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BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Background: Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown., Methods: A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue., Results: In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19-0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor-β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB., Conclusion: A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted., Competing Interests: Conflict of interest statement Haratani received honoraria from AS ONE Corp., AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD K.K. and Ono Pharmaceutical Co. Ltd. as well as research funding from AstraZeneca K.K. and MSD K.K. Hayashi received honoraria from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Kyorin Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Shanghai Haihe Biopharma, Taiho Pharmaceutical Co. Ltd. and Takeda Pharmaceutical Co. Ltd.; consulting fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Merck Biopharma Co. Ltd., Pfizer Japan Inc., Shanghai Haihe Biopharma, and Takeda Pharmaceutical Co. Ltd.; and research funding from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd. and Ono Pharmaceutical Co. Ltd. Tanizaki received honoraria from AstraZeneca K.K., Boehringer-Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K. and Taiho Pharmaceutical Co. Ltd. Kato received honoraria from Bristol-Myers Squibb Co. Ltd. and Eli Lilly Japan K.K. Mitani received honoraria from Ono Pharmaceutical Co. Ltd. and Taiho Pharmaceutical Co. Ltd.; research funding from Taiho Pharmaceutical Co. Ltd. Tanaka received honoraria from AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Eisai Co. Ltd., Kyowa Kirin Co. Ltd., Merck Biopharma Co. Ltd., MSD K.K. and Ono Pharmaceutical Co. Ltd. Nishio received honoraria from Amgen Inc., AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., F. Hoffmann-La Roche Ltd., Guardant Health Inc., Ignyta Inc., Korea Otsuka Pharmaceutical Co. Ltd., Life Technologies Japan Ltd., Merck Biopharma Co. Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., North East Japan Study Group, Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., Sanofi K.K., Solasia Pharma K.K., SymBio Pharmaceuticals Ltd., Thoracic Oncology Research Group and Yakult Honsha Co. Ltd. Nakagawa received honoraria from AbbVie Inc., Amgen Inc., Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin Ltd., Bristol Myers Squibb Co. Ltd., Care Net Inc., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Hisamitsu Pharmaceutical Co. Inc., Kyorin Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Medical Mobile Communications Co. Ltd, Medical Review Co. Ltd., Medicus Shuppan Publishers Co. Ltd., Merck Biopharma Co. Ltd., Merck Serono Co. Ltd., MSD K.K., Nanzando Co. Ltd., Nichi-Iko Pharmaceutical Co. Ltd., Nikkei Business Publications Inc., Nippon Boehringer Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., Roche Diagnostics K.K., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Thermo Fisher Scientific K.K., Yodosha Co. Ltd., Yomiuri Telecasting Corp., 3H Clinical Trial Inc.; consulting fees from Eli Lilly Japan K.K., Kyorin Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc. and Takeda Pharmaceutical Co. Ltd.; and research funding from AbbVie Inc., Astellas Pharma Inc., AstraZeneca K.K., A2 Healthcare Corp., Bayer Yakuhin Ltd., Bristol Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., CMIC Shift Zero K.K., Covance Japan Inc., Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., EPS Corp., EPS International Co. Ltd., GlaxoSmithKline K.K., ICON Japan K.K., IQVIA Services Japan K.K., Japan Clinical Research Operations, Kissei Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., MSD K.K., Medical Research Support, Merck Serono Co. Ltd., Merck Biopharma Co. Ltd., Mochida Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Parexel International Corp., Pfizer Japan Inc., Pfizer R&D Japan G.K., PPD-SNBL K.K, PRA Health Sciences, Sanofi K.K., SymBio Pharmaceuticals Ltd., Syneos Health, Sysmex Corp., Taiho Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Treatment with KRAS G12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRAS G12C NSCLC cells., Experimental Design: Clones of sotorasib-sensitive KRAS G12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy-number evaluation. The underlying mechanisms of resistance were investigated using immunologic examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo ., Results: Unbiased screening detected subclonal evolution of MET amplification in KRAS G12C NSCLC cells that had developed resistance to sotorasib in vitro . MET knockdown using small interfering RNA (siRNA) restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK-ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS-MEK-ERK as well as AKT signaling. MET/ KRAS G12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice., Conclusions: MET amplification leads to the development of resistance to KRAS G12C inhibitors in NSCLC. Dual blockade of MET and KRAS G12C could be a treatment option for MET -amplified, KRAS G12C -mutated NSCLC., (©2021 American Association for Cancer Research.)

Background: The utility of bronchoscopy for patients with suspected immune checkpoint inhibitor (ICI)-related pneumonitis is currently debatable. The purpose of this study was to examine the findings of bronchoalveolar lavage (BAL) analysis and transbronchial lung biopsy (TBLB) in non-small cell lung cancer (NSCLC) patients with ICI-related pneumonitis, and to elucidate the clinical significance of bronchoscopy for this health condition., Patients and Methods: Consecutive NSCLC patients treated with ICIs, diagnosed with ICI-related pneumonitis after undergoing bronchoscopy between October 2015 and March 2019 were retrospectively screened. Findings of BAL fluid analysis and/or TBLB specimen histology were reviewed., Results: Twelve patients underwent bronchoscopy for the diagnosis of ICI-related pneumonitis, ten of whom underwent BAL. An increase in the proportion of lymphocytes higher than 20% was observed in all ten patients. An increase in the proportion of neutrophils (> 10%) and eosinophils (> 10%) was observed in two and one patient, respectively. TBLB specimens were analyzed for eight patients. Major histologic findings included alveolitis in seven (87.5%) and organizing pneumonia (OP) in five (62.5%) patients. Other findings included acute lung injury and fibrosis. All twelve patients demonstrated favorable outcomes., Conclusion: A major characteristic of BAL analysis in ICI-related pneumonitis with NSCLC was an increased proportion of lymphocytes. The histologic features of lung tissue included alveolitis and/or OP. Acute lung injury and fibrosis were observed. Although the necessity of bronchoscopy should be determined on a case-by-case basis, it is necessary to assess these parameters when proper differential diagnosis is needed.

Purpose: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear., Experimental Design: We retrospectively identified 138 patients with EGFR -mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing., Results: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI ( P = 0.0010). Whereas CD8 + and FOXP3 + TIL densities were significantly lower after EGFR-TKI treatment than before, CD8 + TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months., Conclusions: EGFR-TKI treatment was associated with changes in the TME of EGFR -mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment., (©2020 American Association for Cancer Research.)

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.