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Background: At the first interim analysis of the KEYNOTE-671 trial, adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage non-small-cell lung cancer (NSCLC). We report overall survival and health-related quality of life outcomes from the second interim analysis., Methods: KEYNOTE-671 was a global phase 3 trial done at 189 medical centres. Eligible participants (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) or to four cycles of neoadjuvant placebo (administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every 3 weeks). Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were overall survival and event-free survival evaluated in the intention-to-treat population. This study is registered at ClinicalTrials.gov, NCT03425643, and is ongoing but closed to enrolment., Findings: Between May 11, 2018, and Dec 15, 2021, 797 participants were randomly assigned to the pembrolizumab group (n=397) or the placebo group (n=400). Median study follow-up at the second interim analysis was 36·6 months (IQR 27·6-47·8). 36-month overall survival estimates were 71% (95% CI 66-76) in the pembrolizumab group and 64% (58-69) in the placebo group (hazard ratio 0·72 [95% CI 0·56-0·93]; one-sided p=0·0052; threshold, one-sided p=0·0054). Median event-free survival was 47·2 months (95% CI 32·9 to not reached) in the pembrolizumab group and 18·3 months (14·8-22·1) in the placebo group (hazard ratio 0·59 [95% CI 0·48-0·72]). In the as-treated population, grade 3-5 treatment-related adverse events occurred in 179 (45%) of 396 participants in the pembrolizumab group and in 151 (38%) of 399 participants in the placebo group. Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group., Interpretation: The significant overall survival benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone coupled with a manageable safety profile support the use of perioperative pembrolizumab in patients with resectable, early-stage NSCLC., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA., Competing Interests: Declaration of interests JDS, MCG, HW, ML, TK, MT, S-HL, K-NC, CD, MM, EE, GLM, OB, DR-A, JEC, SN, and SG report funding to their institution from Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co, Rahway, NJ, USA to support conduct of this study. JDS, MCG, HW, ML, TK, MT, S-HL, K-NC, CD, MM, EE, GLM, OB, DR-A, JEC, SN, JY, AA, SMK, AS, and SG received medical writing and editorial support for the preparation of this manuscript from MSD. JDS additionally reports receiving grants to the institution from AstraZeneca, MSD, Roche, BMS, CLS Therapeutics, Protalix Biotherapeutics, Pfizer, and Regeneron; receiving consulting fees from AstraZeneca, Merck, Roche, BMS, Novartis, Chemocentryx, Amgen, Protalix Biotherapeutics, Xenetic Biosciences, Regeneron, Eisai, and Pfizer; receiving payment for a speaking role from Peerview, OncLive, and Medscape; receiving support for attending meetings or travel from AstraZeneca, Merck, and BMS; participating on a clinical trial safety monitoring board for AstraZeneca; and receiving equipment, materials, drugs, gifts, or other services via grant to the institution from Roche, MSD, BMS, and AstraZeneca. MCG additionally reports receiving consulting fees from AstraZeneca, Abion, MSD International, Bayer, BMS, Boehringer Ingelheim Italia, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi-Sankyo, Regeneron, Merck & Co, Blueprint, Janssen, Sanofi, AbbVie, BeiGene, Oncohost, Medscape, Gilead, Io Biotech, and Revolution Medicines; receiving payment or honoraria for lectures, presentations, speakers' bureaus, or educational events from AstraZeneca, Merck & Co, Daiichi Sankyo, Gilead, Eli Lilly, and Regeneron; and receiving support for attending meetings or travel from AstraZeneca. HW additionally reports research funding to the institution from Bayer, AstraZeneca, BMS, Genentech/Roche, MSD, Helsinn, SeaGen, and Xcovery; serving as a compensated advisory board member for Mirati, IOBiotech, OncoC4, and BeiGene; serving as an uncompensated advisory board member for MSD, Genentech/Roche, BMS, and AstraZeneca; serving as a past president of the International Association for the Study of Lung Cancer (IASLC); and serving on the executive committee of ECOG-ACRIN. TK additionally reports research grants to the institution from AbbVie, Amgen, Arrivent, AstraZeneca, Bayer, BeiGene, BluePrint, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Haihe, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Regeneron, and Takeda; receiving honoraria for lectures, presentations, speakers' bureaus, or educational events from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck KGaA, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda; receiving honoraria for participation on a data safety monitoring board or advisory board from AstraZeneca, BeiGene, Chugai, Daiichi-Sankyo, Janssen, Merck KGaA, MSD, Novartis, and Pfizer; and having a spouse who is an employee of Eli Lilly. MT additionally reports research grants to the institution from MSD, AstraZeneca KK, Bristol-Myers Squibb KK, Ono Pharmaceutical Co, Eli Lilly Japan, Novartis, MiRXES, and Johnson & Johnson Japan; receiving honoraria for lectures from Amgen KK, Johnson & Johnson Japan, Medtronic Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co, Taiho Pharma, Bristol-Myers Squibb KK, Ono Pharmaceutical Co, Novartis, MSD, and Daiichi-Sankyo; serving as a participant on an advisory board for Bristol-Myers Squibb KK, AstraZeneca KK, MSD, Novartis, and MiRXES; and serving as a participant on a data safety monitoring board for Chugai Pharmaceutical Co. S-HL additionally reports research grants to the institution from MSD and receiving honoraria for a lecture from MSD. MM additionally reports receiving honoraria for lectures, presentations, speakers' bureaus, or educational events from MSD, Lilly, Pfizer, AstraZeneca, Roche, Sanofi, Regeneron, BeiGene, Immedica, Novartis, and BMS; and receiving support to attend meetings or travel from MSD, Pfizer, AstraZeneca, and Roche. EE additionally reports receiving payment for expert testimony from MSD. OB additionally reports support for attending meetings or travel from MSD for ASCO 2023 and from AstraZeneca for ESMO 2023 and ASCO 2024; and participating as a compensated advisory board member for BMS, Roche, Takeda, MSD, AstraZeneca, Janssen, and MSD. DR-A additionally reports receiving honoraria for lectures from MSD, Roche, BMS, Novartis, Takeda, Lilly, and AstraZeneca; receiving support for attending meetings or travel from Roche, MSD, Novartis, and Sanofi; and participation on an advisory board from MSD, Regeneron, BMS, GSK, and Lilly. JEC additionally reports receiving research grants to the institution from AstraZeneca, BMS, Novartis, Genentech, Merck & Co, and BeiGene; and receiving consulting fees from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Genentech, Merck & Co, Regeneron-Sanofi, Janssen, Guardant Health, Flame Biosciences, and Roche. SN additionally reports receiving honoraria for lectures, presentations, speakers' bureaus, or educational events from AstraZeneca, Amgen, BeiGene, Pfizer, MSD, Sanofi, Takeda, Thermo Fisher, Janssen, Novartis, and Roche; and participating on a data safety monitoring board or advisory board from AstraZeneca, Amgen, BeiGene, Pfizer, MSD, Sanofi, Takeda, Janssen, and Roche. JY additionally reports receiving salary for full-time employment from MSD. AA, SMK, and AS additionally report receiving salary for full-time employment from MSD and holding stock in Merck & Co, Rahway, NJ, USA., (Copyright © 2024 Elsevier Ltd. 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Objectives: The study objectives were to assess the outcomes of lung resection in patients with non-small cell lung cancer previously treated with nonoperative treatment and to identify prognostic factors associated with survival., Methods: Patients who underwent surgery (2010-2022) after initial nonoperative treatment at a single institution were identified from a prospectively maintained database. Exclusion criteria included metachronous cancer, planned neoadjuvant therapy, and surgery for diagnostic or palliative indications. Cox models were constructed for overall survival and event-free survival. Survival of patients with stage IV disease was compared with survival of a nonstudy cohort who did not undergo surgery., Results: In total, 120 patients met the inclusion criteria. Initial clinical stage was early stage in 16%, locoregionally advanced in 25%, and metastatic in 59% of patients. The indication for surgery was recurrence in 18%, local persistent disease in 23%, oligoprogression in 22%, and local control of oligometastatic disease in 38% of patients. Grade 3 or greater complications occurred in 5% of patients; 90-day mortality was 3%. Three-year event-free survival and overall survival were 39% and 73%, respectively. Male sex and lymphovascular invasion were associated with shorter event-free survival and overall survival; younger age and prior radiation therapy were associated with shorter overall survival. Patients with stage IV disease who received salvage lung resection had better overall survival than similar patients who received subsequent systemic therapy and no surgery., Conclusions: In this selected, heterogeneous population, lung resection after initial nonoperative treatment for non-small cell lung cancer was safe. Surgery as local consolidative therapy was associated with encouraging outcomes and should be considered for these patients., Competing Interests: Conflict of Interest Statement Dr Adusumilli declares research funding from ATARA Biotherapeutics; is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion, and Outpace Bio; has patents, royalties, and intellectual property on mesothelin-targeted chimeric antigen receptor and other T-cell therapies, which have been licensed to ATARA Biotherapeutics; and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. MSK Cancer Center has licensed intellectual property related to mesothelin-targeted chimeric antigen receptors and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. Dr Rocco has financial relationships with Scanlan International, Medtronic, and Merck. Dr Molena serves on a steering committee for AstraZeneca and as a consultant for Johnson & Johnson, Bristol Myers Squibb, Merck, and Genentech. Dr Park is a consultant for Intuitive Surgical, Medtronic, AstraZeneca, and CEEVRA. Dr Bott is a consultant for AstraZeneca. Dr Rusch reports grant support (institutional) from Genelux and Genentech, travel support from Intuitive Surgical, and travel support and payments from National Institutes of Health/Coordinating Center for Clinical Trials. Dr Sihag is a member of the AstraZeneca Advisory Board. Dr Isbell has stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. Dr Chaft serves as a consultant for AstraZeneca, Bristol Myers Squibb, Flame Biosciences, Regeneron-Sanofi, Guardant Health, and Arcus Biosciences and receives institutional research funding from AztraZeneca, Bristol Myers Squibb, Merck, and Novartis. Dr Li has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly; has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly; has received academic travel support from Amgen, Jiangsu Hengrui Medicine, and MORE Health; and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Dr Gomez reports research funding from Merck, AstraZeneca, Varian, and Bristol Myers Squibb and serves on the advisory boards of MedLearning Group, Medtronic, GRAIL, Johnson & Johnson, AstraZeneca, and Varian. Dr Rimner is a consultant for AstraZeneca, Merck, and MoreHealth, serves as an advisory board member for Merck, and reports institutional grant support from Varian Medical Systems, AstraZeneca, Merck, Pfizer, and Boehringer Ingelheim. Dr Jones serves as a consultant for Merck, AstraZeneca, Genentech, and DAVA Oncology. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. 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.)

Purpose: Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase 1 trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3 cm., Methods and Materials: A 3 + 3 dose-escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3 cm (T2-4) were eligible. Select ipsilateral hilar and single-station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute grade (G) 4+ or persistent G3 toxicities (Common Terminology Criteria for Adverse Events version 4.03). Secondary endpoints included local failure (LF), distant metastases, disease progression, and overall survival., Results: The median age was 80 years; tumor size was >3 cm and ≤5 cm in 20 (59%) and >5 cm in 14 patients (41%). In cohort A (n = 9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose-expansion cohort B (n = 25), no radiation therapy-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year overall survival was 53%. A biologically effective dose (BED) <100 Gy was associated with higher LF (P = .006); advanced stage and higher neutrophil/lymphocyte ratio were associated with greater disease progression (both P = .004)., Conclusions: Fifty Gy in 5 fractions is the MTD for SBRT to tumors >3 cm. A higher BED is associated with fewer LFs even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clinical investigation of immune checkpoint inhibitors (ICIs) has expanded from indications in metastatic non-small cell lung cancer (NSCLC) to add to the treatment of early-stage or resectable NSCLC. Although completed randomized trials supported the approvals of some ICIs as perioperative therapies (ie, adjuvant, neoadjuvant, or neoadjuvant followed by adjuvant), ongoing trials are evaluating other anti-PD-(L)1 antibodies for similar indications, or in combination with stereotactic body radiotherapy (SBRT). The incorporation of immunotherapy brings potential to improve outcomes of patients with resectable NSCLC, but these advances have also increased the complexity of the treatment landscape and created important knowledge gaps. This article reviews the current standards for local therapies in NSCLC, describes the clinical trials exploring the combination of ICIs to SBRT, and explains the recent approvals of ICIs as perioperative therapies. A discussion follows to highlight three important areas of uncertainty: (1) the contribution of ICIs given in each treatment phase (neoadjuvant and adjuvant) to the overall effect of neoadjuvant chemoimmunotherapy followed by adjuvant ICIs; (2) the selection of regimens to serve as comparators in future randomized trials of perioperative therapies; and (3) the role of pathologic complete response as an intermediate end point and aid for selection of patients for adjuvant therapy. Moving forward, stakeholders will need to engage in concerted research efforts to address the relevant clinical questions regarding the optimal management of resectable NSCLC.

Objective: There is a lack of knowledge regarding the use of prognostic features in stage I lung adenocarcinoma (LUAD). Thus, we investigated clinicopathologic features associated with recurrence after complete resection for stage I LUAD., Methods: We performed a retrospective analysis of patients with pathologic stage I LUAD who underwent R0 resection from 2010 to 2020. Exclusion criteria included history of lung cancer, induction or adjuvant therapy, noninvasive or mucinous LUAD, and death within 90 days of surgery. Fine and Gray competing-risk regression assessed associations between clinicopathologic features and disease recurrence., Results: In total, 1912 patients met inclusion criteria. Most patients (1565 [82%]) had stage IA LUAD, and 250 developed recurrence: 141 (56%) distant and 109 (44%) locoregional only. The 5-year cumulative incidence of recurrence was 12% (95% CI, 11%-14%). Higher maximum standardized uptake value of the primary tumor (hazard ratio [HR], 1.04), sublobar resection (HR, 2.04), higher International Association for the Study of Lung Cancer grade (HR, 5.32 [grade 2]; HR, 7.93 [grade 3]), lymphovascular invasion (HR, 1.70), visceral pleural invasion (HR, 1.54), and tumor size (HR, 1.30) were independently associated with a hazard of recurrence. Tumors with 3 to 4 high-risk features had a higher cumulative incidence of recurrence at 5 years than tumors without these features (30% vs 4%; P < .001)., Conclusions: Recurrence after resection for stage I LUAD remains an issue for select patients. Commonly reported clinicopathologic features can be used to define patients at high risk of recurrence and should be considered when assessing the prognosis of patients with stage I disease., Competing Interests: Conflict of Interest Statement Dr Rocco has financial relationships with Scanlan International, AstraZeneca, and Medtronic. Dr Molena serves on a steering committee for AstraZeneca, consults for Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, Boston Scientific, and has been an invited speaker for Merck and Genentech. Dr Park has received honoraria from Intuitive Surgical, AstraZeneca, Medtronic, consults for CEEVRA, and has received research support from Intuitive Surgical. Dr Chaft consults for AstraZeneca, Bristol-Myers Squibb, Merck, Regeneron-Sanofi, Guardant Health, and Lily and receives research funding from AztraZeneca, Bristol-Myers Squibb, Merck, and Beigene. Dr Bott consults for AstraZeneca, Iovance Biotherapeutics, Intuitive Surgical, and receives research support from Obsidian Therapeutics. Dr Rusch reports grant support from Genelux and Genentech, and travel support from Intuitive Surgical and National Institutes of Health/Coordinating Center for Clinical Trials. Dr Adusumilli declares research funding from ATARA Biotherapeutics; is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion, and Outpace Bio; has patents, royalties, and intellectual property on T-cell therapies licensed to ATARA Biotherapeutics; and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. Dr Sihag serves on the AstraZeneca advisory board. Dr Isbell has served on advisory boards for AstraZeneca and Merck; as an uncompensated steering board member for Genentech; has received research support from ArcherDx/Invitae, Guardant Health, GRAIL, Intuitive Surgical; has received travel support from Intuitive Surgical; and has equity/ownership interest in LumaCyte. Dr Jones serves on the advisory council for AstraZeneca and receives research grant support from Merck. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: NUT carcinoma (NC) is an underdiagnosed and aggressive poorly differentiated or squamous cell cancer. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown. Experts have recommended platinum- and ifosfamide-based therapy based on case reports., Methods: Patients with pathologically confirmed NC with known survival outcomes after chemotherapy and consented to participate in a worldwide registry were studied. Results were summarized using descriptive methods., Results: The study included 118 patients with NC. Median age was 34 (range: 1-82) years, 39% were women, and 61% harbored a BRD4::NUTM1 fusion. Patients received platinum (74%) or ifosfamide (26%, including regimens with both, 13%). Of 62 patients with nonmetastatic disease, 40% had a thoracic primary. Compared with platinum-based chemotherapy, patients who received ifosfamide-based chemotherapy had nominally higher progression-free survival (12 mo: 59% [95% CI: 32-87] versus 37% [95% CI: 22-52], hazard ratio = 0.68 [0.32, 1.42], p = 0.3) but not overall survival (OS). Among the 56 patients with metastatic disease, 80% had a thoracic primary. Ifosfamide had an objective response rate (ORR) of 75% (six of eight) and platinum had an ORR of 31% (11 of 36). Nevertheless, there was no difference in progression-free survival or OS. The 3-year OS of the entire cohort was 19% (95% CI: 10%-28%). Of the 11 patients alive greater than 3 years, all presented with nonmetastatic and operable or resectable disease., Conclusion: There is a numerically higher ORR for ifosfamide-based therapy compared with platinum-based therapy, with limited durability. OS at 3 years is only 19%, and development of effective therapies is an urgent unmet need for this patient population., Competing Interests: Disclosure Dr. Luo reports receiving research support to her institution from Erasca, Genentech, Kronos Bio, Novartis, and Revolution Medicines; receiving honoraria from Targeted Oncology, Physicians’ Education Resource, VJ Oncology, Cancer GRACE, and Community Cancer Education, Inc.; having advisory board participation from Astellas, AstraZeneca, and Amgen; receiving personal fees from Erasca, Blueprint Medicines, and Daiichi Sankyo; and having a pending patent filed by Memorial Sloan Kettering related to multimodal features to predict response to immunotherapy (PCT/US2023/115872). Dr. Paik receives compensation for consulting or advisory board participation from Bicara Therapeutics, Inc., EMD Serono, Inc., Novartis, Mirati Therapeutics, and Janssen; and receives honoraria for participation in CME educational programs from IDEOlogy, Excerpta Medica, PeerVoice, Physicians Education Resource, Medscape, Agile, Axis Medical Education, Aptitude Health, MJH, Annenberg Center, Cardinal Health, and Touch Independent Medical Education Ltd. Dr. Chaft has served as a consultant for AstraZeneca, Bristol-Myers Squib, Genentech, Merck, Flame Biosciences, Novartis, Regeneron-Sanofi, Guardant Health, and Janssen; and has received research funding to her institution from AstraZeneca, Bristol-Myers Squib, Genentech, and Merck. Dr. Cheng reports receiving honoraria from Lynx Group, WebMD, and Potomac Center for Medical Education; having consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Mirati Therapeutics, Cepheid, Janssen, and Pfizer; receiving research funding from Palleon Pharmaceuticals (Inst); and receiving travel, accommodations, and expenses from Daiichi Sankyo, AstraZeneca, and Genzyme. Dr. Piha-Paul reports receiving clinical trial research support/grant funding through the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol-Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix Inc., Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immorna Biotherapeutics, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Ltd., Loxo Oncology, Inc., Lytix Biopharma AS, Medimmune, LLC, Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, Nurix, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune, Roche/Blueprint, Seattle Genetics, Silverback Therapeutics, Shasqi, Inc., Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., Theradex Oncology, Toragen Therapeutics, Inc., TransThera Bio, Xencor, Inc., ZielBio, Inc., NCI/NIH, and P30CA016672 – Core Grant (CCSG Shared Resources); and having consulting for CRC Oncology. Dr. Sholl reports receiving research support to her institution from Genentech; and consulting from GV20 Therapeutics, Genentech, and Lilly. Dr. Nishino reports having consulting for AstraZeneca; and receiving research grants to the institution from Canon Medical Systems, AstraZeneca, Daiichi Sankyo, and Konica-Minolta. Dr. Jänne reports receiving grants from The Mark Foundation for Cancer Research and the American Cancer Society during the conduct of the study; personal fees outside of submitted work from Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Ignyta, LOXO Oncology, Eli Lilly, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Takeda Oncology, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, and Mirati Therapeutics; and grants outside the submitted work from Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, Takeda Oncology, PUMA, Astellas Pharmaceuticals, and Revolution Medicines. Dr. DuBois reports receiving honoraria or having advisory board participation from Amgen, Bayer, and Jazz Pharmaceuticals; and receiving travel expenses from LOXO Oncology, Roche, and Salarius, all outside the submitted work. Dr. Hanna reports receiving grants/contracts outside the submitted work from ACCRF, Actuate Therapeutics, ASCO CCF, Bicara, Bristol-Myers Squibb, Elevar Therapeutics, Exicure, Gateway for Cancer Research, Genentech, GlaxoSmithKline, ImmunityBio, Kartos, Kite, KSQ, Kura Oncology, Regeneron, Repertoire, Sanofi Genzyme, Secura Bio, and V Foundation; and having advisory role and/or receiving honoraria outside the submitted work from Bicara, Bio-Rad, Boxer Capital, Bristol-Myers Squibb, Coherus, Elevar, Exicure, General Catalyst, Guardian Bio, KSQ, Kura Oncology, Massachusetts Medical Society, Merck, Naveris, Nextech, Prelude, Rain, Regeneron, Remix, Replimune, Sanofi Genzyme, SIRPant, and Surface Oncology. Dr. Shapiro reports receiving personal fees from Merck KGaA/EMD-Serono, Bicycle Therapeutics, Cybrexa Therapeutics, Boehringer Ingelheim, Bayer, ImmunoMet, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, Kymera Therapeutics, Janssen, Xinthera, and Artios; receiving grants from Merck KGaA/EMD-Serono, Tango, Bristol-Myers Squibb, Pfizer, and Eli Lilly; and having a patent for “Dosage regimen for sapacitabine and seliciclib” issued to Cyclacel Pharmaceuticals and GIS and a patent for “Compositions and methods for predicting response and resistance to CDK4/6 inhibition” issued to Liam Cornell and GIS. Dr. French reports receiving research funding from Boehringer Ingelheim and consultant fees from Boehringer Ingelheim. The remaining authors declare no conflict of interest., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Surrogate endpoints for overall survival in patients with resectable non-small cell lung cancer receiving neoadjuvant therapy are needed to provide earlier treatment outcome indicators and accelerate drug approval. This study's main objectives were to investigate the association among pathological complete response, major pathological response, event-free survival and overall survival and to determine whether treatment effects on pathological complete response and event-free survival correlate with treatment effects on overall survival., Methods: A comprehensive systematic literature review was conducted to identify neoadjuvant studies in resectable non-small cell lung cancer. Analysis at the patient level using frequentist and Bayesian random effects (hazard ratio [HR] for overall survival or event-free survival by pathological complete response or major pathological response status, yes vs no) and at the trial level using weighted least squares regressions (hazard ratio for overall survival or event-free survival vs pathological complete response, by treatment arm) were performed., Results: In both meta-analyses, pathological complete response yielded favorable overall survival compared with no pathological complete response (frequentist, 20 studies and 6530 patients: HR = 0.49, 95% confidence interval = 0.42 to 0.57; Bayesian, 19 studies and 5988 patients: HR = 0.48, 95% probability interval = 0.43 to 0.55) and similarly for major pathological response (frequentist, 12 studies and 1193 patients: HR = 0.36, 95% confidence interval = 0.29 to 0.44; Bayesian, 11 studies and 1018 patients: HR = 0.33, 95% probability interval = 0.26 to 0.42). Across subgroups, estimates consistently showed better overall survival or event-free survival in pathological complete response or major pathological response compared with no pathological complete response or no major pathological response. Trial-level analyses showed a moderate to strong correlation between event-free survival and overall survival hazard ratios (R2 = 0.7159) but did not show a correlation between treatment effects on pathological complete response and overall survival or event-free survival., Conclusion: There was a strong and consistent association between pathological response and survival and a moderate to strong correlation between event-free survival and overall survival following neoadjuvant therapy for patients with resectable non-small cell lung cancer., (© The Author(s) 2024. Published by Oxford University Press.)

Radiation pneumonitis (RP) that develops early (i.e., within 3 mo) (RP Early ) after completion of concurrent chemoradiation (cCRT) leads to treatment discontinuation and poorer survival for patients with stage III non-small cell lung cancer. Since no RP Early risk model exists, we explored whether published RP models and pretreatment 18 F-FDG PET/CT-derived features predict RP Early Methods: One hundred sixty patients with stage III non-small cell lung cancer treated with cCRT and consolidative immunotherapy were analyzed for RP Early Three published RP models that included the mean lung dose (MLD) and patient characteristics were examined. Pretreatment 18 F-FDG PET/CT normal-lung SUV featured included the following: 10th percentile of SUV (SUV P10 ), 90th percentile of SUV (SUV P90 ), SUV max , SUV mean , minimum SUV, and SD. Associations between models/features and RP Early were assessed using area under the receiver-operating characteristic curve (AUC), P values, and the Hosmer-Lemeshow test (pHL). The cohort was randomly split, with similar RP Early rates, into a 70%/30% derivation/internal validation subset. Results: Twenty (13%) patients developed RP Early Predictors for RP Early were MLD alone (AUC, 0.72; P = 0.02; pHL, 0.87), SUV P10 , SUV P90, and SUV mean (AUC, 0.70-0.74; P = 0.003-0.006; pHL, 0.67-0.70). The combined MLD and SUV P90 model generalized in the validation subset and was deemed the final RP Early model (RP Early risk = 1/[1+e (- x ) ]; x = -6.08 + [0.17 × MLD] + [1.63 × SUV P90 ]). The final model refitted in the 160 patients indicated improvement over the published MLD-alone model (AUC, 0.77 vs. 0.72; P = 0.0001 vs. 0.02; pHL, 0.65 vs. 0.87). Conclusion: Patients at risk for RP Early can be detected with high certainty by combining the normal lung's MLD and pretreatment 18 F-FDG PET/CT SUV P90 This refined model can be used to identify patients at an elevated risk for premature immunotherapy discontinuation due to RP Early and could allow for interventions to improve treatment outcomes., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Colitis induced by treatment with immune-checkpoint inhibitors (ICI), termed irColitis, is a substantial cause of morbidity complicating cancer treatment. We hypothesized that abnormal fecal microbiome features would be present at the time of irColitis onset and that restoring the microbiome with fecal transplant from a healthy donor would mitigate disease severity. Herein, we present fecal microbiota profiles from 18 patients with irColitis from a single center, 5 of whom were treated with healthy-donor fecal microbial transplantation (FMT). Although fecal samples collected at onset of irColitis had comparable α-diversity to that of comparator groups with gastrointestinal symptoms, irColitis was characterized by fecal microbial dysbiosis. Abundances of Proteobacteria were associated with irColitis in multivariable analyses. Five patients with irColitis refractory to steroids and biologic anti-inflammatory agents received healthy-donor FMT, with initial clinical improvement in irColitis symptoms observed in four of five patients. Two subsequently exhibited recurrence of irColitis symptoms following courses of antibiotics. Both received a second "salvage" FMT that was, again, followed by clinical improvement of irColitis. In summary, we observed distinct microbial community changes that were present at the time of irColitis onset. FMT was followed by clinical improvements in several cases of steroid- and biologic-agent-refractory irColitis. Strategies to restore or prevent microbiome dysbiosis in the context of immunotherapy toxicities should be further explored in prospective clinical trials., (©2023 American Association for Cancer Research.)

Objective: Despite neoadjuvant chemoradiotherapy, Pancoast tumors still present surgical and oncologic challenges. To optimize outcomes, we used a multidisciplinary care paradigm with medical and radiation oncology, and involvement of spine neurosurgery for most T3 and all T4 tumors. Spine neurosurgery permitted resection of transverse process for T3 and vertebral body resection for T4 tumors., Methods: Retrospective analysis of single institution, prospective database of patients undergoing resection for cT3 4M0 Pancoast tumors. Patients were grouped as cT3 with combined resection with spine neurosurgery (T3 Neuro), cT3 without spine neurosurgery (T3 NoNeuro), and cT4. Overall survival, progression-free survival were analyzed by Kaplan-Meier and compared between groups using log-rank test. Cumulative incidence of local-regional and distant recurrence were compared using Gray test. P value <.05 was considered significant., Results: From 2000 to 2021, 155 patients underwent surgery: median age was 58 years, and 81 were (52%) men. Most patients received neoadjuvant platinum-based neoadjuvant chemoradiotherapy (n = 127 [82%]). Operations were 48 cT3 Neuro, 41 cT3 NoNeuro, 66 cT4. R0 resection was achieved in 49 (94%) cT3 NoNeuro, 35 (85%) cT3 Neuro, and 57 (86%) cT4 patients (P = .4). Complete or major pathologic response occurred in 71 (55%) patients. Lower local-regional cumulative incidence was seen in cT3 Neuro versus cT3 NoNeuro (P = .05) and after major pathologic response. Overall survival and progression-free survival were associated with complete response, pathologic stage, and nodal status but not cT category., Conclusions: This treatment paradigm was associated with a high frequency of R0 resection, complete response, and major pathologic response. cT3 and cT4 tumors had similar outcomes. Novel therapies are needed to improve complete response., Competing Interests: Conflict of Interest Statement Dr Rusch is a member of the Data Safety and Monitoring Committee for the Mesothelioma and Radical Surgery 2 (MARS2) and Radical Management of Advanced Non-Ssmall Cell Lung Cancer (RAMON) trials (in the United Kingdom) and serves as co-chair of the National Cancer Institute Thoracic Staging Malignancy Committee. She reports institutional funding from Genentech unrelated to this project. Dr Chen reports institutional funding from the National Institutes of Health (NIH), stock ownership of Nordik, Quest, and DOCS, and is a recipient of the American Society of Clinical Oncology young investigator award. Dr Chaft serves as an advisor to Genentech/Roche, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, Flame Biosciences, Janssen Oncology, Guardant Health, Regeneron/Sanofi, and Novartis. She reports research funding from Genentech/Roche, Bristol Myers Squibb, AstraZeneca/MedImmune, and Merck unrelated to this project. Dr Rimner is vice president of the International Thymic Malignancies Interest Group, and a board member of the International Mesothelioma Interest Group. He reports institutional funding from The Joanne & John DallePezze Foundation, Varian Medical Systems, AstraZeneca, Merck, Boehringer Ingelheim, Pfizer, NIH, and consulting fees from AstraZeneca, Merck and More Health. Dr Travis serves as an unpaid consultant for the Lung Cancer Mutation Consortium 3 (LCMC3) and Lung Cancer Mutation Consortium 4 (LCMC4) trials supported by Genentech. Dr Isbell reports stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. Dr Molena serves on a steering committee for AstraZeneca and as a consultant for Johnson & Johnson, Bristol Myers Squibb, Merck, and Genentech. Dr Park has served as a proctor for Intuitive Surgical and as a consultant for COTA. Dr Jones serves as a consultant for AstraZeneca and is on a clinical trial steering committee for Merck. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

The standard of care (SoC) for medically operable patients with early-stage (stages I-IIIB) NSCLC is surgery combined with (neo)adjuvant systemic therapy for patients with stages II to IIIB disease and some stage IB or, rarely, chemoradiation (stage III disease with mediastinal lymph node metastases). Despite these treatments, metastatic recurrence is common and associated with poor survival, highlighting the need for systemic therapies that are more effective than the current SoC. After the success of targeted therapy (TT) in patients with advanced NSCLC harboring oncogenic drivers, these agents are being investigated for the perioperative (neoadjuvant and adjuvant) treatment of patients with early-stage NSCLC. Adjuvant osimertinib is the only TT approved for use in the early-stage setting, and there are no approved neoadjuvant TTs. We discuss the importance of comprehensive biomarker testing at diagnosis to identify individuals who may benefit from neoadjuvant targeted treatments and review emerging data from neoadjuvant TT trials. We also address the potential challenges for establishing neoadjuvant TTs as SoC in the early-stage setting, including the identification and validation of early response markers to guide care and accelerate drug development, and discuss safety considerations in the perioperative setting. Initial data indicate that neoadjuvant TTs are effective and well tolerated in patients with EGFR- or ALK-positive early-stage NSCLC. Data from ongoing trials will determine whether neoadjuvant targeted agents will become a new SoC for individuals with oncogene-addicted resectable NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: We sought to identify features of patients with advanced non-small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICI), and how these might differ from features predictive of short-term response (STR)., Experimental Design: We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with ICIs between 2011 and 2022. LTR and STR were defined as response ≥ 24 months and response < 12 months, respectively. Tumor programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), next-generation sequencing (NGS), and whole-exome sequencing (WES) data were analyzed to identify characteristics enriched in patients achieving LTR compared with STR and non-LTR., Results: Among 3,118 patients, 8% achieved LTR and 7% achieved STR, with 5-year overall survival (OS) of 81% and 18% among LTR and STR patients, respectively. High TMB (≥50th percentile) enriched for LTR compared with STR (P = 0.001) and non-LTR (P < 0.001). Whereas PD-L1 ≥ 50% enriched for LTR compared with non-LTR (P < 0.001), PD-L1 ≥ 50% did not enrich for LTR compared with STR (P = 0.181). Nonsquamous histology (P = 0.040) and increasing depth of response [median best overall response (BOR) -65% vs. -46%, P < 0.001] also associated with LTR compared with STR; no individual genomic alterations were uniquely enriched among LTR patients., Conclusions: Among patients with advanced NSCLC treated with ICIs, distinct features including high TMB, nonsquamous histology, and depth of radiographic improvement distinguish patients poised to achieve LTR compared with initial response followed by progression, whereas high PD-L1 does not., (©2023 The Authors; Published by the American Association for Cancer Research.)

There is a need to identify predictive biomarkers to guide treatment strategies in stage III non-small cell lung cancer (NSCLCs). In this multi-institutional cohort of 197 patients with stage III NSCLC treated with concurrent chemoradiation (cCRT) and durvalumab consolidation, we identify that low tumor aneuploidy is independently associated with prolonged progression-free survival (HR 0.63; p=0.03) and overall survival (HR 0.50; p=0.03). Tumors with high aneuploidy had a significantly greater incidence of distant metastasis and shorter median distant-metastasis free survival (p=0.04 and p=0.048, respectively), but aneuploidy level did not associate with local-regional outcomes. Multiplexed immunofluorescence analysis in a cohort of NSCLC found increased intratumoral CD8-positive, PD-1-positive cells, double-positive PD-1 CD8 cells, and FOXP3-positive T-cell in low aneuploid tumors. Additionally, in a cohort of 101 patients treated with cCRT alone, tumor aneuploidy did not associate with disease outcomes. These data support the need for upfront treatment intensification strategies in stage III NSCLC patients with high aneuploid tumors and suggest that tumor aneuploidy is a promising predictive biomarker., Competing Interests: Competing interests: NS reports research funding from Novartis. MA serves as a consultant to Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Maverick, Blueprint Medicine, Syndax, AbbVie, Gritstone, ArcherDX, Mirati, NextCure and EMD Serono. Research funding: Bristol-Myers Squibb, Lilly, Genentech and AstraZeneca. BJ receives post marketing royalties for EGFR mutation testing from Dana-Farber Cancer Institute, is a paid consultant to Novartis, Checkpoint Therapeutics, Hummingbird Diagnostics, Daichi Sankyo, AstraZeneca, G1 Therapeutics, BlueDotBio, GSK, Hengrui Therapeutics, Simcere Pharmaceutical, and unpaid member of a steering committee for Pfizer, and receives research support from Novartis and Cannon Medical Imaging. DRG has received consulting fees from Johnson and Johnson, Medtronic, AstraZeneca and GRAIL. He has received honoraria from MedLearning Group and Varian. He has received research funding from Varian and AstraZeneca. ESL has an equity interest and fiduciary role in Oncia Technologies. ALR reports grants from Varian Medical Systems, Boehringer Ingelheim, Pfizer, Astra Zeneca and Merck in addition to personal fees from Astra Zeneca, Merck, Cybrexa, Research to Practice, and MoreHealth, and reports non-financial support from Philips/Elekta. AS reports grants from GSK, PACT pharma, Iovance Biotherapeutics, Achilles Therapeutics, Merck and Harpoon Therapeutics, and consulting fees from J&J, KSQ Therapeutics, BMS, Enara Bio, Perceptive Advisors and Heat Biologics. JEC reports grants from Merck, Brystol Myers Squibb, Genentech and AstraZeneca., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sensitive and reliable biomarkers for early detection of recurrence are needed to improve post-definitive radiation risk stratification, disease management, and outcomes for patients with unresectable early-stage or locally advanced non-small cell lung cancer (NSCLC) who are treated with definitive radiation therapy (RT). This prospective, multistate single-center, cohort study investigated the association of circulating tumor DNA (ctDNA) status with recurrence in patients with unresectable stage I-III NSCLC who underwent definitive RT., Methods: A total of 70 serial plasma samples from 17 NSCLC patients were collected before, during, and after treatment. A personalized, tumor-informed ctDNA assay was used to track a set of up to 16 somatic, single nucleotide variants in the associated patient's plasma samples., Results: Pre-treatment ctDNA detection rate was 82% (14/17) and varied based on histology and stage. ctDNA was detected in 35% (6/17) of patients at the first post-RT timepoint (median of 1.66 months following the completion of RT), all of whom subsequently developed clinical progression. At this first post-RT time point, patients with ctDNA-positivity had significantly worse progression-free survival (PFS) [hazard ratio (HR): 24.2, p=0.004], and ctDNA-positivity was the only significant prognostic factor associated with PFS (HR: 13.4, p=0.02) in a multivariate analysis. All patients who developed clinical recurrence had detectable ctDNA with an average lead time over radiographic progression of 5.4 months, and post-RT ctDNA positivity was significantly associated with poor PFS (p<0.0001)., Conclusion: Personalized, longitudinal ctDNA monitoring can detect recurrence early in patients with unresectable NSCLC patients undergoing curative radiation and potentially risk-stratify patients who might benefit most from treatment intensification., Competing Interests: NS reports research funding from Novartis. DG reports research funding from Astra Zeneca and Varian and receives Honoraria from Johnson and Johnson, MedLearning Gropu, and GRAIL. YM-G reports travel, accommodation, and expenses from AstraZeneca and Loxo Oncology/Eli Lilly. She acknowledges honoraria from Virology Education and Projects in Knowledge for a CME program funded by an educational grant from Amgen. She acknowledges associated research funding to the institution from Mirati Therapeutics, Loxo Oncology at Eli Lilly, Elucida Oncology, Taiho Oncology, Hengrui USA, Ltd/Jiangsu Hengrui Pharmaceuticals, Luzsana Biotechnology, and Endeavor Biomedicines. She acknowledges royalties from Rutgers University Press and Wolters Kluwer. She acknowledges food/beverages from Endeavor Biomedicines. YM-G acknowledges receipt of training through an institutional K30 grant from the NIH CTSA UL1TR00457. She has received funding from a Kristina M. Day Young Investigator Award from Conquer Cancer, the ASCO Foundation, endowed by Dr. Charles M. Baum and Carol A. Baum. She is also funded by the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, the Andrew Sabin Family Foundation, the Society for MSK, and a Paul Calabresi Career Development Award for Clinical Oncology NIH/NCI K12 CA184746. JJ has a patent licensed by MDSeq Inc. JC has served as a consultant for Astra Zeneca, Bristol-Myers Squib, Genentech, Merck, Flame Biosciences, Novartis, Regeneron-Sanofi, Guardant Health, and Janssen as well as received research funding to her institution from Astra Zeneca, Bristol-Myers Squib, Genentech, and Merck. MGK receives personal fees from Novartis, Sanofi-Genzyme, AstraZeneca, Pfizer, Janssen, and Daiichi-Sankyo. He has also received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, and AstraZeneca. MGK has received travel support from AstraZeneca, Pfizer, and Genentech as well as editorial support from Hoffman La-Roche. EK, JF, CBS, SS, CCP, MMa, MK, HS, AA, and MCL reported employment and stock ownership or option at Natera, Inc outside the submitted work. MCL reported receiving grants funding to Mayo Clinic from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics and Tesaro, and travel support from AstraZeneca, Genomic Health and Ionis, outside the submitted work. AS has stock ownership in ArcellX and Doximity. AW reports research support from CivaTech Oncology, Inc, Honoraria from Nanovi A/S, serves on the Scientific Advisory Board of Simphotek, Inc, and has stock in Simphotek, Inc. CS reports Honoraria from Varian and Novocure and serves in a Leadership position for the Proton Collaborative Group, American Society for Radiation Oncology, NRG Oncology, American Radium Society, and Annals of Palliative Medicine. DG reports research funding to her institution from Merck. CR reports personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, and Harpoon Therapeutics, outside the submitted work. DG reports grants to his institutions from Varian, AstraZeneca, Merck, and Bristol Myers Squibb, personal fees from Varia, AstraZeneca, Merck, US Oncology, Bristol Myers Squibb, Relfexion, WebMD, Vindico, and Medscape; and has served on the advisory board for AstraZeneca; he has also received Honoraria from Johnson and Johnson, MedLearning Group, and GRAIL. PR received institutional grant/funding from Grail, Illumina, Novartis, Epic Sciences, ArcherDx and Consultation/Ad board/Honoraria from Novartis, Foundation Medicine, AstraZeneca, Epic Sciences, Inivata, Natera, and Tempus. JR-F is a paid consultant of Goldman Sachs, Paige.AI and REPARE Therapeutics, a member of the Scientific Advisory Board of Goldman Sachs, Paige.AI and Volition RX, and ad hoc member of the scientific advisory board of Roche, Genetech, Roche Tissue Diagnostics, Ventana, Novartis, InVicro and GRAIL. JR-F reports receiving personal/consultancy fees from Goldman Sachs, Bain Capital, REPARE Therapeutics, Saga Diagnostics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Astrazeneca, Merck, Daiichi Sankyo, Roche Tissue Diagnostics and Personalis, outside the scope of this study. JR-F is funded in part by the Breast Cancer Research Foundation, by a Susan G Komen Leadership grant, and by the NIH/NCI P50 CA247749 01 grant. JI reports equity in LumaCyte, LLC and has served as an uncompensated member of a steering committee for Genentech. BL has served as an uncompensated advisor and consultant to Amgen, Genentech, Boehringer Ingelheim, Lilly, AstraZeneca, Daiichi Sankyo. He has received research grants to his institution from Amgen, Genentech, AstraZeneca, Daiichi Sankyo, Lilly, Illumina, GRAIL, Guardant Health, Hengrui Therapeutics, MORE Health and Bolt Biotherapeutics. He has received academic travel support from MORE Health, and Jiangsu Hengrui Medicine. He is an inventor on two institutional patents at MSK US62/685,057, US62/514,661 and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. AR reports research funding from Varian Medical Systems, Boehringer Ingelheim, Astra Zeneca, Merck, and Pfizer and serves in Leadership Positions for the International Thymic Malignancies Group and International Mesothelioma Interest group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lebow, Shaverdian, Eichholz, Kratochvil, McCune, Murciano-Goroff, Jee, Eng, Chaft, Kris, Kalashnikova, Feeney, Scalise, Sudhaman, Palsuledesai, Malhotra, Krainock, Sethi, Aleshin, Liu, Shepherd, Wu, Simone, Gelblum, Johnson, Rudin, Gomez, Razavi, Reis-Filho, Isbell, Li and Rimner.)

Background: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone., Methods: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety., Results: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events., Conclusions: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.)., (Copyright © 2023 Massachusetts Medical Society.)

Introduction: Although first-line immunotherapy approaches are standard, in patients with non-small cell lung cancer (NSCLC) previously treated with programmed cell death protein-1 or programmed death-(ligand)1 (PD-[L]1) inhibitors, the activity of combined CTLA-4 plus PD-(L)1 inhibition is unknown. This phase 1b study evaluated the safety and efficacy of durvalumab plus tremelimumab in adults with advanced NSCLC who received anti-PD-(L)1 monotherapy as their most recent line of therapy., Methods: Patients with PD-(L)1-relapsed or refractory NSCLC were enrolled between October 25, 2013, and September 17, 2019. Durvalumab 20 mg/kg plus tremelimumab 1 mg/kg was administered intravenously every 4 weeks for four doses, followed by up to nine doses of durvalumab monotherapy every 4 weeks for up to 12 months of treatment or disease progression. Primary end points included safety and objective response rate (ORR) on the basis of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per blinded independent central review; secondary end points were ORR on the basis of RECIST v1.1 per investigator; duration of response, disease control, and progression-free survival on the basis of RECIST v1.1 per blinded independent central review and investigator; and overall survival., Clinicaltrials: gov identifier: NCT02000947., Results: PD-(L)1-refractory (n = 38) and PD-(L)1-relapsed (n = 40) patients were treated. The most common treatment-related adverse events were fatigue (26.3%, PD-(L)1-refractory patients) and diarrhea (27.5%, PD-(L)1-relapsed patients). Grade 3 to 4 treatment-related adverse events occurred in 22 patients. Median follow-up duration was 43.6 months for PD-(L)1-refractory patients and 41.2 months for PD-(L)1-relapsed patients. The ORR was 5.3% for PD-(L)1-refractory patients (one complete response, one partial response) and 0% for PD-(L)1-relapsed patients., Conclusions: Durvalumab plus tremelimumab had a manageable safety profile, but the combination did not have efficacy after PD-(L)1 treatment failure., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP., Methods and Materials: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual., Results: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism., Conclusions: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Although concurrent chemoradiation (CRT) and durvalumab consolidation has become a standard treatment for stage III non-small cell lung cancer (NSCLC), clinicopathologic and genomic factors associated with its efficacy remain poorly characterized. Here, in a multi-institutional retrospective cohort study of 328 patients treated with CRT and durvalumab, we identify that very high PD-L1 tumor proportion score (TPS) expression ( ≥ 90%) and increased tumor mutational burden (TMB) are independently associated with prolonged disease control. Additionally, we identify the impact of pneumonitis and its timing on disease outcomes among patients who discontinue durvalumab: compared to patients who experienced early-onset pneumonitis ( < 3 months) leading to durvalumab discontinuation, patients with late-onset pneumonitis had a significantly longer PFS (12.7 months vs not reached; HR 0.24 [95% CI, 0.10 to 0.58]; P = 0.001) and overall survival (37.2 months vs not reached; HR 0.26 [95% CI, 0.09 to 0.79]; P = 0.017). These findings suggest that opportunities exist to improve outcomes in patients with lower PD-L1 and TMB levels, and those at highest risk for pneumonitis., (© 2023. The Author(s).)

Background: Single-agent PD-(L)1 blockade (IO) alone or in combination with chemotherapy (Chemotherapy-IO) is approved first-line therapies in patients with advanced lung adenocarcinomas (LUADs) with PD-L1 expression ≥1%. These regimens have not been compared prospectively. The primary objective was to compare first-line efficacies of single-agent IO to Chemotherapy-IO in patients with advanced LUADs. Secondary objectives were to explore if clinical, pathological, and genomic features were associated with differential response to Chemotherapy-IO versus IO., Methods: This was a multicenter retrospective cohort study. Inclusion criteria were patients with advanced LUADs with tumor PD-L1 ≥1% treated with first-line Chemotherapy-IO or IO. To compare the first-line efficacies of single-agent IO to Chemotherapy-IO, we conducted inverse probability weighted Cox proportional hazards models using estimated propensity scores., Results: The cohort analyzed included 866 patients. Relative to IO, Chemotherapy-IO was associated with improved objective response rate (ORR) (44% vs 35%, p=0.007) and progression-free survival (PFS) in patients with tumor PD-L1≥1% (HR 0.84, 95% CI 0.72 to 0.97, p=0.021) or PD-L1≥50% (ORR 55% vs 38%, p<0.001; PFS HR 0.68, 95% CI 0.53 to 0.87, p=0.002). Using propensity-adjusted analyses, only never-smokers in the PD-L1≥50% subgroup derived a differential survival benefit from Chemotherapy-IO vs IO (p=0.013). Among patients with very high tumor PD-L1 expression (≥90%), there were no differences in outcome between treatment groups. No genomic factors conferred differential survival benefit to Chemotherapy-IO versus IO., Conclusions: While the addition of chemotherapy to PD-(L)1 blockade increases the probability of initial response, never-smokers with tumor PD-L1≥50% comprise the only population identified that derived an apparent survival benefit with treatment intensification., Competing Interests: Competing interests: JEC has consulted for: AstraZeneca, BMS, Genentech, Merck, Flame Biosciences, Regeneron-Sanofi, Guardant Health, Arcus Biosciences and also declared research funding to institution from: AstraZeneca, BMS, Genentech, Merck, Novartis. CMR has consulted with AbbVie, Amgen, Astra Zeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros. He serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. GJR reports institutional research support from Mirati, Lilly, Takeda, Merck, Roche, Pfizer, and Novartis. MGK reports honoraria from AstraZeneca, Pfizer, Merus, and BerGenBio. MDH reports grants from BMS; and personal fees from Achilles; Adagene; Adicet; Arcus; AstraZeneca; Blueprint; BMS; DaVolterra; Eli Lilly; Genentech/Roche; Genzyme/Sanofi; Janssen; Immunai; Instil Bio; Mana Therapeutics; Merck; Mirati; Natera; Pact Pharma; Shattuck Labs; and Regeneron; as well as equity options from Factorial, Immunai, Shattuck Labs, Arcus, and Avail Bio. A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. Subsequent to the completion of this work, MDH began as an employee (and equity holder) at AstraZeneca. MA reports that he was a consultant to: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, Mirati, Novartis, Blueprint Medicine, Abbvie, Gritstone, NextCure, EMD Serono and received research funding (to institute) from: Bristol-Myers Squibb, Eli Lilly, Genentech, AstraZeneca, Amgen. AS reports consulting/advising role to J&J, KSQ therapeutics, BMS, Merck, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Lyell Immunopharma and Heat Biologics, research funding from GSK (Inst), PACT pharma (Inst), Iovance Biotherapeutics (Inst), Achilles therapeutics (Inst), Merck (Inst), BMS (Inst), Harpoon Therapeutics (Inst) and Amgen (Inst). AS reports consulting/advising role to J&J, KSQ therapeutics, BMS, Merck, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Lyell Immunopharma and Heat Biologics. Research funding: GSK (Inst), PACT pharma (Inst), Iovance Biotherapeutics (Inst), Achilles therapeutics (Inst), Merck (Inst), BMS (Inst), Harpoon Therapeutics (Inst) and Amgen (Inst)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Targeted therapy improves outcomes in patients with advanced-stage non-small cell lung cancer (NSCLC) and in the adjuvant setting, but data on its use before surgery are limited. We sought to investigate the safety and feasibility of preoperative targeted therapy in patients with operable NSCLC., Methods: We retrospectively reviewed 51 patients with clinical stage I to III NSCLC who received targeted therapy, alone or in combination with chemotherapy, before surgical resection with curative intent, treated from 2004 to 2021. The primary outcome was the safety and feasibility of preoperative targeted therapy; secondary outcomes included objective response rate, major pathologic response (defined as ≤10% viable tumor) rate, recurrence-free survival (RFS), and overall survival., Results: Of the 51 patients included, 46 had an activating epidermal growth factor receptor gene alteration and 5 had an anaplastic lymphoma kinase fusion. Overall, 37 of 46 evaluable patients experienced at least 1 adverse event before surgery; however, only 3 patients experienced a grade 3 or 4 event. The objective response rate was 38% (17/45) for all evaluable patients and 44% (14/32) for patients with clinical stage II or III disease. The major pathologic response rate was 20% (9/44); 2 patients had a complete pathologic response. Median RFS was 3.8 years (95% CI, 2.8 to not reached). Targeted therapy alone was associated with better RFS than combination therapy (P = .009) in patients with clinical stage II or III disease., Conclusions: Preoperative targeted therapy was well tolerated and associated with good outcomes, with or without induction chemotherapy. In addition, radiographic response and pathologic response were strongly correlated., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8 + T cells, regulatory CD4 + T cells (Treg), and follicular helper CD4 + T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8 + T cells are clonally linked to TCF7 + SELL + progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8 + T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8 + and CD4 + T cell clones reveals persistence in the peripheral blood for years after ICB therapy., Competing Interests: Declaration of interests M.D.H. reports advisory/consulting fees from Achilles, Adagene, Adicet, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Da Volaterra, Eli Lilly, Genentech, Genzyme/Sanofi, Immunai, Instill Bio, Janssen, Mana Therapeutics, Merk, Mirati, Pact Pharma, Regeneron, Roche, and Shattuck Labs; research funding from Bristol Myers Squibb; stock interest with Arcus, Factorial, Immunai, and Shattuck Labs; a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics (PGDx); after the completion of this work, M.D.H .began as an employee (and equity holder) at AstraZeneca. J.D.W. has Equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: Xenogeneic (Canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, and PharmaMar and is on the scientific advisory boards of Elucida, Bridge, and Harpoon. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. The remaining authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted therapies, implementation of new treatments in resectable NSCLC has been limited due to the long follow-up needed for overall survival (OS). Until recently, treatment for patients with early-stage resectable NSCLC has been limited to perioperative chemotherapy, which provides modest benefits. However, the regulatory acceptance of two surrogate endpoints for OS has allowed recent approval of both adjuvant osimertinib and atezolizumab, providing patients with new treatment options to improve outcomes. In phase 3 oncology trials, OS has historically been viewed as the gold-standard efficacy measure, but disease-free survival and event-free survival (EFS) are now validated surrogate endpoints for OS in clinical trials and should be considered when mature OS data is unavailable. Another potential surrogate endpoint in the adjuvant NSCLC setting is circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), although prospective validation is needed. For neoadjuvant targeted therapies, EFS, major pathologic response and ctDNA-based MRD are potential surrogate endpoints. To fully translate the success of the personalized treatment advances in the metastatic setting to earlier-stage disease, prospective validation studies of these potential surrogate endpoints that can accelerate the evaluation of drug efficacy are needed. A collaborative effort is also needed from all clinical and regulatory parties to collate surrogate endpoint data for large-scale validation. In this review we discuss the trends in surrogate endpoints used in oncology trials, with a focus on considerations for selecting appropriate primary endpoints in early-stage resectable EGFR-mutant NSCLC, an area of unmet need for novel treatment options., Competing Interests: Declaration of Competing Interest C.B. has been on an advisory council or committee for Blueprints Medicines; received consulting fee from Amgen; grants or funds from AstraZeneca, Novartis, Mirati, Spectrum, Roche, and Takeda. W.W. has received consulting fees from AstraZeneca. L.B. has ownership of stocks and shares from Roche and Novartis; been on an advisory council or committee for Amgen, AstraZeneca, Takeda, Boehringer Ingelheim, Bayer, Eli Lilly, and Merck Sharpe & Dohme; received honoraria from AstraZeneca, Bayer, Amgen, and Takeda; consulting fee from Johnson & Johnson; and grants and funds from Thermo Fisher and Systems Oncology. J.H. has no conflict of interest. M.M. has received honoraria from Merck Sharpe & Dohme, Boehringer Ingelheim, AstraZeneca, Roche AG, Kyowa Kyrin, Pierre Fabre, Takeda Pharmaceutical, Bayer AG, Amgen, Helsinn, Janssen, and Sanofi; consulting fees from Roche and AstraZeneca; and grants or funds from Bristol-Myers Squibb, Roche, and AstraZeneca. Y.S. has no conflict of interest. J.C. has received consulting fees from Merck, AstraZeneca, Genentech, Flame Biosciencea, Guardant Health, Janssen, Novartis, Arcus Biosciences, Bristol-Myers Squibb, and Regeneron-Sanofi; and grants or funds to institution from AstraZeneca, Bristol-Myers Squibb, Merck, Genetech, and Novartis., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery., Methods: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0., Results: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached., Conclusions: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: While anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard of care treatment for metastatic ALK -positive non-small cell lung cancer (NSCLC), the benefit of moving ALK inhibitors to earlier disease stages is unclear. The objective of this review is to summarize the literature regarding the prevalence and prognosis of early-stage ALK -positive NSCLC and the utility of targeted therapies, immunotherapy, and chemotherapy in the neoadjuvant and adjuvant settings., Methods: We identified the references for this narrative review through a literature search of papers about early stage ALK -positive NSCLC using PubMed and clinicaltrials.gov. Last search was run on July 3, 2022. There were no language or time frame restrictions., Key Content and Findings: The incidence of oncogenic ALK alterations in early-stage NSCLC ranges from 2-7%, and ALK -positive NSCLC patients are more likely to be younger and never or light smokers. Studies on the prognostic impact of ALK in early-stage disease have had conflicting results. ALK TKIs are not approved in the neoadjuvant or adjuvant setting and there is a lack of large, randomized trial results. Several trials are currently accruing but results are not expected for several years., Conclusions: Attempts at large, randomized trials to evaluate the benefit of ALK TKIs in the adjuvant and neoadjuvant has been hampered by slow recruitment given the rarity of ALK alterations, lack of universal genetic testing, and the rapid pace of drug development. Expanded lung cancer screening recommendations, liberalization of surrogate endpoints (i.e., pathological complete response and major pathological response), growth of multicenter national clinical trials, and new diagnostic technologies (i.e., cell-free DNA liquid biopsies) provide hope of generating much needed data to definitively answer the question of the utility of ALK-directed therapies in the early-stage setting., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-631/coif). The series “ALK Positive NSCL” was commissioned by the editorial office without any funding or sponsorship. MFC reports financial support to the institution related to this project from a T32 training grant. JEC reports financial support to the institution related to this project from the NCI and personal consulting fees from AstraZeneca, BMS, Genentech, Flame Biosciences, Arcus Biosciences, Merck, Jansen, Novartis, Regeneron-Sanofi, Guardant Health. The authors have no other conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Purpose: Neoadjuvant anti-PD-1 therapy has shown promise for resectable non-small cell lung cancer (NSCLC). We reported the first phase I/II trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti-PD-1 in any cancer type., Patients and Methods: Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I-IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated., Results: With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15-2.44] and HR, 0.36 (95% CI, 0.07-1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 6/11 patients without MPR experienced tumor relapse, and 3 died., Conclusions: Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size., (©2023 The Authors; Published by the American Association for Cancer Research.)

Importance: The addition of consolidative durvalumab to chemoradiation has improved disease control and survival in locally advanced non-small cell lung cancer (NSCLC). However, there remains a need to identify biomarkers for response to this therapy to allow for risk adaptation and personalization., Objectives: To evaluate whether TMB or other variants associated with radiation response are also associated with outcomes following definitive chemoradiation and adjuvant durvalumab among patients with locally advanced unresectable NSCLC., Design, Setting, and Participants: This cohort study included consecutive patients with unresectable locally advanced NSCLC treated with chemoradiation and adjuvant durvalumab between November 2013 and March 2020 who had prospective comprehensive genomic profiling. This study was completed at a multisite tertiary cancer center. The median (IQR) follow-up time was 26 (21-36) months. Statistical analysis was conducted from April to October 2022., Exposures: Patients were grouped into TMB-high (≥10 mutations/megabase [mt/Mb]) and TMB-low (<10 mt/Mb) groups and were additionally evaluated by the presence of somatic alterations associated with radiation resistance (KEAP1/NFE2L2) or radiation sensitivity (DNA damage repair pathway)., Main Outcomes and Measures: The primary outcomes were 24-month local-regional failure (LRF) and progression-free survival (PFS)., Results: In this cohort study of 81 patients (46 [57%] male patients; median [range] age, 67 [45-85] years), 36 patients (44%) had TMB-high tumors (≥10 mt/Mb). Patients with TMB-high vs TMB-low tumors had markedly lower 24-month LRF (9% [95% CI, 0%-46%] vs 51% [95% CI, 36%-71%]; P = .001) and improved 24-month PFS (66% [95% CI, 54%-84%] vs 27% [95% CI, 13%-40%]; P = .003). The 24-month LRF was 52% (95% CI, 25%-84%) among patients with KEAP1/NFE2L2-altered tumors compared with 27% (95% CI, 17%-42%) among patients with KEAP1/NFE2L2-wildtype tumors (P = .05). On Cox analysis, only TMB status was associated with LRF (hazard ratio [HR], 0.17; 95% CI, 0.03-0.64; P = .02) and PFS (HR, 0.45; 95% CI, 0.21-0.90; P = .03). Histology, disease stage, Eastern Cooperative Oncology Group status, programmed cell death ligand 1 expression, and pathogenic KEAP1/NFE2L2, KRAS, and DNA damage repair pathway alterations were not significantly associated with LRF or PFS., Conclusions and Relevance: In this cohort study, TMB-high status was associated with improved local-regional control and PFS after definitive chemoradiation and adjuvant durvalumab. TMB status may facilitate risk-adaptive radiation strategies in unresectable locally advanced NSCLC.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We previously identified a chemotherapy-induced paracrine inflammatory loop that paradoxically mitigates the anti-tumor effect of chemotherapy and triggers metastatic propagation in breast and lung cancer models. Therefore, we sought to further validate and translate these findings into patient care by coupling the anti-TNF-α drug certolizumab pegol with standard cisplatin doublet chemotherapy. Here we first validate the anti-metastatic effect of certolizumab in a liver-metastatic Lewis Lung Carcinoma model. We then evaluate the safety, efficacy, and pharmacodynamic effects of certolizumab with cisplatin and pemetrexed in an open label Phase 1 clinical trial (NCT02120807) of eighteen adult patients with stage IV lung adenocarcinomas. The primary outcome is maximum tolerated dose. Secondary outcomes are response rate and progression-free survival (PFS); pharmacodynamic changes in blood and tumor are evaluated as a correlative outcome. There were nine partial responses among 16 patients evaluable (56%, 95% CI 30 to 80%). The median duration of response was 9.0 months (range 5.9 to 42.6 months) and median PFS was 7.1 months (95% CI 6.3 to NR). The standard 400 mg dose of certolizumab, added to cisplatin and pemetrexed, is well-tolerated and, as a correlative endpoint, demonstrates potent pharmacodynamic inhibition of peripheral cytokines associated with the paracrine inflammatory loop., (© 2022. The Author(s).)

Human gut microbial species found to associate with clinical responses to immune checkpoint inhibitors (ICIs) are often tested in mice using fecal microbiota transfer (FMT), wherein tumor responses in recipient mice may recapitulate human responses to ICI treatment. However, many FMT studies have reported only limited methodological description, details of murine cohorts, and statistical methods. To investigate the reproducibility and robustness of gut microbial species that impact ICI responses, we performed human to germ-free mouse FMT using fecal samples from patients with non-small cell lung cancer who had a pathological response or nonresponse after neoadjuvant ICI treatment. R-FMT mice yielded greater anti-tumor responses in combination with anti-PD-L1 treatment compared to NR-FMT, although the magnitude varied depending on mouse cell line, sex, and individual experiment. Detailed investigation of post-FMT mouse microbiota using 16S rRNA amplicon sequencing, with models to classify and correct for biological variables, revealed a shared presence of the most highly abundant taxa between the human inocula and mice, though low abundance human taxa colonized mice more variably after FMT. Multiple Clostridium species also correlated with tumor outcome in individual anti-PD-L1-treated R-FMT mice. RNAseq analysis revealed differential expression of T and NK cell-related pathways in responding tumors, irrespective of FMT source, with enrichment of these cell types confirmed by immunohistochemistry. This study identifies several human gut microbial species that may play a role in clinical responses to ICIs and suggests attention to biological variables is needed to improve reproducibility and limit variability across experimental murine cohorts., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181 patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches., (© 2022. The Author(s).)

Background: Despite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor-immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade., Methods: Using machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance., Results: Integrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts., Conclusions: Our findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade., Competing Interests: Competing interests: VA receives research funding to her institution from Bristol-Myers Squibb and Astra Zeneca. PMF has received research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Novartis, Corvus, Kyowa. He has also served as a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Iteos, Janssen, Mirati, Novartis, Sanofi and as a DSMB member for Polaris and Flame Therapeutics. KNS receives research funding to her institution from Bristol-Myers Squibb, Astra Zeneca, and Enara Bio, and holds founder’s equity in manaT Bio. VEV is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. VEV is an inventor of multiple licensed patents related to technologies from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and VEV. VEV is an advisor to Bristol-Myers Squibb, Danaher, Genentech, and Takeda Pharmaceuticals. Within the last five years, VEV has been an advisor to Merck and Ignyta. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. JW is a consultant for Personal Genome Diagnostics, is the founder and owner of Resphera Biosciences and holds patents, royalties or other intellectual property from Personal Genomic Diagnostics. JER is in the advisory board/consultant of Oncocyte, receives speaking fees for Astrazeneca, and has received research funding to his institution from Genetech/Roche, and Verastem. JB is in the advisory board/consultant of Amgen, AstraZeneca, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi and Regeneron, receives grant research funding from AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Inc and Revolution Medicines and is in the Data and Safety Monitoring Board/Committees of GlaxoSmithKline, Sanofi and Janssen. TS is in the advisory board/consultant of Cue Biopharma, Dracen, Innate, Nanobiotix, Merck, Sanofi, Synthekine, receives grant research funding from AstraZeneca, BMS, Cue Biopharma, Genentech/Roche, Merck, Nanobiotix, Synthekine, and is in the Data and Safety Monitoring Board/Committees of Astra Zeneca, and Nektar. VL has received research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Merck, SeaGen. He has also served as a consultant for Takeda, SeaGen, Bristol-Myers Squibb, AstraZeneca, and Guardant Health., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Postoperative radiation therapy (PORT) in resected non-small cell lung cancer (NSCLC) improves locoregional outcomes, but recent randomized data do not support its unselected use. We assessed if tumor mutational burden (TMB) and mutations in genes associated with radiation sensitivity can select patients for PORT., Methods and Materials: Patients with resected NSCLC treated with and without PORT who underwent tumor genomic profiling were examined. The incidence of locoregional failures (LRFs) in patients with deleterious mutations in DNA damage response and repair (DDR) genes and genes associated with radiation resistance (KEAP1/NFE2L2/STK11/PIK3CA) were investigated. Cox modeling and receiver operating characteristic curve (ROC) analysis assessed the relationship between TMB and locoregional control (LRC)., Results: Eighty-nine patients with NSCLC treated with PORT were analyzed, with a 2-year LRF rate of 19% (95% confidence interval, 10%-27%). Among patients treated with PORT, those with mutations in radiation resistance genes (n = 16 [18%]) had significantly more LRFs than patients without mutations (2-year LRF rate: 60% vs 11%; P < .001). On multivariate analysis, radiation-resistance mutations were associated with LRF after PORT (hazard ratio, 7.42; P < .001). Patients with mutations identified in DDR genes (n = 15 [17%]) had significantly improved LRC (P = .048) and no LRF events after PORT. On multivariate analysis, a higher TMB was associated with improved LRC after PORT (hazard ratio, 0.86; P = .01), and TMB was associated with PORT outcomes (area under ROC curve, 0.67-0.77). These genomic markers were not similarly associated with LRF in patients not treated with PORT., Conclusions: The data suggest that patients with radiation-resistance gene alterations may derive minimal benefit from PORT, whereas patients with high TMB and/or alterations in DDR genes may benefit from PORT and be suited for future precision-RT strategies. Prospective studies are necessary to validate these findings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cisplatin-based adjuvant chemotherapy remains the standard of care for patients with resected stage II or III non-small-cell lung cancer. However, biomarker-informed clinical trials are starting to push the management of early-stage lung cancer beyond cytotoxic chemotherapy. This review explores recent and ongoing studies focused on improving cytotoxic chemotherapy and incorporating targeted and immunotherapies in the management of early-stage, resectable lung cancer. Adjuvant osimertinib for patients with EGFR -mutant tumors, preoperative chemoimmunotherapy, and adjuvant immunotherapy could improve outcomes for selected patients with resectable lung cancer, and ongoing or planned studies leveraging biomarkers, immunotherapy, and targeted therapy may further improve survival. We also discuss the unique barriers associated with clinical trials of early-stage lung cancer and the need for innovative trial designs to overcome these challenges., Competing Interests: Jamie E. ChaftConsulting or Advisory Role: Genentech/Roche, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, Flame Biosciences, Janssen Oncology, Guardant Health, Regeneron/Sanofi, NovartisResearch Funding: Genentech/Roche, Bristol Myers Squibb, AstraZeneca/MedImmune, Merck Yu ShyrConsulting or Advisory Role: Janssen Research & Development, Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, AstraZenecaPatents, Royalties, Other Intellectual Property: Royalty for TNBCType for Insight Genetics. TNBCType is a Web-based subtyping tool for candidate TNBC samples using our gene expression metadata and classification method Boris SepesiConsulting or Advisory Role: Bristol Myers Squibb/MedarexSpeakers' Bureau: AstraZeneca Patrick M. FordeConsulting or Advisory Role: AstraZeneca/MedImmune, Bristol Myers Squibb, Janssen, Daiichi Sankyo/UCB Japan¸ Amgen, ITeos Therapeutics, Mirati Therapeutics, Sanofi¸ NovartisResearch Funding: Bristol Myers Squibb, AstraZeneca/MedImmune, Kyowa Hakko Kirin, Novartis, Corvus Pharmaceuticals,No other potential conflicts of interest were reported.

Background: The impact of peripheral blood immune measures and radiation-induced lymphopenia on outcomes in non-small cell lung cancer (NSCLC) patients treated with concurrent chemoradiation (cCRT) and immune check point inhibition (ICI) has yet to be fully defined., Methods: Stage III NSCLC patients treated with cCRT and ≥1 dose of durvalumab across a cancer center were examined. Peripheral blood counts were assessed pre-cCRT, during cCRT and at the start of ICI. These measures and risk-scores from two published models estimating radiation dose to immune-bearing organs were tested for association with disease control., Results: We assessed 113 patients treated with cCRT and a median of 8.5 months of durvalumab. Median PFS was 29 months (95% CI 18-35 months). A lower pre-cCRT ALC (HR: 0.51 (95% CI: 0.32-0.82), p = 0.02) and a higher pre-cCRT ANC (HR: 1.14 (1.06-1.23), p = 0.005) were associated with poor PFS. Neither ALC nadir, ALC at ICI start, ANC at ICI start or the normalized change in ALC from pre-cCRT to nadir were significantly associated with PFS (p = 0.07-0.49). Also, risk scores from the two radiation-dose models were not associated with PFS (p = 0.14, p = 0.21) but were so with the ALC Nadir (p = 0.001, p = 0.002). A higher pre-cCRT NLR was the strongest predictor for PFS (HR: 1.09 (1.05-1.14), p = 0.0001). The 12-month PFS in patients with the bottom vs. top NLR tertile was 84% vs 46% (p = 0.000004)., Conclusions: Baseline differences in peripheral immune cell populations are associated with disease outcomes in NSCLC patients treated with cCRT and ICI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Thor: No COI to report A. F. Shepard: Reports honoraria from ASCO. I. Preeshagul: Reports serving ono advisory board for Pfizer and AstraZeneca. M. Offin: Reports advisory role for PharMar, Novartis and Targeted Oncology. Reports honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme. D. Y. Gelblum: No COI to report. A. J. Wu: Reports research support from CivaTech Oncology, Inc., non-financial support from AlphaTau Medical, personal fees from MoreHealth, and personal fees from AstraZeneca. A. Apte: No COI to report. C. B. Simone II: Reports honoraria from Varian Medical Systems. M. D. Hellmann: Reports personal fees from Genentech, grants, personal fees and non-financial support from Bristol Myers Squibb, personal fees from Merck, personal fees and non-financial support from AstraZeneca, personal fees from Mirati, personal fees from Syndax, personal fees and equity from Shattuck Labs, personal fees and equity from Immunai, personal fees from Nektar, personal fees from Blueprint Medicines. In addition, Dr. Hellmann has a pending patent Determinants of Cancer Response to Immunotherapy by PD-1 Blockade (PCT/US2015/062208) licensed to PGDx. A. Rimner: Reports grants from Varian Medical Systems, grants from Boehringer Ingelheim, grants from Pfizer, grants and personal fees from AstraZeneca, grants and personal fees from Merck, personal fees from Research to Practice, personal fees from Cybrexa, non-financial support from Philips/Elekta, personal fees from MoreHealth. J. E. Chaft: Reports both research funding and consulting roles with Bristol-Myers Squibb, Merck, Genentech and AstraZeneca. D. R. Gomez: Reports honoraria from Merck, BMS, AstraZeneca, Reflexion, Medscape, Vindico, US Oncology, and Varian. Reports research support from Merck, BMS, AstraZeneca, and Varian. Serves on advisory board for AstraZeneca. J. Deasy: No COI to report. N. Shaverdian: Reports research funding from Novartis., (Published by Elsevier B.V.)

Osimertinib is a third-generation, irreversible oral EGFR-tyrosine kinase inhibitor), that potently inhibits EGFR-tyrosine kinase inhibitor-sensitizing mutations and T790M resistance mutations together with efficacy in CNS metastases in patients with non-small-cell lung cancer (NSCLC). Here we describe the rationale and design for the Phase III NeoADAURA study (NCT04351555), which will evaluate neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone prior to surgery, in patients with resectable stage II-IIIB N2 EGFR mutation-positive NSCLC. The primary end point is centrally assessed major pathological response at the time of resection. Secondary end points include event-free survival, pathological complete response, nodal downstaging at the time of surgery, disease-free survival, overall survival and health-related quality of life. Safety and tolerability will also be assessed. Trial Registration number: NCT04351555 (ClinicalTrials.gov).