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Background: Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions., Materials and Methods: Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action., Results: Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority., Conclusions: Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer commissioned a diverse multidisciplinary international expert panel to evaluate the current landscape and provide diagnostic, staging, and therapeutic recommendations for patients with rNSCLC, with particular emphasis on patients with American Joint Committee on Cancer-Union for International Cancer Control TNM eighth edition stages II and III disease. Using a team-based approach, we generated 19 recommendations, of which all but one achieved greater than 85% consensus among panel members. A public voting process was initiated, which successfully validated and provided qualitative nuance to our recommendations. Highlights include the following: (1) the critical importance of a multidisciplinary approach to the evaluation of patients with rNSCLC driven by shared clinical decision-making of a multispecialty team of expert providers; (2) biomarker testing for rNSCLC; (3) a preference for neoadjuvant chemoimmunotherapy for stage III rNSCLC; (4) equipoise regarding the optimal management of patients with stage II between upfront surgery followed by adjuvant therapy and neoadjuvant or perioperative strategies; and (5) the robust preference for adjuvant targeted therapy for patients with rNSCLC and sensitizing EGFR and ALK tumor alterations. Our primary goals were to provide practical recommendations sensitive to the global differences in biology and resources for patients with rNSCLC and to provide expert consensus guidance tailored to the individualized patient needs, goals, and preferences in their cancer care journey as these are areas where physicians must make daily clinical decisions in the absence of definitive data. These recommendations will continue to evolve as the treatment landscape for rNSCLC expands and more knowledge is acquired on the best therapeutic approach in specific patient and disease subgroups., Competing Interests: Disclosure Dr. Spicer reports receiving grants or contracts from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen, Roche, Regeneron, and Pfizer; consulting fees from AstraZeneca, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, and Merck Sharp & Dohme; honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pfizer; meeting support from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; data safety monitoring board for AstraZeneca; and receipt of other services from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme, outside the submitted work. Dr. Cascone reports receiving speaker fees and/or honoraria from the American Society for Clinical Oncology Post, AstraZeneca, Bio Ascend, Bristol-Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medical, PeerView, Physicians' Education Resource, Society for Immunotherapy of Cancer, and Targeted Oncology; advisory role/consulting fees from Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Mark Foundation for Cancer Research, Merck, oNKo-innate, Pfizer, RAPT Therapeutics, and Regeneron; and institutional research funding from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. Dr.Ahn reports receiving consulting fees from AstraZeneca, Alpha Pharmaceuticals, Genxin, and Pfizer; and honoraria from Takeda, Roche, Merck, Merck Sharp & Dohme, AstraZeneca, Amgen, Boronoi, Arcus, Daiichi Sankyo, Bayer, and Janssen, outside the submitted work. Dr.Dacic reports receiving consulting fees from AstraZeneca, Genentech, and Medscape, outside the submitted work. Dr. Felip reports receiving consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, and Daiichi Sankyo; honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; travel support from AstraZeneca, Janssen, and Roche; and other from Grifols as an independent member of the board, outside the submitted work. Dr. Forde reports receiving grants or contracts from AstraZeneca, Bristol-Myers Squibb, Novartis, Regeneron, and BioNTech; consulting fees from Ascendis, AstraZeneca, Bristol-Myers Squibb, Curevac, Novartis, Regeneron, G1, Genlux, Genentech, Gritstone, Merck, Janssen, F Star, Sanofi, Amgen, Fosun, Teva, Synthekine, Flame, Iteos, and Tavotek. Dr. Higgins reports receiving grants or contracts from Jazz Pharmaceuticals, RefleXion Medicalx; consulting fees from AstraZeneca and Janssen; positions on the NRG Oncology Board of Directors and RTOG Foundation Board of Directors; and stock or stock options in Picture Health. Dr. Kris reports receiving grant or contracts from BerGenBio, Merus, AstraZeneca, Mirati, Pfizer, Janssen, Sanofi, and Novartis; honoraria from Pfizer and AstraZeneca; and personal fees from AstraZeneca and Roche/Genentech, outside the submitted work. Dr. Mitsudomi reports receiving grants or contracts from Boehringer Ingelheim, AstraZeneca, Chugai, Pfizer, Ono, Daiichi Sankyo, and Eli Lilly; consulting fees from AstraZeneca, Novartis, Chugai, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Thermo Fisher, Roche Diagnostics, Bristol-Myers Squibb, Ono Pharmaceuticals, Taiho, Takeda, Janssen, Daiichi Sankyo, and Regeneron; honoraria from AstraZeneca, Chugai, Boehringer Ingelheim, Pfizer, Taiho, Eli Lilly, Daiichi Sankyo, Thermo Fisher, Merck Sharp & Dohme, Bristol-Myers Squibb, Ono Pharmaceuticals, Invitae, Guardant, Novartis, Amgen, Merck biopharma, and Kyorin; data safety monitoring board for Taiho Pharmaceutical, outside the submitted work. Dr. Provencio reports receiving grants or contracts from Bristol-Myers Squibb, AstraZeneca, Roche, Janssen, and Takeda; consulting fees from Bristol-Myers Squibb, Roche, AstraZeneca, Merck Sharp & Dohme, and Takeda; honoraria from Bristol-Myers Squibb, Takeda, Roche, AstraZeneca, and Merck Sharp & Dohme; and meeting attendance support from Merck Sharp & Dohme, Roche, and Bristol-Myers Squibb, outside the submitted work. Dr. Senan reports receiving grants or contracts from AstraZeneca, Merck Sharp & Dohme, and Bristol-Myers Squibb; consulting fees from AstraZeneca and Bristol-Myers Squibb; honoraria from AstraZeneca; advisory board participation for AstraZeneca and Merck Sharp & Dohme; and membership on ETOP scientific committee, outside the submitted work. Dr. Solomon reports receiving travel support from IASLC to attend meeting related to manuscript; consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lily, Merck Sharp & Dohme, Pfizer, Roche, GlaxoSmithKline, Janssen, and Amgen; honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, and GlaxoSmithKline; unpaid leadership roles at the IASLC, Thoracic Oncology Group of Australasia, and Cancer Council of Victoria. Dr. Tsao reports receiving travel support from IASLC to attend meeting related to manuscript; grants or contracts from AstraZeneca, Bayer, and Lily; consulting fees from AstraZeneca, Bayer, Amgen, AbbVie, Regeneron, Sanofi, Daiichi Sankyo, and Lily; honoraria from AbbVie and Sanofi; and board of directors for IASLC. Dr. Tsuboi reports receiving grant from AstraZeneca KK, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb KK, Novartis Japan, BMG KK, MiRXES, and Johnson & Johnson Japan; honoraria from Amgen KK, Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co., Ltd., Taiho Pharma, Medtronic Japan, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme KK, Bristol-Myers Squibb KK, Daiichi Sanko KK, and Novalis; advisory committee participation for Chugai Pharmaceutical Co., Ltd., and AstraZeneca KK; and Board of Directors for Japan Lung Cancer Society (JLCS), Bronchology Committee Chair for JLCS, and Educational Committee working group chair for IASLC, outside the submitted work. Dr. Wakelee reports receiving grants or contracts from ACEA Biosciences, Arrys Therapeutics, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; advisory board participation for AstraZeneca, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership positions on the IASLC Board of Directors and ECOG-ACRIN executive committee. Dr. Wu reports receiving grants and contracts form AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Henqrui, and Roche; honoraria from AstraZeneca, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi; and unpaid leadership role for Chinese Thoracic Oncology Group. Dr. Yang reports receiving personal fees and other from Amgen, Bayer Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Merck KGaA, Merck Sharp & Dohme, Novartis, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceuticals; grants, personal fees, and other from AstraZeneca; other from Eli Lilly; personal fees from Ono Pharmaceuticals and Pfizer; and other from JNJ, Puma Technology, Gilead, and GlaxoSmithKline, outside the submitted work. Dr. Zhou reports receiving consulting fees from Innovent Biologics, Hengrui, Qila, and TopAlliance Biosciences; honoraria from Lily China, Sanofi, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, LUYE Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart. Dr. Kelly reports receiving grants from AstraZeneca, during the conduct of the study; grants and personal fees from Genentech and Bristol-Myers Squibb; and personal fees from AstraZeneca, outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Despite surgical resection, long-term survival of patients with resectable non-small cell lung cancer (NSCLC) remains poor. Adjuvant chemotherapy, the standard of care for locally advanced NSCLC, provides a marginal 5.4% benefit in survival. Immune checkpoint inhibitors (ICIs) have shown a significant survival benefit in some patients with advanced NSCLC and are being evaluated for perioperative use in resectable NSCLC., Methods: We conducted a literature search using the PubMed online database to identify clinical trials of immunotherapy in resectable NSCLC and studies analyzing biomarkers and immune priming strategies., Results: Building on previous phase I and II trials, randomized phase III trials have shown efficacy of neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant atezolizumab, and adjuvant pembrolizumab in the treatment of NSCLC with improvement of event-free/disease-free survival of 24% to 42%, leading to United States Food and Drug Administration approval of these drugs in the treatment of resectable NSCLC. Three additional phase III trials have also recently reported the use of immunotherapy both before and after surgery, with pathologic complete response rates of 17% to 25%, significantly better than chemotherapy alone. Perioperative ICI therapy has comparable perioperative morbidity to chemotherapy alone and does not impair surgical outcomes., Conclusions: Perioperative immunotherapy, in combination with chemotherapy, is safe and improves outcomes in patients with resectable NSCLC. Questions regarding patient selection, the need for adjuvant ICI therapy after neoadjuvant chemoimmunotherapy, and the duration of perioperative immunotherapy remain to be answered by future trials., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC., Methods: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R 2 with 95% confidence interval were calculated by the bootstrapping approach., Results: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R 2 of pCR and MPR with 2-year EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For the 2-year OS, the R 2 of pCR and MPR were 0.55 (0.09-0.98) and 0.52 (0.10-0.96), respectively. At the trial level, the R 2 for the association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97), respectively., Conclusions: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed., Competing Interests: Disclosure Drs. Hines and Cameron were supported by the National Institute for General Medical Sciences (T32 GM07019). Dr. Bestvina reports receiving institutional research funding from AstraZeneca and Bristol Myers Squibb; and advisory board membership/consulting for Amgen, AstraZeneca, Bristol Myers Squibb, CVS, Daiichi Sankyo, EMD Serono, Gilead, JNJ, Mirati, Novocure, Regeneron, Sanofi, Takeda, and Tempus. Dr. Garassino reports receiving personal financial support from AstraZeneca, Abion, Merck Sharp & DohmeInternational GmbH, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Blueprint, Janssen, Sanofi, AbbVie, BeiGenius, Oncohost, and Medscape; received institutional financial support from Eli Lilly, Merck Sharp & Dohme, Pfizer (MISP), AstraZeneca, Merck Sharp & Dohme International GmbH, Bristol-Myers Squibb, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, GlaxoSmithKline, and Spectrum pharmaceuticals; received other forms of support from AIRC, AIFA, Italian Moh, and Transcan; and received research funding from Horizon 2020. Dr. Veronesi has received honoraria from Ab Medica Spa, AstraZeneca, Roche, and Merck Sharp & Dohme outside the submitted work. Dr. Cascone reports receiving speaker fees/honoraria from ASCO Post, AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and Society for Immunotherapy of Cancer; has advisory role/consulting fees from Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Genentech, Merck & Co., Pfizer, and Regeneron; and received institutional research funding from AstraZeneca and Bristol Myers Squibb. Dr. Taube reports having an advisory role or have received consulting fees from Akoya Biosciences, AstraZeneca, Bristol Myers Squibb, Merck & Co., Genentech, Lunaphore, Compugen, Elephas, and Regeneron; received institutional research funding from Bristol Myers Squibb and Akoya Biosciences; and received reagents and equipment loan and has stock options from Akoya Biosciences. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Brain metastasis (BRM) is uncommon in gastroesophageal cancer. As such, clinicopathologic and molecular determinants of BRM and impact on clinical outcome remain incompletely understood., Methods: We retrospectively analyzed clinicopathologic data from advanced esophageal/gastroesophageal junction (E/GEJ) patients at Johns Hopkins from 2003 to 2021. We investigated the association between several clinical and molecular features and the occurrence of BRM, with particular focus on human epidermal growth factor receptor 2 (HER2) overexpression. Survival outcomes and time to BRM onset were also evaluated., Results: We included 515 patients with advanced E/GEJ cancer. Tumors were 78.3% esophageal primary, 82.9% adenocarcinoma, 31.0% HER2 positive. Cumulative incidence of BRM in the overall cohort and within HER2+ subgroup was 13.8% and 24.3%, respectively. HER2 overexpression was associated with increased risk of BRM [odds ratio 2.45; 95% confidence interval (CI) 1.10-5.46]. On initial presentation with BRM, 50.7% had a solitary brain lesion and 11.3% were asymptomatic. HER2+ status was associated with longer median time to onset of BRM (14.0 versus 6.3 months, P < 0.01), improved median progression free survival on first-line systemic therapy (hazard ratio 0.35, 95% CI 0.16-0.80), and improved median overall survival (hazard ratio 0.20, 95% CI 0.08-0.54) in patients with BRM., Conclusion: HER2 overexpression identifies a gastroesophageal cancer molecular subtype that is significantly associated with increased risk of BRM, though with later onset of BRM and improved survival likely reflecting the impact of central nervous system-penetrant HER2-directed therapy. The prevalence of asymptomatic and solitary brain lesions suggests that brain surveillance for HER2+ patients warrants prospective investigation., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Consolidation durvalumab immunotherapy following definitive chemoradiation (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. As therapeutic options for patients with KRAS-driven disease evolve, more understanding regarding genomic determinants of response and patterns of progression for durvalumab consolidation is needed to optimize outcomes., Methods: We conducted a single-institutional retrospective analysis of real-world patients with locally advanced, unresectable NSCLC who completed CRT and received durvalumab consolidation. Kaplan-Meier analyses compared progression-free survival (PFS) and overall survival (OS) from start of durvalumab consolidation between patients with KRAS-mutated and non-mutated tumors. Fisher's exact test was used to compare rates of intrathoracic or extrathoracic progression., Results: Of 74 response-evaluable patients, 39 had clinical genomic profiling performed. 18 patients had tumors with KRAS mutations, 7 patients had tumors with non-KRAS actionable alterations (EGFR, ALK, ERBB2, BRAF, MET, RET, or ROS1), and 14 patients had tumors without actionable alterations. Median PFS for the overall cohort was 16.1 months. PFS for patients with KRAS-mutated NSCLC was 12.6 months versus 12.7 months for patients with non-actionable tumors (P= 0.77, log-rank). Fisher's exact test revealed a statistically significantly higher rate of extrathoracic progression versus intrathoracic-only progression for patients with KRAS-driven disease compared to patients with non-actionable tumors (P= 0.015)., Conclusion: Patients with KRAS-mutated NSCLC derived similar benefit from durvalumab as patients with non-actionable tumors. A higher rate of extrathoracic progression was also observed among the patients with KRAS-mutated NSCLC compared to patients with non-actionable tumors. This highlights the potential unmet needs for novel systemic therapies and surveillance methods for KRAS-mutated stage III NSCLC., (Copyright © 2022. Published by Elsevier Inc.)

Background: Immunotherapy represents the standard of care in the first-line treatment of advanced non-small-cell lung cancer (NSCLC), either as monotherapy in high programmed death-ligand 1 (PD-L1)-positive tumors (≥50%) or in combination with platinum-based chemotherapy regardless of PD-L1 status. However, most pivotal clinical trials of immune checkpoint inhibitors (ICIs) did not include patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. Hence, a consensus is lacking on the safety and efficacy of ICIs in this specific subgroup of patients., Materials and Methods: A virtual International Expert Panel took place in July 2021 with the aim of reviewing the available evidence on the use of ICIs in NSCLC patients with ECOG PS 2, both in clinical practice and in a research setting., Results: All panelists expressed concern about the applicability of currently available PS scales to evaluate patients for ICI treatment. The panelists agreed that, though limited, the available data support the safety of single-agent immunotherapy in PS 2 NSCLC patients, whereas concern was raised on the safety of ICI combinations, mainly related to chemotherapy and/or anti-cytotoxic T-lymphocyte-associated antigen 4 toxicity. On the basis of reviewed data, ICI efficacy may be speculated in PS 2 NSCLC patients; however, PS 2 remains a negative prognostic category as compared to PS 0-1 in patients treated with ICI, as it is for chemotherapy. The panelists defined high, medium and low priorities in clinical research. High priority was attributed to the inclusion of PS 2 patients in prospective clinical trials and the specific evaluation of combined ICI treatments with attenuated chemotherapy doses., Conclusions: Based on the current evidence, the panelists outlined the major limitations affecting PS 2 patients with NSCLC and reached common considerations on the feasibility, safety and effectiveness of ICI monotherapy and ICI combinations in the first-line setting., Competing Interests: Disclosure CG received honoraria as speaker bureau or advisory board member or as consultant from MSD, BMS, Roche, AstraZeneca, Novartis, Pfizer, Menarini, Boehringer, Karyopharm and Eli Lilly. SP reports personal fees for speaking or attending advisory boards, and has participated in investigation in trials for Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp & Dohme, Merck Serono, Novartis and Pfizer; and personal fees for speaking or attending advisory boards for AbbVie, Bayer, Biocartis, Bioinvent, Daiichi Sankyo, Debiopharm, ecancer, Foundation Medicine, Janssen, Lilly, Medscape, Merrimack, Pharma Mar, Regeneron, Sanofi, Seattle Genetics and Takeda (all fees to institution). TM reported receiving personal fees, grants or other fees from AbbVie, 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, Gritstone Oncology Inc, Guardant Health, Hengrui Therapeutics, Ignyta Inc, IQVIA, Incyte Corporation, InMed Medical Communication, Janssen, Lilly, Loxo-Oncology, Lunit Inc, MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc, MORE Health, Novartis, OrigiMed, PeerVoice, Physicians' Education Resource, Permanyer SL, Pfizer Inc, PrIME Oncology, Puma Technology Inc, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Virtus Medical Group, Yuhan Corporation, AstraZeneca PLC, Hutchison Chi-Med, Sanomics Ltd, Clovis Oncology, SFJ Pharmaceuticals, Xcovery, Curio Science, Inivata, Berry Oncology, G1 Therapeutics Inc and Aurora. PMF received honoraria or consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Novartis, Janssen, Iteos, Flame, Sanofi, Genentech, F-Star, G1 therapeutics and Surface Oncology; and research funding from AstraZeneca, BMS, Kyowa, Corvus and Novartis. MR reports honoraria for consultancy and lecture roles from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck, Mirati, Merck Sharp & Dohme, Novartis and Pfizer. FdM received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Xcovery and Roche. IA has declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with stage IV oligometastatic (≤ 3 sites) non-small-cell lung cancer have a progression-free survival (PFS) and overall survival benefit when all sites of metastatic disease and the primary tumor are treated radically with consolidative radiotherapy (cRT). However, the optimal selection of patients most likely from cRT is yet to be defined., Patients and Methods: Patients with metastatic non-small-cell lung cancer treated with definitive radiotherapy to all metastatic sites and primary tumor (2008-2019) were retrospectively identified. Univariable Cox proportional-hazards model was used to compare outcomes with demographic and clinical characteristics. A predictive nomogram model for selection of patients most likely to benefit from cRT was constructed., Results: There were 91 patients identified with a total of 114 metastases treated. Median PFS from the start of cRT was 10.9 months (95% confidence interval [CI], 8.1-16.6), while the median survival time was 37.0 months (95% CI, 31.3-NR). On univariable modeling, patients with squamous histology (hazard ratio, 4.16; 95% CI, 1.99-8.71; P < .001) and those treated with non-stereotactic body radiotherapy hypofractionated therapy (hazard ratio, 5.43; 95% CI, 2.10-14.01; P < .001) had worse overall survival, while patients with targetable mutations (hazard ratio, 0.49; 95% CI, 0.25-0.98; P = .04) had a longer survival. Using a predictive nomogram model, patients with a solitary site of metastasis, targetable mutations, intracranial disease, and metachronous timing of oligometastases had a larger PFS benefit from cRT., Conclusion: cRT is associated with favorable outcomes in PFS and overall survival. These results may aid in patient counseling, selection for aggressive local therapy, and stratification in future prospective clinical trials., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Low rates of adult patient participation have been a persistent problem in cancer clinical trials and have continued to be a barrier to efficient drug development. The routine use of significant exclusion criteria has contributed to this problem by limiting participation in studies and creating significant clinical differences between the study cohorts and the real-world cancer patient populations. These routine exclusions also unnecessarily restrict opportunities for many patients to access potentially promising new therapies during clinical development. Multiple efforts are underway to broaden eligibility criteria, allowing more patients to enroll in studies and generating more robust data regarding the effect of novel therapies in the population at large. Focusing specifically on lung cancer as an example, a multistakeholder working group empaneled by the LUNGevity Foundation identified 14 restrictive and potentially outdated exclusion criteria that appear frequently in lung cancer clinical trials. As a part of the project, the group evaluated data from multiple recent lung cancer studies to ascertain the extent to which these 14 criteria appeared in study protocols and played a role in excluding patients (screen failures). The present report describes the working group's efforts to limit the use of these routine exclusions and presents clinical justifications for reducing the use of 14 criteria as routine exclusions in lung cancer studies, potentially expanding trial eligibility and improving the generalizability of the results from lung cancer trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In the past 10 years, a deeper understanding of the immune landscape of cancers, including immune evasion processes, has allowed the development of a new class of agents. The reactivation of host antitumor immune response offers the potential for long-term survival benefit in a portion of patients with thoracic malignancies. The advent of programmed cell death protein 1/programmed death ligand-1 immune checkpoint inhibitors (ICIs), both as single agents and in combination with chemotherapy, and more recently, the combination of ICI, anti-programmed cell death protein 1, and anticytotoxic T-lymphocyte antigen 4 antibody, have led to breakthrough therapeutic advances for patients with advanced NSCLC, and to a lesser extent, patients with SCLC. Encouraging activity has recently emerged in pretreated patients with thymic carcinoma (TC). Conversely, in malignant pleural mesothelioma, pivotal positive signs of activity have not been fully confirmed in randomized trials. The additive effects of chemoradiation and immunotherapy suggested intriguing potential for therapeutic synergy with combination strategies. This has led to the introduction of ICI consolidation therapy in stage III NSCLC, creating a platform for future therapeutic developments in earlier-stage disease. Despite the definitive clinical benefit observed with ICI, primary and acquired resistance represent well-known biological phenomena, which may affect the therapeutic efficacy of these agents. The development of innovative strategies to overcome ICI resistance, standardization of new patterns of ICI progression, identification of predictive biomarkers of response, optimal treatment duration, and characterization of ICI efficacy in special populations, represent crucial issues to be adequately addressed, with the aim of improving the therapeutic benefit of ICI in patients with thoracic malignancies. In this article, an international panel of experts in the field of thoracic malignancies discussed these topics, evaluating currently available scientific evidence, with the final aim of providing clinical recommendations, which may guide oncologists in their current practice and elucidate future treatment strategies and research priorities., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the relationship between radiotherapy (RT), in particular chest RT, and development of immune-related (IR) pneumonitis in non-small-cell lung cancer (NSCLC) patients treated with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1)., Patients and Methods: Between June 2011 and July 2017, NSCLC patients treated with anti-PD-1/PD-L1 at a tertiary-care academic cancer center were identified. Patient, treatment, prior RT (intent, technique, timing, courses), and IR pneumonitis details were collected. Treating investigators diagnosed IR pneumonitis clinically. Diagnostic IR pneumonitis scans were overlaid with available chest RT plans to describe IR pneumonitis in relation to prior chest RT. We evaluated associations between patient, treatment, RT details, and development of IR pneumonitis by Fisher exact and Wilcoxon rank-sum tests., Results: Of the 188 NSCLC patients we identified, median follow-up was 6.78 (range, 0.30-79.3) months and median age 66 (range, 39-91) years; 54% (n = 102) were male; and 42% (n = 79) had stage I-III NSCLC at initial diagnosis. Patients received anti-PD-1/PD-L1 monotherapy (n = 127, 68%) or PD-1/PD-L1-based combinations (n = 61, 32%). In the entire cohort, 70% (132/188) received any RT, 53% (100/188) chest RT, and 37% (70/188) curative-intent chest RT. Any grade IR pneumonitis occurred in 19% (36/188; 95% confidence interval, 13.8-25.6). Of those who developed IR pneumonitis and received chest RT (n = 19), patients were more likely to have received curative-intent versus palliative-intent chest RT (17/19, 89%, vs. 2/19, 11%; P = .051). Predominant IR pneumonitis appearances were ground-glass opacities outside high-dose chest RT regions., Conclusion: No RT parameter was significantly associated with IR pneumonitis. On subset analysis of patients who developed IR pneumonitis and who had received prior chest RT, IR pneumonitis was more common in patients who received curative-intent chest RT. Attention should be paid to NSCLC patients receiving curative-intent RT followed by anti-PD-1/PD-L1 agents., (Copyright © 2019 Elsevier Inc. All rights reserved.)

With increasing use of immune checkpoint inhibitors (ICIs) for advanced NSCLC, there is increasing recognition of immune-related adverse events associated with ICI use. We recently reported increased incidence of checkpoint inhibitor pneumonitis (CIP) in ICI-treated NSCLC patients. Since development of immune-related adverse events in other organ systems has been associated with either no change or even improvement in tumor response/cancer outcomes, we sought to better understand the impact of CIP development on overall survival in ICI-treated NSCLC patients. Using baseline and follow-up data collected on a cohort of 205 ICI-treated NSCLC patients, we used a multi-state modeling approach to understand the effect of developing CIP on the risk of death. We observed time-dependent changes in risk of developing and recovery from CIP, with an increased risk of both developing and recovering from CIP in the first year after initiating ICI. We found that developing CIP independently increased the risk of transitioning to death in both adjusted and unadjusted models. In the multivariate model, we found that the increase in mortality associated with CIP was only seen in patients with adenocarcinoma tumor histology. Collectively, these findings suggest that in NSCLC, development of CIP worsens survival in patients receiving immunotherapy., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that can occur after initiation of anti-programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial-enrolled and non-trial-enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti-programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%-5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher-grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life-threatening complication of ICI therapy., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Carcinoids of the lung and thymus are rare thoracic cancers. In general, lung carcinoid tumors have a favorable prognosis, particularly when diagnosed at an early stage and treated with surgical resection. Thymic neuroendocrine tumors may be associated with multiple endocrine neoplasia-1 syndrome, tend to have a more aggressive natural history, and relatively frequently secrete ectopic adrenocorticotropic hormone., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed., Patients and Methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed., Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002)., Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

Background: Data to guide the management of advanced pulmonary carcinoid (APC) come from retrospective reports and subgroup analyses of trials that included mainly extrapulmonary carcinoid tumors. We report the largest series to date of 49 patients with locally advanced or metastatic pulmonary carcinoid., Methods: The Johns Hopkins Pathology Database was reviewed for APC patients treated between January 1992 and December 2012. Data on time to recurrence, progression-free survival, and overall survival were estimated by using the Kaplan-Meier method., Results: Forty-nine patients were treated for APC in the specified time period. Median time to recurrence after surgical resection was 2.5 years (atypical carcinoid [AC] versus typical carcinoid [TC], 2.5 versus 6.3 years; p = 0.063). Median survival with advanced disease was 7.1 years and significantly longer for TC compared with AC (10.2 versus 4 years; p = 0.009). Among the diverse systemic therapies used, responses occurred in four of 17 patients (23.5%) who received platinum/etoposide with a median progression-free survival of 7 months., Conclusion: Although systemic chemotherapy has moderate activity for APC, novel approaches are required. TC and AC, although both classified as pulmonary carcinoid, are clearly different clinical and molecular entities and require separate treatment paradigms in the advanced/metastatic setting.

Introduction: : Esophageal cancer represents a major health care problem worldwide and its prevalence is rapidly increasing. A key challenge in the treatment of both locally advanced and metastatic disease is to improve our understanding of the underlying molecular biology. Herein we discuss the most active chemotherapies and targeted agents for esophageal cancer, and explore potential differences in the disease between Eastern and Western countries., Methods: : We reviewed the literature for trials involving chemotherapy and targeted agents in locally advanced and metastatic disease in the last 20 years. The search was supplemented by a review of the abstracts presented at the annual American Society of Clinical Oncology meetings from 1992 to 2012., Results: : Neoadjuvant chemo-radiation followed by surgery remains standard of care for operable disease. Definitive chemo-radiation can be considered for locally advanced squamous cell tumors. Platinum-based combination chemotherapy is preferable in the first-line metastatic setting. Recently, HER2, EGFR, and VEGF-targeted agents have been extensively investigated as single agents or in combination with chemotherapy. Several new targets are being explored., Conclusions: : There have been incremental improvements in our understanding of the molecular biology of esophageal cancer, and ethnic differences between Asian and Western populations are becoming apparent. Next-generation sequencing has failed to demonstrate significant oncogenic drivers; however, the addition of trastuzumab to chemotherapy for HER2-amplified tumors has been validated in the metastatic setting and is undergoing investigation in operable disease. Epigenetic therapeutics may provide additional benefit in future years for this difficult-to-treat disease.