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Background: Capmatinib is a selective MET inhibitor with demonstrated efficacy in a phase II study of non-small cell lung cancer (NSCLC) patients harboring METex14 mutations. However, the real-world outcomes of capmatinib are largely unknown. From June 2019, the French Early Access Program (EAP) provided capmatinib to METex14 NSCLC patients who were ineligible for or for whom first-line standard therapies had failed., Methods: IFCT-2104 CAPMATU was a multicenter study that included all METex14 NSCLC patients who received capmatinib as part of the EAP until August 2021. The primary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS) and objective response rate (ORR)., Results: A total of 146 patients were included. The median age was 74.9 years, 56.6 % were never-smokers, and 32.4 % had brain metastases. The median TTF, median PFS and median OS from capmatinib initiation were 5.1 months (95 % CI 4.2-6.0), 4.8 months (95 % CI 4.0-6.0) and 10.4 months (95 % CI 8.3-13.2), respectively. Evaluation of the best response to capmatinib was available for 134 patients and resulted in an ORR of 55.3 % (95 % CI 46.8 %-63.6 %). The median PFS was 7.7 months for treatment-naïve patients and 6.0 and 4.1 months for patients who had received one or 2 + prior lines of treatment, respectively. For patients with brain metastases, the median PFS was 3.0 months. Capmatinib had a known and manageable safety profile, with grade 3 to 4 adverse events, mostly peripheral edema (8.2 %), occurring in 17.8 % of patients., Conclusion: In this large real-world study of METex14 NSCLC patients, the efficacy of capmatinib was confirmed, with a manageable safety profile, even in patients with brain metastases and in those who received several lines of treatment. This study reinforces the key role of capmatinib for these patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Ferreira: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, BMS. A. Swalduz: Financial Interests, Personal, Other, honoraria: AstraZeneca, Janssen, Roche, Amgen, BMS; Financial Interests, Personal, Advisory Role: AstraZeneca, Janssen, Roche, Amgen, BMS, Pfizer, Lilly. P. du Rusquec: Financial Interests, Personal, Other, Travel, Accommodations: Roche, Pfizer, Sandoz, Daiichi Sankyo, Merck, Novartis, Lilly, Amgen, Eisai, BMS, Takeda, AstraZeneca, Janssen, Sanofi. Advisory Role: Sanofi, Takeda. A.C. Toffart: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, BMS, Roche, Amgen, Takeda, Jannsen. J. Raimbourg: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS. V. Gounant: Financial Interests, Personal, Advisory Role: BMS, AstraZeneca, Takeda; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Sanofi, Pfizer. S. Couraud: Financial Interests, Personal, Other, honoraria: Amgen, AstraZeneca, BMS, MSD, Roche, Sanofi, Fabentech, Boehringer Ingelheim, Takeda; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, BMS, MSD, Roche, Sanofi, Chugai, Novartis, Pfizer, Sysmex, Cellgene, Takeda, Janssen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, Roche, Takeda. M. Wislez: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, Amgen, BMS, Roche; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, MSD, Amgen, BMS, Roche; Financial Interests, Institutional, Funding, research funding: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, MSD, Amgen, BMS, Roche. C. Descarpentries reports personal fees and nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Novartis Pharma SAS, nonfinancial support from Roche SAS, nonfinancial support from Boehringer Ingelheim france, nonfinancial support from Pfizer, outside the submitted work; G. Herbreteau reports personal fees and nonfinancial support from Pierre Fabre Oncology. V. Westeel: Financial Interests, Personal, Other, Honoraria: AstraZeneca, BMS, Amgen, Roche; Financial Interests, Personal, Advisory Role: MSD, Takeda; Financial Interests, Personal, Speaker’s Bureau: BMS, AstraZeneca, Roche, MSD, Pfizer, Amgen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS, AstraZeneca, Sanofi. A. B. Cortot: Financial Interests, Personal, Other, Consulting fees: Roche Novartis; Financial Interests, Personal, Other, Honoraria: Novartis Pfizer Takeda Roche; Financial Interests, Personal, Advisory Board: Roche Novartis Pfizer Takeda. All other authors have declared no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: [ 18 F]FDG PET denoising by SubtlePET™ using deep learning artificial intelligence (AI) was previously found to induce slight modifications in lesion and reference organs' quantification and in lesion detection. As a next step, we aimed to evaluate its clinical impact on [ 18 F]FDG PET solid tumour treatment response assessments, while comparing "standard PET" to "AI denoised half-duration PET" ("AI PET") during follow-up., Results: 110 patients referred for baseline and follow-up standard digital [ 18 F]FDG PET/CT were prospectively included. "Standard" EORTC and, if applicable, PERCIST response classifications by 2 readers between baseline standard PET1 and follow-up standard PET2 as a "gold standard" were compared to "mixed" classifications between standard PET1 and AI PET2 (group 1; n = 64), or between AI PET1 and standard PET2 (group 2; n = 46). Separate classifications were established using either standardized uptake values from ultra-high definition PET with or without AI denoising (simplified to "UHD") or EANM research limited v2 (EARL2)-compliant values (by Gaussian filtering in standard PET and using the same filter in AI PET). Overall, pooling both study groups, in 11/110 (10%) patients at least one EORTC UHD or EARL2 or PERCIST UHD or EARL2 mixed vs. standard classification was discordant, with 369/397 (93%) concordant classifications, unweighted Cohen's kappa = 0.86 (95% CI: 0.78-0.94). These modified mixed vs. standard classifications could have impacted management in 2% of patients., Conclusions: Although comparing similar PET images is preferable for therapy response assessment, the comparison between a standard [ 18 F]FDG PET and an AI denoised half-duration PET is feasible and seems clinically satisfactory., (© 2024. The Author(s).)

Purpose: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is an effective first-line therapy for patients with common EGFR mutation-positive non-small cell lung cancer (NSCLC). However, almost all patients become resistant to treatment. In some patients, emergence of tertiary EGFR mutations is implicated as a resistance mechanism. This study describes patients with NSCLC who acquired the rare EGFR mutations, L718Q or G724S, following EGFR TKI treatment., Patients and Methods: This was a retrospective, observational study undertaken in France from Feb-Nov 2021, in patients with EGFR mutation-positive NSCLC with an acquired L718Q or G724S mutation. Primary objectives were description of tumor characteristics, progression, and progression under treatment., Results: Nine eligible patients were identified. Acquired resistance to initial EGFR TKI treatment was associated with T790M emergence in six patients, who then received osimertinib monotherapy. Overall, eight patients received osimertinib monotherapy treatment at some point (average treatment duration: 18.3 months). Following the emergence of L718Q or G724S, patients received chemotherapy (n = 4; two of whom subsequently received afatinib), nivolumab (n = 2), afatinib (n = 2), or immunochemotherapy (n = 1). In the four patients who received afatinib after identification of L718Q or G724S, 2 achieved a partial response, one had stable disease and one had progressive disease. Treatment duration was 1.6-31.7 months. In patients with controlled disease (n = 3), progression-free survival was 6.1-31.7 months. Two of these patients had previously received osimertinib., Conclusion: Currently, there is no consensus regarding the treatment of EGFR mutation-positive NSCLC following emergence of the osimertinib resistance mutations, L718Q or G724S. Afatinib appears to be a promising treatment option in this setting., Competing Interests: Mateo Sanchis-Borja reports no conflicts of interest in this work. Florian Guisier personal fees from MSD, MSD/Merck US, AstraZeneca, Boehringer Ingelheim, Amgen, Roche, Viatris, and non-financial support from BMS, Boehringer Ingelheim, Chugai, and Pfizer. Aurelie Swalduz reports receiving honoraria for advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Ipsen, Janssen, Lilly, Pfizer, and Roche; receiving consulting fees from AstraZeneca, BMS, Janssen, and Roche; participating in symposiums for Amgen, AstraZeneca, BMS, Janssen, Pfizer, Sanofi, and Takeda; and participating in congresses for Janssen, Pfizer. Hubert Curcio reports receiving meeting support from BMS and Sanofi. Victor Basse reports no conflicts of interest in this work. Christophe Maritaz reports employment at Boehringer Ingelheim. Christos Chouaid reports serving as an advisory board member for and receiving research funding, honoraria and travel fees from AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen, Viatris, Chugai, and Amgen. Jean-Bernard Auliac reports personal fees and non-financial support from AstraZeneca, Roche, and BMS; non-financial support from MSD and Boehringer Ingelheim., (© 2024 Sanchis-Borja et al.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Osimertinib has been established as a standard of care for patients with common sensitizing EGFR -mutant advanced non-small-cell lung cancer (NSCLC) although the sequential approach (first-generation inhibitor gefitinib followed by osimertinib) has not been formally compared. The phase II APPLE trial (ClinicalTrials.gov identifier: NCT02856893) enrolled 156 treatment-naïve patients, and two treatment strategies were evaluated: osimertinib up front or the sequential treatment approach with gefitinib up front followed by osimertinib at the time of progression, either molecular progression (detection of plasma T790M resistance mutation) regardless of the radiologic status or just at the time of radiologic progression. Patients' characteristics were well balanced, except for the higher proportion of baseline brain metastases in the sequential approach (29% v 19%). Per protocol, 73% of patients switched to osimertinib in the sequential arm. Up-front treatment with osimertinib was associated with a lower risk of brain progression versus the sequential approach (hazard ratio [HR], 0.54 [90% CI, 0.34 to 0.86]), but a comparable overall survival was observed between both strategies (HR, 1.01 [90% CI, 0.61 to 1.68]), with the 18-month survival probability of 84% and 82.3%, respectively. The APPLE trial suggests that a sequential treatment approach is associated with more frequent progression in the brain but a similar survival in advanced EGFR -mutant NSCLC.

Non-small cell lung cancer (NSCLC) is the most common cause of brain metastasis (BM). Little is known about immune checkpoint inhibitor activity in the central nervous system, especially in patients receiving monotherapy for tumors with a tumor proportion score (TPS) ≥ 50%. This noninterventional, retrospective, multicenter study, conducted with the GFPC, included treatment-naïve patients strongly positive for PD-L1 (TPS ≥ 50%) with BM receiving first-line single-agent pembrolizumab treatment between May 2017 and November 2019. The primary endpoints were centrally reviewed intracranial overall response rates (ORRs), centrally reviewed intracranial progression-free survival (cPFS), extracranial PFS, and overall survival were secondary endpoints. Forty-three patients from five centers were included. Surgical or local radiation therapy was administered to 31 (72%) patients, mostly before initiating ICI therapy (25/31). Among 38/43 (88.4%) evaluable patients, the intracranial ORR was 73%. The median PFS was 8.3 months. The cerebral and extracerebral median PFS times were 9.2 and 5.3 months, respectively. The median OS was 25.5 months. According to multivariate analysis, BM surgery before ICI therapy was the only factor significantly associated with both improved PFS (HR = 0.44) and OS (HR = 0.45). This study revealed the feasibility and outcome of front-line pembrolizumab treatment in this population with BM.

Background: Few epidemiological data are available on surgically treated Caucasian patients with non-small-cell lung cancers (NSCLCs) harboring epidermal growth factor receptor ( EGFR ) mutations. The main objective of this study was to describe, in the real-world setting, these patients' incidence, clinical, and tumoral characteristics., Methods: The participating centers included all consecutive localized non-squamous NSCLC patients undergoing surgery between January 2018 and December 2019 in France. EGFR status was determined retrospectively when not available before surgery., Results: The study includes 1391 no squamous NSCLC patients from 16 centers; EGFR status was determined before surgery in 692 (49.7%) of the cases and conducted as part of the study for 699 (50.3%); 171 (12.3%) were EGFR mutated; median age: 70 (range: 36-88) years; female: 59.6%; never smokers: 75.7%; non-squamous histology 97.7%, programmed death ligand-1 expression 0%/1-49%/⩾50 in 60.5%/25.7%/13.8%, respectively. Surgery was predominantly lobectomy (81%) or segmentectomy (14.9%), with systematic lymph node dissection in 95.9%. Resection completeness was R0 for 97%. Post-surgery staging was as follows: IA: 52%, IB: 16%, IIA: 4%, IIB: 10%, IIIA: 16%, and IIIB: 0.05%; EGFR mutation exon was Del19/exon 21 ( L858R )/20/18 in 37.4%/36.8%/14%, and 6.4% of cases, respectively; 31 (18%) patients received adjuvant treatment (chemotherapy: 93%, EGFR tyrosine kinase inhibitor: 0%, radiotherapy: 20%). After a median follow-up of 31 (95% confidence interval: 29.6-33.1) months, 45 (26%) patients relapsed: 11/45 (24%) locally and 34 (76%) with metastatic progression. Median disease-free survival (DFS) and overall survival were not reached and 3-year DFS was 60%., Conclusion: This real-world analysis provides the incidence and outcomes of resected EGFR -mutated NSCLCs in a European patient cohort., Competing Interests: J-BA: In the last 5 years, J-BA has received honoraria for attending scientific meetings, speaking, organizing research, or consulting, from Boehringer Ingelheim, Hoffman-Roche, Takeda, BMS, MSD, Astra Zeneca, Amgen, and Pfizer., (© The Author(s), 2024.)

Background: Few data are available on the impact of venous thrombotic events (VTE) in patients with metastatic non-small cell lung cancer (mNSCLC) treated with immunotherapy., Methods: This is a secondary analysis of the ESKEYP study, a national, retrospective, multicenter study that consecutively included all PD-L1 ≥ 50% mNSCLC patients who initiated first-line treatment with pembrolizumab monotherapy. From May 2017 to November 2019, 845 patients were included (from availability of pembrolizumab in this indication in France to the authorization of the combination with chemotherapy). Impact of VTE and patient characteristics were analyzed., Results: Of the 748 patients (88.5%) with available data, the incidence of VTE was 14.8% (111/748). At pembrolizumab initiation, Khorana score was ≥ 2 for 55.0% (61/111) of them. Recurrence of VTE was reported for 4 of the 111 patients and 5 had bleeding complications. Patients with VTE were significantly younger, had more frequently long-term corticosteroids treatment and more often liver metastases. Progression-free survival (PFS) was significantly shorter in patients with VTE compared to patients without VTE: 6.1 (95% CI 4.1-9.0) months vs. 8.3 (6.9-10.3) months (p = 0.03). VTE did not significantly impact overall survival (OS): 15.2 (10.0-24.7) months with VTE and 22.6 (18.4-29.8) months without VTE (p = 0.07). In multivariate analysis for PFS and OS, HRs for VTE were 1.3 (0.99-1.71), p = 0.06 and 1.32 (0.99-1.76), p = 0.05., Conclusion: The incidence of VTE appears to be as high with in first-line immunotherapy as with chemotherapy in patients with mNSCLC, with in patient with VTE, a no significant trend for lower PFS and OS in multivariate analysis. more marked impact on PFS than on OS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Outside clinical trials, few data are available on the effect of long-term first-line pembrolizumab in patients with advanced non-small-cell lung cancers with ≥50% of tumor cells expressing programmed cell death ligand 1 (PD-L1). This French, multicenter study included consecutive advanced patients with non-small-cell lung cancer given first-line pembrolizumab alone between May 2017 (authorization date for this indication) and November 2019 (authorization date for pembrolizumab-chemotherapy combination). Information was collected from patients' medical files, with a local evaluation of the response and progression-free survival (PFS). Overall survival (OS) was calculated from pembrolizumab onset using the Kaplan-Meier method. The analysis concerned 845 patients, managed in 33 centers: median age: 65 (range: 59-72) years, 67.8% men, 78.1% Eastern Cooperative Oncology Group performance status 0/1, 38.9%/51.5%/6.6% active, ex or never-smokers, respectively, 10.9%/16.8% taking or recently took corticosteroids/antibiotics, 69.6% nonsquamous histology, 48.9% ≥75% PD-L1-positive, and 20.8% had brain metastases at diagnosis. After a median (95% CI) follow-up of 45 (44.1-45.9) months, respective median (95% CI) PFS and OS lasted 8.2 (6.9-9.2) and 22 (8.5-25.9) months; 3-year PFS and OS rates were 25.4% and 39.4%, respectively. Multivariate analysis retained never-smoker status, adenocarcinoma histology, Eastern Cooperative Oncology Group performance status ≥2, and neutrophil/lymphocyte ratio >4 as being significantly associated with shorter survival, but not brain metastases at diagnosis or <75% PD-L1 tumor-cell expression. These long-term results of pembrolizumab efficacy based on a nationwide "real-world" cohort reproduced those obtained in clinical trials., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: MET-targeted tyrosine kinase inhibitors (TKIs) demonstrated efficacy in advanced non-small cell lung cancer (aNSCLC) with MET exon14 skipping mutations (METexon14); yet, data on the management of these patients in clinical practice is sparse., Objective: The aim of this study was to describe the management of METexon14 aNSCLC patients., Patients and Methods: This real-life, retrospective study analyzed the management of METexon14 aNSCLC. The primary endpoint was the median overall survival (mOS). Secondary endpoints were to assess investigator-progression-free survival (PFS) and mOS in different subgroups: patients treated with (a) crizotinib, regardless of treatment line; (b) anti-MET TKIs (crizotinib, tepotinib, capmatinib); and (c) immunotherapy., Results: A total of 118 patients were included between December 2015 and January 1, 2020 in 13 centers. Median age was 73 years, 62.7% were female, 83.9% had adenocarcinoma, 92.4% at stage IV, and 27% had more than three metastatic sites. The majority of the patients (106, 89.8%) received at least one systemic treatment; 73% received at least one anti-MET TKI: crizotinib (68.6%), tepotinib (16%), capmatinib (10%). Only 10% received two anti-MET TKIs in their treatment sequences. With a median follow-up of 16 months (95% CI 13.6-29.7), mOS was 27.1 months (95% CI 18-31.4). There was no significant difference between mOS of patients treated and never treated with crizotinib, 19.7 (95% CI 13.6-29.7) and 28 (95% CI 16.4-NR) months, respectively (p = 0.16); mOS of the TKI cohort and of the TKI-naïve patient cohort were 27.1 (95% CI 18-29.7) and 35.6 (95% CI 8.6-NR) months respectively, with no significant difference (p = 0.7)., Conclusions: In this real-life study, there was no evidence of benefit in mOS with anti-MET TKIs., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To evaluate the safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage IV non-small-cell lung cancer., Methods: This was a multicenter, open-label, single-arm Phase II study performed in patients with advanced NSCLC without activating EGFR mutation or ALK rearrangement who progressed after first-line platinum-doublet chemotherapy. Combination treatment was atezolizumab (1200 mg IV day 1, every 3 weeks) and oral vinorelbine (40 mg, 3 times by week). The primary outcome was progression-free survival (PFS) during the 4-month follow-up from the first dose of treatment. Statistical analysis was based on the exact single-stage Phase II design defined by A'Hern. Based on literature data, the Phase III trial threshold was set at 36 successes in 71 patients., Results: 71 patients were analyzed (median age, 64 years; male, 66.2%; ex-smokers/active smokers, 85.9%; ECOG performance status 0-1, 90.2%; non-squamous NSCLC, 83.1%; PD-L1 ≥ 50%, 4.4%). After a median follow-up of 8.1 months from treatment initiation, 4-month PFS rate was 32% (95% CI, 22-44), i.e. 23 successes out 71 patients. OS rate was 73.2% at 4 months and 24.3% at 24 months. Median PFS and OS were 2.2 (95% CI, 1.5-3.0) months and 7.9 (95% CI, 4.8-11.4) months, respectively. Overall response rate and disease control rate at 4 months were 11% (95% CI, 5-21) and 32% (95% CI, 22-44), respectively. No safety signal was evidenced., Conclusion: Metronomic oral vinorelbine-atezolizumab in the second-line setting did not achieve the predefined PFS threshold. No new safety signal was reported for vinorelbine-atezolizumab combination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Bone metastases (BM) in renal cell carcinoma (RCC) are associated with a poor prognosis based on retrospective studies evaluating antiangiogenic agents. Few data are available regarding immune checkpoint inhibitors (ICI) in patients with bone metastatic RCC. NIVOREN is a multicentre prospective study in which patients were treated with nivolumab after the failure of antiangiogenic agents. We aim to assess the impact of BM on prognosis, and the efficacy and safety of nivolumab in patients enrolled in the NIVOREN trial., Materials and Methods: All patients with BM at inclusion were included in our study. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), safety, and skeletal-related events (SRE)., Results: Among 720 patients treated with nivolumab, 194 presented BM at inclusion. The median follow-up was 23.9 months. Median OS was 17.9 months in patients with BM versus 26.1 months in patients without BM (p = 0.0023). The difference was not statistically significant after adjustment (p = 0.0707). The median PFS was shorter in patients with BM even after adjustment (2.8 versus 4.6 months, p = 0.0045), as well as the ORR (14.8% versus 23.3%). SRE occurred for 36% of patients with BM. A post-hoc analysis evaluating the impact of bone-targeting agents (BTA) on SRE incidence showed a significant benefit of BTA on the incidence of SRE (OR = 0.367, CI95% [0.151-0.895])., Conclusion: Nivolumab is associated with shorter PFS, and lower ORR in RCC patients with BM. Our study suggests that BTA in association with immunotherapy decreases the incidence of SRE., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MaudVELEV, Cecile Dalban, Florence Joly, Mathieu Laramas, Berangère Narciso, Jean-François BERDAH, Victoria FERRARI, Quentin Dominique THOMAS, Cecile Mione, Florence Tantot and Sylvie Chabaud have nothing to disclose. Christine Chevreau: consulting or advisory role – BMS; Ipsen; Novartis; Pfizer. Travel, accommodations, and expenses – AstraZeneca, BMS, Pfysez-Ipsen. Gwenaelle Gravis: AstraZeneca (Inst); Bayer (Inst); BMS (Inst); IPSEN (Inst); Janssen (Inst); MSD Oncology (Inst); Pfizer (Inst); Sanofi/Aventis (Inst). Speaker's: Amgen (Inst); Astellas Pharma (Inst); BMS (Inst); Ipsen (Inst); Janssen Oncology (Inst); MSD Oncology (Inst); Sanofi/Aventis (Inst), Research Funding: BMS. Sylvie Negrier: Honoraria: Bristol-Myers Squibb; Ipsen; MSD Oncology; Novartis; Pfizer. Consulting or advisory role – Bristol-Myers Squibb; Ipsen; MSD Oncology; Novartis; Pfizer. Research Funding: IPSEN (Inst); Pfizer (Inst). Travel, accommodations, and expenses – Bristol-Myers Squibb; IPSEN; Novartis; Pfizer. Brigitte Laguerre: Honoraria: Astellas Pharma; AstraZeneca; Ipsen; Ipsen; Ipsen; Janssen-Cilag; MSD Oncology. Travel, accommodations, and expenses – Astellas Pharma; Janssen; Janssen Oncology; Novartis; Pfizer. Marine Gross-Goupil: consulting or advisory role – Amgen; Astellas Medivation; AstraZeneca; Bayer/Onyx; Bristol-Myers Squibb; Ipsen; Janssen-Cilag; MSD Oncology; Pfizer; Roche; Sanofi. Research Funding – AstraZeneca (Inst); AstraZeneca (Inst); BMS (Inst); Ipsen (Inst); Janssen-Cilag (Inst); Merck (Inst); MSD Oncology (Inst); Pfizer (Inst); Roche (Inst). Sylvain Ladoire: Expert testimony – Astellas Pharma; Bristol-Myers Squibb; Ipsen; Janssen Oncology; Lilly; Novartis; Pfizer; Roche; Sanofi. Travel, accommodations, and expenses – Astellas Pharma; AstraZeneca; Bristol-Myers Squibb; Ipsen; Janssen Oncology; Novartis; Pfizer; Sanofi. Delphine Borchiellini has received consulting and advisory fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, MSD Oncology, Novartis, Pfizer, and Sanofi; research funding from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Exelixis, Infinity Pharmaceuticals, Janssen, MSD, and Roche; and travel and accommodations expenses from Bristol-Myers Squibb, Janssen, Pfizer, and Roche. Lionnel Geoffrois: Honoraria: BMS; Ipsen; Merck serono; Pfizer. Consulting or advisory role – Ipsen. Frank Priou: consulting or advisory role – AstraZeneca. Philippe Barthélémy: Honoraria Astellas Pharma; BMS; IPSEN; Janssen-Cilag; Merck KGaA; MSD; Novartis; Pfizer. Consulting or advisory role – Amgen; AstraZeneca; BMS; Eisai; Ipsen; Janssen-Cilag; Merck KGaA; MSD Oncology; Pfizer. Travel, accommodations, and expenses – Astellas Pharma; BMS; IPSEN; Janssen-Cilag; MSD; Pfizer. Antoine Thiery-Vuillemin has received honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche/Genentech, and Sanofi; consulting and advisory fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, and Sanofi; research funding from Pfizer; and travel and accommodations expenses from AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, and Roche. Hubert Curcio: Honoraria or consultation fees: Bristol Myers Squibb. Stephane Oudard has received honoraria from Astellas Pharma, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche/Genentech, and Sanofi; consulting and advisory fees from Astellas Pharma, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, MSD Oncology, Novartis, Pfizer, Roche, Roche, and Sanofi; research funding from Ipsen and Sanofi; and travel and accommodation expenses from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck, MSD Oncology, Novartis, Pfizer, and Roche. Bernard Escudier: Honoraria Bristol-Myers Squibb; Ipsen; Oncorena; Pfizer. Consulting or Advisory Role – AVEO; Bristol-Myers Squibb; Ipsen; Oncorena; Pfizer. Research Funding - BMS France (Inst). Travel, accommodations, and expenses - Bristol-Myers Squibb; Ipsen; MSD. Laurence Albiges: consulting or advisory role – Amgen (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Corvus Pharmaceuticals (Inst); Exelixis (Inst); Ipsen (Inst); Janssen (Inst); Merck (Inst); MSD (Inst); Novartis (Inst); Peloton therapeutics (Inst); Pfizer (Inst); Roche (Inst). Research Funding – Bristol-Myers Squibb (Inst). Travel, accommodations, and expenses – Bristol-Myers Squibb; MSD. Constance Thibault: consulting or advisory role – Astellas/Agensys; AstraZeneca; Bristol-Myers Squibb; Ipsen; Janssen; Merck; MSD; Pfizer; Sanofi. Travel, accommodations, and expenses - Astellas/Agensys; Janssen; Sanofi., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.

Introduction: Advanced stage malignant mesothelioma (asMM) patients have poor prognosis. Several trials investigated the role of programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) in pre-treated asMM., Methods: A systematic review of the literature of clinical trials testing single-agent anti PD-1/PD-L1 ICIs in pre-treated asMM was performed. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) data were extracted. The predictive role of PD-L1 was assessed., Results: We selected 13 studies including 888 patients. ORR and DCR were 18.1% (95% confidence interval [CI] 13.9-22.8%) and 55.4% (95% CI: 48.1-62.5%), respectively. Median PFS and OS ranged from 2.1 to 5.9 and from 6.7 to 20.9 months, respectively. ORR according to PD-L1 was 27.0% (95% CI: 18.7-36.2%)., Conclusions: Anti-PD-(L)1 ICIs might be considered a treatment option for chemotherapy-resistant asMM, even if reliable predictive factors are still lacking., (Copyright © 2022 Elsevier B.V. All rights reserved.)