence needed to inform subsequent therapeutic decision making. At the time of writing, there is limited available evidence on the optimum therapeutic options after progression on immunotherapy. Further research is needed to define mechanisms of immunotherapy resistance in patients with advanced NSCLC, and to understand the implications for subsequent treatment response. Pending the availability of robust clinical data and proven therapeutic options to underpin an optimized therapeutic pathway after progression on immunotherapy, attention must turn to the potential utility of currently licensed agents and any available supporting clinical data in this setting. Within this context we review the mechanistic arguments and supporting evidence for the use of anti-angiogenic agents as a means of targeting immunosuppression within the tumor microenvironment. We consider whether VEGF inhibition may help to normalize the tumor vasculature and to address immunosuppression - reinstating, and potentially enhancing, the effect of subsequent therapies. We also highlight evidence needs and signpost ongoing trials that should enable current clinical opinion in this area to be replaced by robust, evidence-based guidance., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Despite the highly immunogenic potential of small cell lung cancer (SCLC), progress in evaluating the therapeutic value of immune checkpoint agents has lagged behind that of non-small cell lung cancer. Results from a number of phase I-III clinical trials that specifically address the use of anti-PD-1, anti-PD-L1 and anti-CTLA-4 agents in SCLC have now been reported. This review will focus on the available evidence for immune checkpoint blockade in SCLC and review current biomarker strategies with the aim of providing perspective and interpretation of this data for clinical practice., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The CONVERT trial showed that twice-daily (BD) concurrent chemoradiotherapy should continue to be considered the standard of care in localised LS-SCLC. A survey was conducted to assess the impact of the CONVERT trial in clinical practice and to identify any relevant research questions for future trials in this setting., Methods and Materials: An EORTC Group online survey of LS-SCLC practice was distributed to the EORTC LCG and to members of several European thoracic oncology societies between April and December 2018., Results: 198 responses were analysed. The majority of respondents (88%, n = 174) were aware of the CONVERT trial. Radiation oncologists comprised 56% of all respondents. Once-daily (OD) radiotherapy is still the most commonly used regimen, however the use of concurrent BD radiotherapy increased after the publication of CONVERT (n = 59/186, 32% prior to and n = 78/187, 42% after the publication, p = 0.053). The main reasons for not implementing BD after the CONVERT publication were logistical issues (n = 88, 44%), inconvenience for patients (n = 56, 28%), and the absence of a statistical survival difference between the two arms in CONVERT (n = 38, 19%). Brain MRI was used by 28% during staging but more than half (60%) of the respondents did not routinely image the brain during follow-up. The main research questions of interest in LS-SCLC were 1) integrating novel targeted therapies-immunotherapies (n = 160, 81%), 2) PCI (+/- hippocampal sparing) vs. MRI surveillance (n = 140, 71%) and, 3) biomarker driven trials (n = 92, 46%)., Conclusion: Once daily radiotherapy (60-66 Gy in 30-33 fractions) remains the most prescribed radiotherapy fractionation, despite the findings suggested by the CONVERT trial., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Most lung cancer diagnoses occur in elderly patients, who are underrepresented in clinical trials. We present a pooled analysis of safety and efficacy in elderly patients (≥75 years) who received pembrolizumab (a programmed death 1 inhibitor) for advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1)‒positive tumors., Methods: The pooled analysis included patients aged ≥18 years with advanced NSCLC with PD-L1-positive tumors from the KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894) studies. In KEYNOTE-010, patients were randomized to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel, as second- or later-line therapy. In KEYNOTE-024 and KEYNOTE-042, patients were randomized to first-line pembrolizumab 200 mg Q3W or platinum-based chemotherapy. Overall survival (OS) was estimated by the Kaplan-Meier method, and safety data were summarized in elderly patients (≥75 years)., Results: The analysis included 264 elderly patients with PD-L1-positive tumors (PD-L1 tumor proportion score [TPS] ≥1%); among these, 132 had PD-L1 TPS ≥ 50%. Pembrolizumab improved OS among elderly patients with PD-L1 TPS ≥ 1% (hazard ratio [HR], 0.76 [95% CI, 0.56-1.02]) and PD-L1 TPS ≥ 50% (HR, 0.40 [95% CI, 0.25-0.64]). Pembrolizumab as first-line therapy also improved OS among elderly patients with PD-L1 TPS ≥ 50% (from KEYNOTE-024 and KEYNOTE-042) compared with chemotherapy (HR, 0.41 [95% CI, 0.23‒0.73]). Pembrolizumab was associated with fewer treatment-related adverse events (AEs) in elderly patients (overall, 68.5% vs 94.3%; grade ≥3, 24.2% vs 61.0%) versus chemotherapy. Immune-mediated AEs and infusion reactions were more common with pembrolizumab versus chemotherapy (overall, 24.8% vs 6.7%; grade 3‒4: 9.4% vs 0%; no grade 5 events)., Conclusions: In this pooled analysis of elderly patients with advanced NSCLC with PD-L1‒positive tumors, pembrolizumab improved OS versus chemotherapy, with a more favorable safety profile. Outcomes with pembrolizumab in patients ≥75 years were comparable to those in the overall populations in the individual studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The development of PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitors (CPI) has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC). The potential of immunotherapy (IO) to induce durable responses for a subset of patients represents a therapeutic milestone. After the approval of front-line single agent pembrolizumab, IO-based combinations are rapidly entering clinical practice resulting in a fast change of treatment algorithms for advanced NSCLC. We hereby summarize the recent first-line phase 3 trials evaluating PD-(L)1 blockade plus chemotherapy (ChT) and PD-1 plus CTLA-4 CPI for advanced NSCLC and provide potential treatment recommendations., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background: The role of consolidative thoracic radiotherapy (TRT) in stage IV small cell lung cancer (SCLC) is not uniformly accepted., Methods: We obtained a list of 13 European medical oncologists from the International Association for the Study of Lung Cancer (IASLC) and 13 European radiation oncologists from the European Society for Therapeutic Radiation Oncology (ESTRO). The strategies in decision making for TRT in stage IV SCLC were collected. Decision trees were created representing these strategies. Frequencies of recommending TRT were analysed for various parameter combinations based on the objective consensus methodology., Results: The factors associated with the recommendation for TRT included fitness of the patient, limited extrathoracic tumour burden, initial bulky thoracic disease and response to chemotherapy. The highest consensus for TRT was in fit patients with limited extrathoracic tumour burden and initial bulky disease with either a complete extrathoracic response or partial thoracic response (92% recommend TRT). For these patients the recommendations were the same for medical and radiation oncologists. In the setting of partial response (intra- and extra-thoracically) without initial bulky thoracic disease radiation oncologists were more likely to recommend TRT than medical oncologists. For unfit patients or for patients with poor overall response to chemotherapy, the majority did not recommend TRT., Conclusion: European radiation and medical oncologists specializing in lung cancer recommend TRT in selected patients with stage IV SCLC and restrict its use primarily to fit patients who responded to chemotherapy with limited extrathoracic tumour burden., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Due to conflicting results between major trials the role of prophylactic cranial irradiation (PCI) in stage IV small cell lung cancer (SCLC) is controversial., Methods: We obtained a list of 13 European experts from both the European Society for Therapeutic Radiation Oncology (ESTRO) and the International Association for the Study of Lung Cancer (IASLC). The strategies in decision making for PCI in stage IV SCLC were collected. Decision trees were created representing these strategies. Analysis of consensus was performed with the objective consensus methodology., Results: The factors associated with the recommendation for the use of PCI included the fitness of the patient, young age and good response to chemotherapy. PCI was recommended by the majority of experts for non-elderly fit patients who had at least a partial response (PR) to chemotherapy (for complete remission (CR) 85% of radiation oncologists and 69% of medical oncologists, for PR: 85% of radiation oncologists and 54% of medical oncologists). For patients with stable disease after chemotherapy, PCI was recommended by 6 out of 13 (46%) radiation oncologists and only 3 out of 13 medical oncologists (23%). For elderly fit patients with CR, a majority recommended PCI (62%) and no consensus was reached for patients with PR., Conclusion: European radiation and medical oncologists specializing in lung cancer recommend PCI in selected patients and restrict its use primarily to fit, non-elderly patients who responded to chemotherapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A majority of patients with advanced or metastatic non-small cell lung cancer (NSCLC) will experience disease progression after first-line therapy. Patients who have advanced NSCLC that is especially aggressive, which is defined as disease that rapidly progresses on first-line treatment or disease that is refractory to first-line treatment, have a critical unmet medical need. These patients have a poor prognosis in the second-line setting. Several studies have recently shown that treatment with an antiangiogenic therapy may benefit these patients. This review summarizes the approved antiangiogenic therapies for the treatment of patients with advanced NSCLC in the second-line setting, specifically focusing on the outcomes from subgroups of patients with rapidly progressing or refractory disease. Several antiangiogenic agents, as monotherapy or in combination with other treatments, have been or are currently being studied in patients with advanced NSCLC. Antiangiogenics that are approved for use in patients with advanced NSCLC are limited to bevacizumab in combination with chemotherapy (nonsquamous NSCLC), ramucirumab in combination with docetaxel (all histologies), and nintedanib in combination with docetaxel (adenocarcinoma histology). This review focuses on the efficacy, safety, and quality of life outcomes in the subpopulation of patients with rapidly progressing or refractory NSCLC treated with approved antiangiogenic therapies in the second-line setting. We also discuss the impact of newly approved immunotherapy agents on the outcomes of patients with aggressive or refractory disease. Studies in progress and planned future research will determine if combination treatment with antiangiogenics and immunotherapies will benefit patients with aggressive, advanced NSCLC., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Limited understanding exists of epidermal growth factor receptor (EGFR) mutation frequency in less common subgroups of advanced non-small-cell lung cancer (aNSCLC) (e.g. squamous cell carcinoma [SCC]), and to what extent local practices exclude patients from EGFR testing based on their clinical characteristics., Materials and Methods: IGNITE (non-comparative/-interventional; NCT01788163) was conducted in 90 centres (Asia-Pacific/Russia). Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly-diagnosed/recurrent disease after resection; ineligible for curative treatment. Patients provided a tissue/cytology (all) and a blood plasma (China/Russia/South Korea/Taiwan) sample. Primary endpoint: EGFR mutation frequency in aNSCLC patients (adenocarcinoma [ADC]/non-ADC), as per local practices., Results: 3382 patients were enrolled. EGFR mutation frequencies for evaluable tissue/cytology samples in Asia-Pacific and Russian patients: 49.3% (862/1749) and 18.0% (90/500) for ADC tumours; 14.1% (74/525) and 3.7% (15/402) for non-ADC; 9.9% (40/403) and 3.7% (13/349) for SCC. Of Russian patients with SCC tumours harbouring common, activating EGFR mutations, 6/9 were never-/former-smokers. Mutation status concordance between 2581 matched tissue/cytology and plasma samples: 80.5% (sensitivity 46.9%, specificity 95.6%)., Conclusion: EGFR mutation testing should be considered in all Asian aNSCLC patients. Also, as activating EGFR mutations were observed in a small number of Caucasian squamous NSCLC patients, testing here may be appropriate, particularly in those with no/remote smoking history. Circulating free tumour-derived DNA is feasible for mutation analysis employing well-validated and sensitive methods, when tumour samples are unavailable., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody inhibiting vascular endothelial growth factor receptor-2, increased overall survival (OS) combined with docetaxel versus docetaxel alone in non-small cell lung cancer (NSCLC) in the REVEL trial. Pre-specified exploratory analysis examined efficacy and safety by histology., Materials and Methods: 1253 patients with NSCLC were randomized to receive ramucirumab (10mg/kg; n=628) plus docetaxel (75mg/m 2 ) or placebo plus docetaxel (n=625) after disease progression on or after platinum-based therapy, with or without bevacizumab or maintenance therapy. OS was analyzed using Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Primary quality-of-life analysis was time to deterioration (TtD) of the Lung Cancer Symptom Scale (LCSS) scores using the Kaplan-Meier method and Cox regression., Results: Median OS for adenocarcinoma was 11.2 months for ramucirumab-docetaxel (n = 377) and 9.8 months for placebo-docetaxel (n=348); HR=0.83 (95% CI: 0.69-0.99). In squamous disease, median OS was 9.5 months for ramucirumab-docetaxel (n=157) versus 8.2 months for placebo-docetaxel (n=171); HR 0.88 (95% CI: 0.69-1.13). Median OS for other nonsquamous was 10.8 months for ramucirumab-docetaxel (n=74) and 9.3 months for placebo-docetaxel (n=78); HR=0.86 (95% CI: 0.59-1.26). Treatment-emergent adverse events were comparable between treatment arms across histologic subgroups. TtD for LCSS scores was similar between treatment arms in the nonsquamous and squamous subgroups., Conclusion: REVEL demonstrated similar favorable efficacy and manageable safety for ramucirumab-docetaxel across histologic subgroups of NSCLC., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: The REVEL study demonstrated improved efficacy for patients with advanced non-small cell lung cancer treated with ramucirumab plus docetaxel, independent of histology. This exploratory analysis characterized the treatment effect in REVEL patients who were refractory to prior first-line treatment., Materials and Methods: Refractory patients had a best response of progressive disease to first-line treatment. Endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), quality of life (QoL), and safety. Kaplan-Meier and Cox proportional hazards regression were performed for OS and PFS, and Cochran-Mantel-Haenszel test was used for response. QoL was assessed with the Lung Cancer Symptom Scale. Sensitivity analyses were performed on subgroups of the intent-to-treat population with limited time on first-line therapy., Results: Of 1253 randomized patients in REVEL, 360 (29%) were refractory to first-line treatment. Baseline characteristics were largely balanced between treatment arms. In the control arm, median OS for refractory patients was 6.3 versus 10.3 months for patients not meeting this criterion, demonstrating the poor prognosis of refractory patients. Median OS (8.3 vs. 6.3 months; HR, 0.86; 95% CI, 0.68-1.08), median PFS (4.0 vs. 2.5 months; HR, 0.71; 95% CI, 0.57-0.88), and ORR (22.5% vs. 12.6%) were improved in refractory patients treated with ramucirumab compared to placebo, without new safety concerns or further deteriorating patient QoL., Conclusions: The effect of ramucirumab in refractory patients is similar to that in the intent-to-treat population. The benefit/risk profile for refractory patients suggests that ramucirumab plus docetaxel is an appropriate treatment option even in this difficult-to-treat population., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Active smokers with non-small-cell lung cancer (NSCLC) have increased erlotinib metabolism versus non-smoking patients, which reduces exposure. Therefore, an increased erlotinib dose may be beneficial. The CurrentS study (NCT01183858) assessed efficacy and safety of 300mg erlotinib (E300) as second-line therapy in current smokers with locally advanced or metastatic NSCLC versus the standard 150mg dose (E150)., Materials and Methods: Patients with stage IIIB/IV NSCLC (current smokers who failed first-line platinum-based chemotherapy) were randomized to receive E150 or E300 until progression/death/unacceptable toxicity., Primary Endpoint: progression-free survival (PFS). Secondary endpoints: overall survival (OS), disease control rate and safety., Results: A total of 342 patients were screened; the intent-to-treat population comprised 159 E300 patients and 154 E150 patients. Median PFS was 7.0 versus 6.9 weeks with E300 versus E150, respectively (unstratified hazard ratio [HR]=1.05, 95% confidence interval [CI]: 0.83-1.33; unstratified log-rank P=0.671). Median OS was 6.8 months in both arms (unstratified HR=1.03, 95% CI: 0.80-1.32; unstratified log-rank P=0.846). Overall, 89.2% (E300 arm) and 84.4% (E150 arm) experienced ≥1 adverse event (AE) of any grade (44.3% and 37%, respectively, experienced grade ≥3 AEs); AEs of special interest were reported in 67.7% and 47.4% of patients, respectively. E300 resulted in higher mean plasma concentrations versus E150, however, this did not improve efficacy., Conclusions: Despite the difference in erlotinib exposure, there was no evidence of an incremental efficacy benefit of a higher erlotinib dose versus the standard dose in this population of highly active smokers., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: REVEL demonstrated that ramucirumab+docetaxel (RAM+DTX) improved overall survival, progression-free survival, and objective response rate in patients with advanced/metastatic non-small cell lung cancer with progression after platinum-based chemotherapy. This analysis examined quality of life (QoL) as assessed by the Lung Cancer Symptom Scale (LCSS) and clinician-reported functional status., Materials and Methods: The LCSS includes 6 symptom and 3 global items measured on a 0-100-mm scale; higher scores represent greater symptom burden. LCSS and ECOG PS data were collected at baseline, every 3-week cycle, the summary visit, and at the 30-day follow-up. LCSS total score and Average Symptom Burden Index (ASBI) were calculated. The primary analysis compared time to deterioration (TtD) between treatment arms for all individual items and summary scores, defined as increase from baseline by ≥ 15 mm using the Kaplan-Meier method and Cox regression. TtD to ECOG PS ≥ 2 was analyzed., Results: There were 1253 patients randomized to receive RAM+DTX or placebo+docetaxel (PL+DTX). Across all assessments, LCSS compliance was approximately 75% and balanced across arms. The mean (SD) baseline LCSS total score was 27.3mm (17.08 mm) on RAM+DTX and 29.6mm (17.59 mm) on PL+DTX. At 30-day follow-up, mean (SD) LCSS total score was 32.0 (19.03) on RAM+DTX and 32.5 (19.87) on PL+DTX. The TtD for all LCSS scores was similar between treatment arms. Stratified HRs (95% CI) for LCSS total score and ASBI were HR=0.99 (0.81, 1.22), p=0.932 and HR=0.93 (0.75, 1.15), p=0.514 with approximately 70% of patients censored. TtD to PS ≥ 2 was similar between treatment arms (HR=1.03 [95% CI: 0.85, 1.26], p=0.743) with approximately two-thirds of the patients censored., Conclusion: In addition to improvement of clinical efficacy outcomes demonstrated in REVEL, these results suggest that adding ramucirumab to docetaxel did not impair patient QoL, symptoms, or functioning., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We investigated the feasibility of cisplatin or carboplatin combined with pemetrexed as adjuvant treatment in patients with completely resected Stage IB/II Non-Small-Cell Lung Cancer (NSCLC)., Materials and Methods: Patients in this multicenter, open-label, parallel-group, non-comparative Phase 2 study were randomized (1:1) to pemetrexed (500 mg/m(2)) with either cisplatin (75 mg/m(2)) or carboplatin (AUC5) for 4 cycles of 21 days. The primary endpoint was treatment feasibility (defined as 4 cycles completed with no cycle delay >42 days and ≤2 dose reductions, with a median relative dose intensity (RDI) ≥95% [overall]; and no Grade ≥3 toxicities at the follow-up visit 30 days after last drug administration). Secondary objectives included overall survival (OS) and safety., Results: We randomized 122 patients and treated 118. 71.9% (46/64) of patients in pemetrexed+cisplatin and 88.9% (48/54) in pemetrexed+carboplatin completed 4 cycles (median RDI >97% for all compounds). Neither treatment met the pre-defined feasibility level >60% of patients: 59.4% (95% confidence interval [CI]: 46.4;71.5) pemetrexed+cisplatin; 50.0% (95%CI: 36.1;63.9) in pemetrexed+carboplatin. In a post-hoc analysis considering only safety, both regimens were feasible with 81.3% (95%CI: 69.5;89.9) in pemetrexed+cisplatin and 90.7% (95%CI: 79.7;96.9) in pemetrexed+carboplatin. OS rates for both groups were 82-83% after 3 years and 80-83% after 5 years. Treatment-related Grade ≥3 adverse events (mostly hematological) were experienced by approximately 30% of patients in each group., Conclusion: Although the study did not meet the primary objective, both treatment groups demonstrated good safety-related feasibility and tolerability as adjuvant treatment in patients with completely resected Stage IB/II NSCLC., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigating nintedanib+docetaxel versus placebo+docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy. Progression-free survival was significantly improved with nintedanib+docetaxel in the overall population and overall survival was significantly improved in the pre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristic adverse events (AEs) commonly seen with existing anti-angiogenic agents., Materials and Methods: The incidence and intensity of AEs were evaluated in all patients who received at least one dose of study medication (N=1307) and for the two main histologies: adenocarcinoma (n=653) and squamous cell carcinoma (SCC; n=553). AEs of special interest were analyzed by category, preferred term, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events, and skin disorders., Results and Conclusion: The incidence of patients with all-grade gastrointestinal (GI) perforations was low and balanced between arms (0.5% in both) and across histologies; the incidence of non-GI perforations was 1.2% with nintedanib+docetaxel versus 0.2% with placebo+docetaxel. The incidence of some events was higher with nintedanib+docetaxel versus placebo+docetaxel; hypertension (3.5% vs 0.9%), rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reactions were predominantly Grade 1-2 with both treatments. The incidence of all-grade bleeding was also slightly higher in nintedanib+docetaxel-treated patients (14.1% vs 11.6%) driven by between-treatment differences in the SCC subpopulation; most events were Grade 1-2. The proportion of patients with a thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade ≥3 (2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib+docetaxel. Survival benefits from addition of nintedanib to docetaxel in patients with adenocarcinoma after first-line therapy can be achieved alongside a manageable safety profile., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: ABIGAIL, a phase II, randomized, open-label, multicenter study evaluated the correlation between biomarkers and best overall response (BOR) to bevacizumab with chemotherapy in patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Exploratory analyses of vascular endothelial growth factor (VEGF) clinical genotyping data are presented., Materials and Methods: A total of 303 patients with NSCLC were randomized to receive bevacizumab 7.5mg/kg or 15mg/kg until progression or unacceptable toxicity (plus six cycles of chemotherapy). Patients provided blood samples for biomarker analysis. Exploratory analyses were conducted to assess whether genetic variants in VEGF-A or VEGFR-1/-2 act as efficacy or safety biomarkers. Single nucleotide polymorphisms (SNPs) were determined using individual genotyping assays. DNA analysis for 12 SNPs across three genes is reported: VEGF-A (five SNPs), VEGFR-1 (three SNPs), and VEGFR-2 (four SNPs)., Results Vegf-A: c.+405/c.-634 (CG), VEGF-A: c.-460 >C; c-1498 >C (CT), and, Vegf-A: c.-2578 C>A were associated with >50% higher odds of responding to treatment. VEGFR-1: rs9554316 (GT) was associated with >30% higher risk of progression and >40% higher risk of death., Vegf-A: c.+936 C>T was associated with higher incidence of hypertension., Conclusions: Four genetic variants of VEGF-A and VEGFR-1 were associated with bevacizumab treatment outcome. Three variants in VEGF-A were associated with increased BOR, one variant in VEGFR-1 was associated with worse progression-free survival/overall survival. These associations were not statistically significant after correction for multiple testing. No genetic variant was associated with significantly higher risk of hypertension. Replication in additional studies may provide insight into the use of these variants to predict response to bevacizumab., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: DISRUPT evaluated whether adding the vascular-disrupting agent ombrabulin to a taxane-platinum doublet in the first-line setting improved progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC)., Methods: Patients were randomised to ombrabulin 35 mg/m(2) or placebo followed by a taxane-platinum regimen every 3 weeks., Results: Overall, 176 patients were randomised. After 124 events, median PFS was not significantly improved with ombrabulin vs placebo (5.65 vs 5.45 months; HR 0.948; 60% CI 0.813-1.106; one-sided P=0.39). The two groups showed similar overall survival (median 11.0 months in both groups), objective response rate (32% ombrabulin; 31% placebo) and safety profiles., Conclusion: This study did not meet its primary endpoint of improving PFS by adding ombrabulin to a taxane-platinum regimen for first-line treatment of metastatic NSCLC., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Targeting the epidermal-growth-factor-receptor (EGFR) in non-small cell lung cancer (NSCLC) is an established treatment option with less toxicity compared to conventional chemotherapy. This study was undertaken to determine whether Erlotinib is non-inferior compared to chemotherapy as a first-line therapy in unselected elderly patients., Materials and Methods: Patients ≥ 70 years with untreated, metastatic NSCLC were randomized to Erlotinib (E), 150 mg/day or Carboplatin (AUC5) plus Vinorelbine (25mg/m(2) on days 1 and 8) every three weeks (CV). Primary endpoint was progression-free survival (PFS). After progression, crossover was strongly recommended. Secondary endpoints were duration of response, 1-year survival, overall survival (OS), response rate (RR), quality of life (FACT-L), assessment of comorbidities by simplified comorbidity score (SCS) and Charlsons' comorbidity score, safety and assessment of molecular markers., Results: Between June 2006 and August 2008 284 pts were randomized to E (144) and CV (140). PFS was significantly inferior with E (median PFS 2.4 versus 4.6 months [HR 1.6, 75% CI 1.22-2.09, p: 0.0005]) as well as RR (7.8% v 28.3%, p: 0.0001). No significant difference in OS appeared (median E: 7.3 months versus CV: 8.4 months, HR: 1.24 [75% CI 0.9-1.71]). In never smokers PFS (median PFS: 3.7 v 4.3 m, E v CV, HR 0.72, 75% CI 0.35-1.48) and OS (median: 16.5 versus 17 months, HR 0.99 [75% CI 0.38-2.57]) were comparable. More skin toxicity and diarrhea was seen with E compared to more myelotoxicity, neurotoxicity and constipation with CV. Less severe adverse events were observed with E (81 v 102, E v CV)., Conclusion: CV had an increased efficacy compared with E in an unselected population of elderly patients with advanced NSCLC., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Adding nitroglycerin to the combination of vinorelbine plus cisplatin has been reported to improve the overall survival (OS) of Asian patients with stage IIIB/IV non-small cell lung cancer (NSCLC) probably due to better drug delivery based on changed vascular tonus. The main objective of our study was to evaluate the effect of adding nitroglycerin to vinorelbine and cisplatin in a Caucasian population., Methods: 66 chemonaïve patients with stage IIIB/IV NSCLC received oral vinorelbine (first cycle 60 mg/m(2), subsequent cycles: 80 mg/m(2) in the absence of any hematological toxicity ≥ grade 3 in cycle 1) once daily on days 1 and 8 of each cycle and cisplatin (80 mg/m(2) i.v.) on day 1 of each cycle (q3w). Nitroglycerin (arm A, n=34) or placebo patches (arm B, n=32) were administered once daily from day -3 to day 2 of each cycle and were removed about 12h after administration. One nitroglycerin patch contained 25mg nitroglycerin., Results: Median age was 62.5 (33-82) years. In the overall population (n=66), the objective response rate (ORR) was 27.3% (all PR; 95%CI: 17.0-39.6), with a disease control rate (DCR) of 57.6% (95%CI: 44.8-69.7), a median time to progression (TTP) of 4.8 months (n=58; 95%CI: 3.4-5.9) and a median overall survival (OS) of 11.5 months (95%CI: 7.9-13.6). ORR and DCR were numerically higher in arm A than in arm B (35.3% vs. 18.8% and 61.8% vs. 53.1%, respectively), whereas TTP and OS were comparable. The main hematological and non-hematological toxicities grade ≥ 3 were moderate with no significant differences between the two treatment arms., Conclusions: Overall, oral vinorelbine plus cisplatin showed a high level of efficacy and adequate tolerability in first line treatment of NSCLC. Despite the low sample size per group the results seem to confirm the previous results reported in Asian patients., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC)., Methods: Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0-1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety., Results: 97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n=25), there was a non-significant trend toward increased PFS with tigatuzumab versus placebo (HR=0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo., Conclusions: Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naïve, unselected advanced NSCLC patients., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Sagopilone is the first fully synthetic epothilone in clinical development and has proven preclinical activity in tumor models. This multicenter, randomized, open-label, phase II study examined the efficacy and safety of three regimens with two doses and two infusion durations of second-line sagopilone in pretreated patients with stage IIIB or IV non-small-cell lung cancer., Methods: Eligibility criteria included: at least one measurable lesion by modified response evaluation criteria in solid tumors; World Health Organization performance status of 0 or 1; and failure of previous platinum-based chemotherapy. Patients were randomized to receive: 16 mg/m2 sagopilone over 3 h (treatment arm A); 22 mg/m(2) sagopilone over 0.5 h (treatment arm B); or 22 mg/m2 sagopilone over 3h (treatment arm C). Treatment duration was two to six courses every 3 weeks; more than six treatment courses were permitted if there was sustained clinical benefit. The primary efficacy endpoint was best overall response after six courses; at least five confirmed responders per arm indicated a successful outcome., Results: In total, 128 patients (44, arm A; 41, arm B; 43, arm C) were randomized; 127 received at least one infusion of sagopilone. Baseline demographic data were similar across all arms. Eight patients across all arms had a confirmed partial response; the primary endpoint was not achieved. The most frequently reported adverse event (AE) was peripheral sensory neuropathy (75%). Most hematologic AEs were grade 1 or 2., Conclusion: As fewer than five patients per arm responded after six treatment courses, the primary endpoint was not met. Sagopilone was only moderately tolerated. Most AEs, including peripheral neuropathy, were grade 1 or 2; hematologic toxicities were rare., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: We examined how crossover therapy might affect the association between progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC)., Methods: We extracted PFS- and OS-hazard ratios (HRs) in phase III trials of molecular-targeted agents for advanced NSCLC. Their relationship was modeled in a linear function with the coefficient of determination (R-squared) to assess the correlation between PFS and OS., Results: Thirty-four trials with 35 pairs for the investigational and reference arms were identified (24,158 patients). Overall, there was little correlation between PFS- and OS-HRs (R-squared = 0.14), suggesting PFS-HR could account only for 14% of variation in OS-HR. The median proportion of crossover therapy per trial was 20%. If patients seldom crossed over (none or <1%), the association between PFS- and OS-HRs was strong (R-squared = 0.69). When the proportion of crossover was ≥1%, however, R-squared declined considerably (≥1% to <20% crossover, R-squared = 0.27; ≥20% to <40%, R-squared = 0.06; and ≥40%, R-squared = 0.27)., Conclusions: A PFS advantage seldom is associated with an OS advantage any longer. Our analysis suggests this is due to a high level of crossover now that an increasing number of active agents are available for NSCLC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Small cell lung cancer (SCLC) is associated with poor prognosis due to its early metastatic potential and lack of improved outcomes with newer cytotoxic agents. Identifying factors associated with clinical outcomes can help clinicians determine which patients are more likely to benefit from therapy. Functional Assessment of Cancer Therapy (FACT) subscales and Eastern Cooperative Oncology Group performance status (ECOG PS) were retrospectively analyzed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage disease (ED)-SCLC., Methods: Using data from a Phase III trial of pemetrexed-carboplatin vs. etoposide-carboplatin, the effect of the prognostic factors on OS and PFS was analyzed via Cox models. The Kaplan-Meier method was used to estimate OS and PFS parameters for the prognostic subgroups (defined by baseline FACT scores and ECOG PS)., Results: Patients with higher baseline FACT-General (FACT-G) score (≥ median) had significantly higher OS (hazard ratio [HR]=0.62, P<.0001) and PFS (HR=0.83, P=.032) compared with patients with lower FACT-G score (

Background: Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis. Solid tumors, including non-small cell lung cancer (NSCLC), are dependent on angiogenesis for growth and metastasis. Anti-VEGF therapy has demonstrated clinical benefits in the first-line treatment of NSCLC. Central nervous system (CNS) metastases are a common occurrence among patients with lung cancer and confer significant morbidity and mortality. The risk of CNS hemorrhage in NSCLC patients receiving anti-VEGF therapy is still relatively unexplored because patients with CNS metastases have generally been excluded from trials of anti-VEGF therapy due to a perceived increased risk of cerebral hemorrhage. Recently, large prospective, randomized trials, open-label studies and observational cohort studies in NSCLC have provided data on the incidence of CNS hemorrhage in large patient populations, reflective of community practice., Methods: We conducted a literature review for the available data on the incidence of CNS hemorrhage in NSCLC patients with brain metastases receiving anti-VEGF therapy., Results: There is no significantly increased risk of CNS hemorrhage in patients with NSCLC and emerging (previously untreated) or pretreated CNS metastases receiving anti-VEGF therapy., Conclusions: We conclude that clinical trial data indicate that anti-VEGF therapy can be considered for NSCLC patients with emerging or pretreated CNS metastases., (Copyright © 2012. Published by Elsevier Ireland Ltd.)

Erlotinib is a highly potent inhibitor of epidermal growth factor receptor tyrosine-kinase activity that significantly prolongs overall survival in patients with non-small-cell lung cancer (NSCLC), and improves symptom control and quality of life compared with placebo. The safety and efficacy of erlotinib has been investigated in a large, international, phase IV, open-label study (TRUST) in patients (n=6665) with advanced stage IIIB/IV NSCLC. An analysis of efficacy and safety outcomes is reported for patients receiving erlotinib as second-line therapy in TRUST (n=3224). Best response data were available for all 3224 patients. Complete response, partial response and stable disease were achieved in 25 (<1%), 368 (14%) and 1444 (54%) patients, respectively, for a disease control rate of 68%. Median progression-free and overall survivals were 13.6 weeks and 8.6 months, respectively; 1-year survival was 39.4%. Safety data were available for all patients. Of these, 389 patients (12%) had an erlotinib-related adverse event (AE) other than pre-specified AEs defined in the protocol; only 96 patients (3%) had an erlotinib-related AE ≥ grade 3. Of 1376 patients (43%) with serious AEs (SAEs), only 122 (4%) had treatment-related SAEs and most were gastrointestinal disorders (mainly diarrhoea and nausea). No treatment-related SAE occurred in ≥ 1% of patients. Data on the incidence of erlotinib-related rash were collected for all patients, 2302 (71%) of whom experienced rash. Of these rash events, 83% were of grade 1/2. These data confirm the good efficacy and tolerability of second-line erlotinib in a broad range of patients with NSCLC., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Lung cancer continues to present an enormous global burden of morbidity and mortality, despite an increasing therapeutic armamentarium of chemotherapy and targeted agents. Recent research efforts have been directed towards identifying predictors of response to treatment, in order to facilitate the selection of patients likely to obtain the greatest benefit from specific therapeutic interventions, with the ultimate goal of providing customized therapy. A strong scientific basis exists for the use of markers to identify patients who are most likely to respond to biological and targeted therapies, based on characteristics such as tumour genotype and histology. Biomarkers have the potential to aid in patient stratification (risk assessment), treatment-response identification (surrogate markers), or differential diagnosis (identifying individuals who are likely to respond well to specific therapies). Numerous trials have demonstrated correlations between molecular biomarkers and the outcome of treatment with targeted therapies such as epidermal growth factor inhibitor tyrosine-kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). The recently completed MarkER Identification Trial (MERIT) found some evidence of a link between the molecular profile of a tumour and the clinical response to erlotinib in patients with relapsed NSCLC. However, MERIT also highlighted the difficulties in obtaining adequate samples for the various procedures involved in genetic analyses in clinical trials. Routine clinical practice brings its own challenges relating to biopsy techniques and tissue availability and this has implications for the application of molecular analyses in treatment decision-making. Applying the lessons learned from tissue sampling and molecular testing in MERIT and other major NSCLC trials will be essential in paving the way for the routine use of biomarker analyses in clinical practice., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The aim of this retrospective study is to present data on patient characteristics, treatment patterns, and treatment results in an unselected contemporary patient population with small cell lung cancer (SCLC) in limited disease (LD) and extensive disease stage (ED)., Patients and Methods: From June 2004 to December 2008, our electronic database including all in-patient and out-patient contacts was searched for patients with newly diagnosed lung cancer. 397 patients were found having SCLC. We collected data on patient characteristics, chemotherapy, side effects, response on treatment and survival., Results: 39% of all patients had LD SCLC. Median age was 63 years. The response rate (RR) reached 76%. Stable disease was the result of first line therapy in 16%. Consecutive thoracic radiotherapy was given in 72%. Additional prophylactic cranial irradiation (PCI) was administered to 33%. 43% received second line therapy. Median survival was 18.8 months. In 61% of cases, ED SCLC was diagnosed. Median age was 61 years. Main metastatic sites were liver, bone, brain and adrenal glands. RR was 69%. Stable disease and progressive disease were the result of first line chemotherapy both in 12%. 15% received palliative cranial irradiation, 3% PCI. 51% were treated with second line therapy. Median survival reached 10.6 months., Conclusion: We provide a comprehensive analysis of a contemporary patient population. Treatment patterns and survival data fit well in the context of current international trials on more selected patients. Multivariate analyses confirmed extend of disease, performance status and LDH serum levels as independent prognostic factors for survival. Age and gender reached no statistical significance., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To determine the maximum tolerated dose (MTD) of sunitinib plus gemcitabine/cisplatin for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Safety, pharmacokinetics, and antitumor activities were evaluated., Methods: Patients ≥18 years with Eastern Cooperative Oncology Group performance status 0/1 and stage IIIB/IV NSCLC were included in this open-label, multicenter, dose-escalation phase I study. Treatment was administered in 3-week cycles: oral sunitinib 37.5 or 50mg/day intermittently (Schedule 2/1: 2 weeks on treatment, 1 week off treatment) or 25mg continuous daily dosing (CDD) schedule with intravenous infusions of gemcitabine (1000 or 1250 mg/m(2) days 1, 8) and cisplatin (80 mg/m(2) day 1)., Results: A total of 28 evaluable patients were assigned to four dose levels. Most adverse events (AEs) on the Schedule 2/1 MTD were mild to moderate. Dose delays due to myelosuppression occurred on both schedules, limiting treatment to a median of four cycles. Four of 18 evaluable patients (22%) on Schedule 2/1 and 1 of 6 patients (17%) on the CDD schedule had confirmed partial responses., Conclusions: The MTD was identified as sunitinib 37.5mg (Schedule 2/1), gemcitabine 1250 mg/m(2), and cisplatin 80 mg/m(2), with most AEs being mild to moderate. However, frequent dose delays due to myelosuppression occurred. There was evidence of antitumor activity with this combination., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: This is a phase II randomized study to evaluate the efficacy and safety of bortezomib and pemetrexed alone or in combination, in patients with previously treated advanced non-small-cell lung cancer (NSCLC). The primary end point was assessment of response rate., Methods: A total of 155 patients were randomized (1:1:1) to pemetrexed (500mg/m(2)) on day 1 plus bortezomib (1.6mg/m(2)) on days 1 and 8 (Arm A) or pemetrexed (500mg/m(2)) on day 1 (Arm B) or bortezomib (1.6mg/m(2)) on days 1 and 8 (Arm C) of a 21 day cycle. Response rate was assessed by investigators using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and toxicity assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading system., Results: Response rate was 7% in Arm A, 4% in Arm B, and 0% in Arm C; disease control rates were 73%, 62%, and 43%, respectively. Median overall survival was 8.6 months in Arm A, 12.7 months in Arm B, and 7.8 months in Arm C; time to progression was 4.0 months, 2.9 months, and 1.4 months, respectively. Most common reported adverse events >/=grade 3 were neutropenia (19%), thrombocytopenia (15%), and dyspnea (13%) in Arm A, neutropenia (10%) in Arm B, and dyspnea (13%) and fatigue (10%) in Arm C., Conclusion: In previously treated NSCLC the addition of bortezomib to pemetrexed was well tolerated but offered no statistically significant response or survival advantage versus pemetrexed alone, while bortezomib alone showed no clinically significant activity., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer, and it is the most common cause of death in men and second only to breast cancer in women. Combination chemotherapy, usually platinum-based, is currently the first-line therapy of choice, however, the prognosis for patients with advanced NSCLC remains poor with a median survival time of 8-11 months and a 1-year survival rate of 30%. The treatment of NSCLC is therefore a major unmet need and new therapies focusing on the molecular mechanisms that mediate growth of NSCLC cells are urgently needed. The availability of agents targeted against the EGF-R, as well as the anti-VEGF agent bevacizumab, have provided some clinical benefit. Numerous other novel targeted therapies are now in clinical development and may have potential for overcoming the limitations associated with currently available drugs. In addition, a few new agents targeting novel pathways are also under clinical evaluation. The search for innovative therapeutic agents in NSCLC that are more effective and have fewer side effects than older chemotherapeutic drugs has spurred the development of more than 500 molecularly targeted agents and thereby has introduced the concept of individualized therapy. In this article we review clinical data for molecular-targeted therapies in NSCLC, with emphasis on EGF-R, VEGF-R and other novel targets. Nonetheless, for most patients with NSCLC targeted therapies have not dramatically changed clinical outcome, and resistance has emerged as a clinical problem. The molecular complexity of lung cancer underlies these disappointments and stresses the need for optimizing treatment by seeking a more personalized approach to care. Therefore, clinical trials that investigate the activity of novel agents, and incorporate patient selection based on clinical and molecular factors, are required. The increased sophistication of preclinical models and the enrollment of patients in clinical trials that include measurements of biomarkers will clearly help to identify patients who are likely to benefit from therapy, as well as further define mechanisms of resistance to therapy.

This single-arm phase II study evaluated the tumor-vascular disrupting agent ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800mg/m(2) plus standard therapy of carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). This ASA404 dose is 50% higher than that used in previous phase II studies. Thirty patients with histologically confirmed stage IIIb or IV NSCLC previously untreated with chemotherapy received carboplatin AUC 6mg/mlmin plus paclitaxel 175mg/m(2) plus ASA404 1800mg/m(2) every 21 days for up to six cycles. The addition of ASA404 1800mg/m(2) to standard therapy produced little change in the systemic exposure of either total or free carboplatin or paclitaxel, and was generally well-tolerated, with no cardiac serious adverse events or clinically relevant ophthalmic abnormalities. The best overall tumor response was partial response, which was seen in 37.9% of patients by independent assessment and in 46.7% by investigator assessment. Stable disease was seen in 48.3% of patients by independent assessment and in 43.3% by investigator assessment. Median time to tumor progression was 5.5 months by investigator assessment and median survival was 14.9 months. The data from this trial corroborate findings from a recent randomized phase II trial, which suggested improvements in efficacy variables, including survival, when ASA404 1200mg/m(2) was added to standard therapy for advanced NSCLC. The manageable safety profile, lack of adverse pharmacokinetic interactions and efficacy outcomes seen in this single-arm study suggest that ASA404 1800mg/m(2) is a viable dose for future combination studies.

Introduction: This phase II study assessed the efficacy and safety of oral vinorelbine given weekly in combination with carboplatin (CBDCA) AUC 5 once every 3 weeks for four cycles in chemonaive patients with advanced non-small cell lung carcinoma (NSCLC), followed by consolidation therapy with single-agent oral vinorelbine in non-progressive patients., Methods: Chemonaive advanced NSCLC patients received four cycles of combination therapy with CBDCA AUC 5 day 1 and oral vinorelbine, 60 mg/m2 on days 1, 8 and 15 (cycle 1), dose increased to 80 mg/m2 (cycles 2-4) in absence of grades 3-4 neutropenia (NCI-CTCv2). Consolidation therapy with oral vinorelbine was continued (cycle 5) at same dosage; if dose was decreased during combination therapy, it was given at 60 mg/m2, then increased at 80 mg/m2 (cycle 6) in absence of grades 3-4 neutropenia until PD, toxicity or patient's refusal., Results: A total of 57 patients were registered and 56 patients were treated (ITT population), median age was 61 years (37-71). Objective response evaluated by RECIST was 17.9% (95% confidence interval, CI [8.9-30.4]) and disease control (CR, PR, NC) 73.2% (95% CI [59.7-84.2]), median progression-free survival 4.3 months (95% CI [3.1-5.1]) with median overall survival 9.7 months (95% CI [7.7-11.9]) and 1-year survival 37.1% (95% CI [24.4, 49.9]). Grades 3-4 neutropenia occurred in 67.9% of patients during combination and 20% during consolidation; febrile neutropenia occurred in 4 patients (7.1%) during combination therapy. Non-hematological toxicities occurred primarily during combination (grade 3 nausea and grade 3 vomiting in 7.1% of patients)., Conclusions: The combination of oral vinorelbine given weekly in 3-week cycles in combination with carboplatin followed by consolidation therapy with oral vinorelbine as a single-agent was able to achieve efficacy results in line with other doublets including carboplatin in terms of response as well as survival. This regimen reported a good profile of tolerability in the treatment of advanced NSCLC, allowing that this combination can be easily proposed for the palliative care of NSCLC patients where the advantages of carboplatin over cisplatin are still appreciated.

Chemotherapy has reached a therapeutic plateau in the treatment of advanced non-small cell lung cancer (NSCLC), and effective, better-tolerated treatment strategies are needed. An improved understanding of the molecular processes underlying tumor biology has led to the development of therapies that target these processes. Intracellular signaling pathways related to the vascular endothelial growth factor and the epidermal growth factor receptor both play a central role in tumorigenesis as well as tumor growth, and are therefore rational targets for anti-cancer drug development. Various agents that target these pathways are in clinical development. Some of these have already changed treatment practice in NSCLC, most notably the monoclonal antibody, bevacizumab, in combination with chemotherapy in the first-line setting and the small-molecule tyrosine-kinase inhibitors, erlotinib and gefitinib, in the second-line setting. We will review the clinical data for various novel therapies and identify how these agents are improving outcomes in the first- and second-line treatment of advanced NSCLC.

Purpose: Based on the promising activity of paclitaxel in small-cell lung cancer (SCLC) we conducted a randomized phase III trial to evaluate whether a combination of paclitaxel, carboplatin and etoposide phosphate (TEC) improves survival and time to progression as well as tolerability and quality of life (QoL) compared to a regimen of carboplatin, etoposide phosphate and vincristine (CEV) in SCLC patients., Patients and Methods: Six hundred and fourteen patients with stages I-IV SCLC were randomly assigned between January 1998 and December 1999 to both treatment arms. All patients were evaluated for response rate, survival, side effects and quality of life with overall survival (OS) serving as primary endpoint. A final analysis was done after a six-year follow-up. Survival curves were estimated using Kaplan-Meier curves and tested with the log-rank test. Quality of life data were assessed in using the EORTC QLQ-C30 questionnaire and evaluated by calculating and comparing the mean scores as well as applying longitudinal techniques., Results: Six hundred and eight patients were evaluable for efficacy and toxicity. The long-term follow-up confirms the significant survival benefit for the paclitaxel, etoposide, carboplatin (TEC) regimen with a median OS of 12.5 months compared to 11.7 months for the CEV arm (HR, 1.21; 95% CI, 1.02-1.43; P=.030). The 5-year survival rates were 14% for the experimental versus 6 % for the CEV arm. Significant survival prolongation was also observed in the subgroup of patients with stage IV disease (HR, 1.27; 95% CI, 1.00-1.60; P=.047). The previously reported clinical benefit in form of an overall reduction of grade 3/4 toxicity was backed by the results of the comprehensive QoL analysis we report hereby. TEC significantly improves the relevant QoL parameters like global overall QoL or physical functioning., Conclusion: When administered in combination with etoposide and carboplatin, paclitaxel is able to offer in SCLC patients with extensive disease a survival benefit without additional toxicities, but with gains in patient-reported quality of life. In terms of efficient palliative care, TEC might be seen as an alternative to standard cisplatin plus etoposide in patients requesting a powerful palliative regimen not compromising any survival benefit.

Background: Gefitinib is the first approved EGFR tyrosine-kinase inhibitor indicated for the treatment of patients with locally advanced (IIIB) or metastatic NSCLC after failure of platinum-based first-line therapy and docetaxel chemotherapy. Following rapid approval in Japan and accelerated approval based on phase-II results in the US, a large compassionate-use program has been set up in parallel to extended phase-III testing. Offering therefore access to state-of-the-art therapy to patients who are not candidates for clinical studies; Iressatrade mark EAP allows physicians to test the new EGFR inhibitor across a heterogeneous patient population characteristic for advanced NSCLC., Patient and Methods: After having treated 240 patients at the Grosshansdorf hospital, we have retrospectively analysed the efficacy and tolerability of 250 mg/day gefitinib in patients showing a long-term tumor control. We reviewed the patient records of 14 patients with advanced NSCLC that received daily gefitinib for at least 9 months., Results: Long-term tumor control, defined as confirmed objective tumor response for at least 6 months or disease stabilisation for above 9 months, was observed in chemo-naive patients as well as in fourth-line therapy patients for the latter ones independently of the composition of prior chemotherapy. Most patients (9/14) with such a lasting benefit were female; patients' histology was in most cases uniform: adenocarcinomas were dominant in women and bronchioloalveolar carcinoma in men. Patients with moderate to severe dyspnoea benefited from a measurable improvement of their respiratory capacity. No cumulative toxicity was observed; characteristic side-effects for gefitinib as grades 1-2 diarrhoea or mild to moderate skin toxicity were well manageable., Conclusion: For 14 (6%) out of 240 patients with patterns of diffuse disseminated metastatic disease, gefitinib offered a lasting tumor control with a disease progression-free survival interval between 9 and 25 months. In parallel to therapy, patients' performance status (PS) could be conserved or even improved in many cases. Patients with lung function impairment, as well as patients with other disease-related symptoms obtained additional therapy benefits.

In the treatment of extensive disease of small cell lung cancer (ED SCLC) there is an urgent need for more effective and better-tolerated drug regimens. We report on a prospective phase II trial performed to evaluate the efficacy and safety of a platinum-free regimen--containing topotecan and etoposide--in the first-line treatment of ED SCLC. Between December 1999 and July 2001, 28 chemotherapy-naive patients with ED SCLC were recruited; 9 patients had stage IIIB disease and 19 patients had stage IV disease. Based on phase I results, patients received treatment with intravenous topotecan 1 mg/m2 (days 1-5) followed by intravenous etoposide 75 mg/m2 (days 8-10). Treatment courses were repeated every 28 days for a maximum of 6 cycles. A confirmed response rate of 46.4% with 1 complete response (CR) and 12 partial responses (PR) (95% CI=27.5-66.1%) was observed. Stable disease (SD) was observed in 18% of patients. The median time to response was 7.9 weeks (range: 7.7-15.1 weeks) and median survival was 29.9 weeks (range from 3.3 to 91.4 weeks). Main toxicities encountered were haematological with Grade III/IV neutropenia in 2.6/1.5% of courses and Grade III/IV thrombocytopenia in 1.8%/0.7% of courses. These toxicities were manageable and were not associated with clinical sequels. Non-haematological toxicities were generally mild with no Grade III/IV toxicities reported apart from Grade III alopecia. The combination therapy of topotecan and etoposide is active in first-line chemotherapy for patients with ED SCLC. The regimen showed a tolerable safety profile. Since drug scheduling plays a critical role in the combination of topoisomerase I and II inhibitors, concurrent administration of topotecan and etoposide might increase the efficacy.

Since cisplatin-based chemotherapy was proven to increase survival in advanced and metastatic NSCLC various new combinations have been tested. The third generation regimens which showed almost comparable efficacy among each other in randomised trials often proved a better response rate and time to progression combined with a remarkable reduction of toxic side effects compared to "classic" combinations, whereas most studies only noted a modest increase in survival. Two-drug regimens were more effective than monotherapy but at the expense of significantly increased toxicity, while monotherapy compared to BSC improved quality of life and survival. The novel antifolate Pemetrexed proved comparable activity to docetaxel with significantly reduced toxicities.