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Neoantigen immunoediting drives immune checkpoint blockade efficacy, yet the molecular features of neoantigens and how neoantigen immunogenicity shapes treatment response remain poorly understood. To address these questions, 80 patients with non-small cell lung cancer were enrolled in the biomarker cohort of CheckMate 153 (CA209-153), which collected radiographic guided biopsy samples before treatment and during treatment with nivolumab. Early loss of mutations and neoantigens during therapy are both associated with clinical benefit. We examined 1,453 candidate neoantigens, including many of which that had reduced cancer cell fraction after treatment with nivolumab, and identified 196 neopeptides that were recognized by T cells. Mapping these neoantigens to clonal dynamics, evolutionary trajectories and clinical response revealed a strong selection against immunogenic neoantigen-harboring clones. We identified position-specific amino acid and physiochemical features related to immunogenicity and developed an immunogenicity score. Nivolumab-induced microenvironmental evolution in non-small cell lung cancer shared some similarities with melanoma, yet critical differences were apparent. This study provides unprecedented molecular portraits of neoantigen landscapes underlying nivolumab's mechanism of action., Competing Interests: Competing interests T.A.C. is a cofounder of and holds equity in Gritstone Oncology. T.A.C. holds equity in An2H. T.A.C. acknowledges grant funding from Bristol Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H and Eisai. T.A.C. has served as an advisor for Bristol-Myers Squibb, MedImmune, Illumina, Eisai, AstraZeneca and An2H. T.A.C. is an inventor on intellectual property and a patent held by MSKCC on using tumor mutational burden to predict immunotherapy response, which has been licensed to PGDx. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The optimal treatment sequencing for patients with metastatic epidermal growth factor receptor ( EGFR )-mutant non-small cell lung cancer (NSCLC) remains a subject of debate. In the United States, osimertinib is the preferred EGFR tyrosine kinase inhibitor (TKI) in the first-line setting. However, small retrospective studies suggest that alternative EGFR TKI sequencing strategies may produce similar outcomes. This study aimed to compare the outcomes of patients with metastatic NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation treated with osimertinib vs. afatinib as first-line therapy., Methods: This retrospective, single-institution study examined 86 patients with metastatic EGFR -mutant NSCLC treated with either afatinib (n=15) or osimertinib (n=71) in the first-line setting. The primary outcome was progression-free survival (PFS), and secondary endpoints included time on EGFR TKI, overall survival (OS), and the incidence of adverse events (AEs)., Results: There was no difference in the PFS (median: 27.9 vs. 29.0 months, P=0.75), OS (P=0.18), and the median time on first-line EGFR TKI (23.9 vs. 15.2 months, P=0.10) between the afatinib and osimertinib groups, respectively. The number of AEs was also similar between the two treatment groups (P=0.17)., Conclusions: In this real-world retrospective study, there were no differences in PFS or OS between patients treated with afatinib or osimertinib in the first-line setting. These findings should be further investigated in larger prospective studies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-686/coif). B.P. has received research support to the institution from Bristol Myers Squibb, speaker honoraria from BioAscend, Merck, MJH Life Science, Play to Know AG, Grupo Pardini, GBOT, Doctaforum, Foundation Medicine, and has done consulting/advisory board work with Guidepoint, Guardant Health, Foundation Medicine, Illumina, BMS, Regeneron, AstraZeneca, and AH Merus. B.P. reports funding to the institution from the Bristol Myers Squibb Foundation/the Robert A. Winn Diversity in Clinical Trials Awards Program. D.M. has done consulting/advisory board work with Dedham Group, Precisionxtract, Pfizer, Eli Lily, and Takeda, and has received speaker honorarium from Jazz Pharmaceuticals. M.S. has done consulting/advisory board work with Jazz Pharmaceuticals and GlaxoSmithKline. M.S. reports funding from Daiichi Sankyo/Lilly and funding to the institution from Merck Serono, Vaccinex, Nektar, Amphivena, and Pfizer. A.S. served as speaker honoraria for MJH Life Science and HMP Global and has done consulting/advisory board work with Daiichi Sankyo, Eli Lilly, and Zymeworks. A.S. reports funding to the institution from Genetech, Genmab, Turning Point Therapeutics, Novartis, Eli Lily, Memgen, Mersana, BioAlta, AstraZeneca, Daiichi Sankyo. B.C. has received speaking fees from AstraZeneca, ARIAD Pharmaceuticals and Hoffmann-La Roche and consultant fees from Xilio, Achilles, ER Squibb, Hoffmann-La Roche, AstraZeneca, AbbVie, KSQ Therapeutics, GlaxoSmithKline, Gilead Sciences, Celgene. B.C. has received speaking fees from AstraZeneca plc, ARIAD Pharmaceuticals, Hoffmann-La Roche Ag, and OMNI Health Media LLC, and consultant fees from AbbVie, Achilles Therapeutics plc, AstraZeneca plc, Celgene, ER Squibb, G1 Therapeutics Inc, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, KSQ Therapeutics, MJH Life Sciences, Regeneron Pharmaceuticals Inc., Techspert IO Ltd., and Xilio and has received research funding from ER Squibb LLC and Iovance Biotherapeutics Inc., and has a patent applications filed US201962865697P and US202062976867P outside the submitted work. A.C. has received speaker bureau funding from Genentech, Merck, Takeda, Novartis, Boehringer Ingelheim, and Celgene and research funding from Novartis and Bristol-Myers Squibb. E.B.H. received speaker honoraria for ASCO 2022 Annual Meeting and the 35th Aspen Cancer Conference, received consulting fees from Ellipses, Kanaph Therapeutics, Inc., and ORI Capital II, Inc. E.B.H. has done data safety monitoring/advisory board work with Amgen, Jassen, RevMed, and reports grants to the institution from Revolution Medicine. J.E.G. has received research support AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genetech, GI Therapeutics, Ludwig Institute of Cancer Research, Merck, Novartis, Pfizer. J.E.G. has done consulting/advisory board work with AbbVie, AstraZeneca, Axiom HC Strategies, Blueprint Medicines, Bristol Myers Squibb, Celgene Corp, Daiichi Sankyo, EMD Serono-Merck KGaA, Genentech, Inivata, Janssen Scientific Affairs, Jazz Pharmaceuticals, Loxo Oncology Inc, Merck, Novartis, OncoCyte Biotechnology Company, Sanofi Pharmaceuticals, Takeda Pharmaceuticals, Triptych Health Partners. G.S. reports funding from AstraZeneca, NovoCure, and Syneos Health, consulting fees and speaker honoraria from AstraZeneca, NovoCure, OncLive, and DAVA Oncology. G.S. has done data safety monitoring/advisory board work with AstraZeneca, NovoCure, and FLASCO. The other authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Purpose: The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non-small cell lung cancer (NSCLC). Taminadenant (PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response., Patients and Methods: In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80-640 mg, orally, twice a day) with or without spartalizumab (anti-programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination., Results: During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea [n = 1 (4.0%) each; 640 mg], and in the combination group were pneumonitis [n = 2 (8.0%); 160 and 240 mg] and fatigue and alanine/aspartate aminotransferase increase [n = 1 (4.0%) each; 320 mg]; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively., Conclusions: Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status., (©2022 American Association for Cancer Research.)

Rationale: Recent studies have discovered several unique tumor response subgroups outside of response classification by Response Evaluation Criteria for Solid Tumors (RECIST), such as mixed response and oligometastasis. These subtypes have a distinctive property, lesion heterogeneity defined as diversity of tumor growth profiles in RECIST target lesions. Furthermore, many cancer clinical trials have been activated to evaluate various treatment options for heterogeneity-related subgroups (e.g., 29 trials so far listed in clinicaltrials.gov for cancer patients with oligometastasis). Some of the trials have shown survival benefit by tailored treatment strategies. This evidence presents the unmet need to incorporate lesion heterogeneity to improve RECIST response classification., Method: An approach for Lesion Heterogeneity Classification (LeHeC) was developed using a contemporary statistical approach to assess target lesion variation, characterize patient treatment response, and translate informative evidence to improving treatment strategy. A mixed effect linear model was used to determine lesion heterogeneity. Further analysis was conducted to classify various types of lesion variation and incorporate with RECIST to enhance response classification. A study cohort of 110 target lesions from 36 lung cancer patients was used for evaluation., Results: Due to small sample size issue, the result was exploratory in nature. By analyzing RECIST target lesion data, the LeHeC approach detected a high prevalence (n = 21; 58%) of lesion heterogeneity. Subgroup classification revealed several informative distinct subsets in a descending order of lesion heterogeneity: mix of progression and regression (n = 7), mix of progression and stability (n = 9), mix of regression and stability (n = 5), and non-heterogeneity (n = 15). Evaluation for association of lesion heterogeneity and RECIST best response classification showed lesion heterogeneity commonly occurred in each response group (stable disease: 16/27; 59%; partial response: 3/5; 60%; progression disease: 2/4; 50%). Survival analysis showed a differential trend of overall survival between heterogeneity and non-heterogeneity in RECIST response groups., Conclusion: This is the first study to evaluate lesion heterogeneity, an underappreciated metric, for RECIST application in oncology clinical trials. Results indicated lesion heterogeneity is not an uncommon event. The LeHeC approach could enhance RECIST response classification by utilizing granular lesion level discovery of heterogeneity., Competing Interests: The authors have read the journal’s policy and have the following competing interests: AC serves on Advisory Boards and/or Speaker Bureaus for Novartis, Merck, Genentech, Takeda, Jazz, Blueprint, Amgen and Pfizer and has research support from Bristol-Myers Squibb, and AstraZeneca. BC is an advisor or consultant with E.R. Squibb & Sons LLC, Celgene Corp, Gilead Sciences Inc., Achilles plc., Xilio Therapeutics, and KSQ Therapeutics. He is on the Speaker’s Bureau for Hoffman-LaRoche AG, E.R. Squibb & Sons LLC, AstraZeneca LLC. He has research support from Prometheus Inc., Iovance Biotherapeutics Inc., Adaptive Biotechnologies Corp. JEG serves in Advisory Board or consultant, or has research support from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono - Merck KGaA, Genetech, G 1 Therapeutics, Inivata, Merck, Novartis, Pfizer, and Ludwig Institute of Cancer Research. EH is advisory board or consultant for Ellipses, Janssen, Amgen and Revolution. AS has travel reimbursement or research support from Novartis, Daiichi Sankyo, Mersana, Genmab, AstraZeneca, and Turning Point Therapeutics, and Prime Oncology. AAB has research support from Bristol-Myers -Squib and serves on the advisory board of Memgen Inc. DTC has research from Bristol-Myers -Squib and Oncologies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Purpose: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non-small cell lung cancer., Patients and Methods: Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens., Results: Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response [two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD)], 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8 + T-cell presence in tumor stromal regions was associated with treatment benefit., Conclusions: Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment., (©2019 American Association for Cancer Research.)

Introduction: CheckMate 153 (NCT02066636) is a phase 3B/4 study assessing nivolumab in previously treated patients with advanced NSCLC. Eligibility criteria allowed enrollment of patients with poor prognostic features of advanced age or diminished Eastern Cooperative Oncology Group performance status (ECOG PS), which are typically underrepresented in or excluded from randomized controlled trials., Methods: Patients with stage IIIB or IV NSCLC and an ECOG PS of 0 to 2 with disease progression after at least one systemic therapy received nivolumab (3 mg/kg every 2 weeks) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was the incidence of grade 3 to 5 select treatment-related adverse events (TRAEs)., Results: Among 1426 treated patients, 556 (39%) were aged 70 years or older and 128 (9%) had an ECOG PS of 2. The median treatment duration was 3.2 months. Across subgroups and the overall population, the incidences of select grade 3 to 5 TRAEs (6%-9%) and grade 3 or 4 TRAEs (12%-14%) were similar. One grade 5 TRAE was documented. The median overall survival time was comparable in the overall population (9.1 months) and patients aged 70 years or older (10.3 months) but shorter in patients with an ECOG PS of 2 (4.0 months). Patient-reported outcomes generally improved., Conclusions: Data from this large predominantly community-based study, which included patients aged 70 years or older and with an ECOG PS of 2, are consistent with registrational studies. As expected, the median overall survival for patients with an ECOG PS of 2 was lower than for the overall population but comparable with historical data., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs)., Methods: EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (formalin-fixed paraffin-embedded tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians., Results: Clinical samples from 3505 unique EGFR+ NSCLCs were identified from June 2012 to October 2017. A total of 31 EGFR+ cases had concurrent kinase fusions detected: 10 (32%) BRAF, 7 (23%) ALK receptor tyrosine kinase (ALK), 6 (19%) ret proto-oncogene (RET), 6 (19%) fibroblast growth factor receptor 3 (FGFR3), 1 (3.2%) EGFR, and 1 (3.2%) neurotrophic receptor tyrosine kinase 1 (NTRK1), including two novel fusions (SALL2-BRAF and PLEKHA7-ALK). Twenty-seven of 31 patients had either a known history of EGFR+ NSCLC diagnosis or prior treatment with an EGFR TKI before the fusion+ sample was collected. Twelve of the 27 patients had paired pre-treatment samples where the fusion was not present before treatment with an EGFR TKI. Multiple patients treated with combination therapy targeting EGFR and the acquired fusion had clinical benefit, including one patient with osimertinib resistance due to an acquired PLEKHA7-ALK fusion achieving a durable partial response with combination of full-dose osimertinib and alectinib., Conclusions: RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)