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Durvalumab is the standard-of-care as consolidation therapy after chemo-radiotherapy in stage III unresectable non-small cell lung cancer (NSCLC); however, its activity across patients with NSCLC harbouring driver genomic alterations (dGA) is poorly characterised. Multicentre retrospective study including patients with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and October 2020 at 26 centres in Europe and America. Clinical and biological data were collected; dGA included: EGFR / BRAF / KRAS mutations (m) and ALK/ROS1 rearrangements (r). We evaluated progression-free survival (PFS) and overall survival (OS) based on dGA. Out of 323 patients included, 43 patients had one dGA: KRAS m (n = 26; 8 G12C), EGFR m (n = 8; 6 del19/ex21), BRAF m (n = 5; 4 V600E) and ALK r (n = 4). The median age was 66 years [39–84], gender ratio 1:1, with 98% performance status (PS) 0–1 and 19% non-smokers; 88% had adenocarcinoma. PD-L1 was positive in 85% (n = 4 missing). In the whole cohort, the median PFS was 17.5 months (mo.) (95% CI, 13.2–24.9) and median OS 47 mo (95%CI, 47-not reached [NR]). No statistically significant differences in terms of the median PFS were observed between patients with dGA vs. non-dGA: 14.9 mo (95% CI, 8.1-NR) vs. 18 mo. (95% CI, 13.4–28.3) (P = 1.0); however, when analysed separately: the median PFS was NR (11.3-NR) in the KRAS m G12C vs. 8.1 mo (5.8-NR) in the EGFR m del19/ex21 vs. 7.8 mo (7.7-NR) in the BRAF m V600E/ ALK r (P = 0.02). We observed limited activity of durvalumab consolidation in patients with stage III unresectable NSCLC with EGFR/BRAF m and ALK r but not for those harbouring KRAS m. Larger prospective studies are needed to confirm these findings. • Similar treatment outcomes to PACIFIC phase III trial. • Different benefits of durvalumab consolidation based on oncogenic alterations. • Significant increase in PFS with durvalumab in patients with KRAS mutations. • ALK- rearranged NSCLC seem to benefit the least to durvalumab consolidation. • Largest retrospective study evaluating durvalumab in oncogenic addicted stage III NSCLC. [ABSTRACT FROM AUTHOR]

Background: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance., Patients and Methods: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16 low cells (immature) by flow cytometry., Results: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%., Conclusion: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance., Competing Interests: Conflict of interest statement LM: Sponsored Research: Amgen, Bristol-Myers Squibb, Boehringer Ingelheim. Consulting, advisory role: Roche Diagnostics, Takeda, Roche. Lectures and educational activities: Bristol-Myers Squibb, Tecnofarma, Roche. Travel, Accommodations, Expenses: Bristol-Myers Squibb, Roche. Mentorship program with key opinion leaders: funded by AstraZeneca. IP has served as a consultant for AstraZeneca, Pfizer and BluePrint Medicines. EA: Travel expenses: Mundipharma. Lectures and educational activities: Sanofi Genzymes. DS, HR, JR, SP, SC, FB, FT, MLR, PS, JG, AJP, MC, MN, CR, APM, LC and WPhad nothing to disclose. LH: none related to the current article, outside of the current article: research funding Roche Genentech, Boehringer Ingelheim, AstraZeneca (all institution), advisory board: Boehringer, BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Boehringer Ingelheim, Amgen (all institution), speaker: MSD, travel/conference reimbursement: Roche Genentech (self); mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Quadia (self), interview sessions funded by Roche Genentech (institution), local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD/Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Janssen Cilag. EN: none related to the current article, outside of the current article: research support from Roche and Pfizer; advisory boards from Bristol Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim, Amgen and AstraZeneca. PM: Principal/subinvestigator of Clinical Trials for Abbvie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Xencor Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. CAV: Personal fees from Roche, AbbVie, MSD, Bristol-Myers Squibb, Novartis, Astra Zeneca, Takeda and Ipsen. PB: Speaker bureau: AstraZeneca, BMS, Roche, MSD. Honoraria: Beigene. SN: Speaker Bureau/Advisor: Amgen, AstraZeneca, Boehringer, Beigene, MSD, Roche, Takeda, Pfizer. MDH receives research support from Bristol-Myers Squibb; has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles and Arcus; received travel support/honoraria from AstraZeneca, Eli Lilly and Bristol-Myers Squibb; has options from Shattuck Labs, Immunai and Arcus; has a patent filed by his institution related to the use of tumour mutation burden to predict response to immunotherapy (PCT/US2015/062,208), which has received licensing fees from PGDx. GZ: Grants and personal fees from BMS, non-financial support from MSD, personal fees from Borhinger, non-financial support from Roche, personal fees from Astra-Zeneca, non-financial support from Abbvie, outside the submitted work. MM: Grants and personal fees from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from BOEHRINGER INGELHEIM, personal fees, non-financial support and other from ASTRA ZENENCA, personal fees, non-financial support and other from ROCHE, personal fees from KYOWA KYRIN, personal fees from PIERRE FABRE, outside the submitted work. LPA: Honoraria (self): Adacap, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Incyte, Ipsen, Merck, Merck Sharp and Dohme, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier, Sysmex, Takeda; Leadership role: Altum sequencing; Research grant/Funding (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer; Officer/Board of Directors Genómica. AMD: Consulting, advisory role or lectures: Roche, Eli Lilly, Boehringer Ingelheim, Astra Zeneca, Pfizer, BMS, Amgen, Novartis, MSD, Takeda, Pharmamar. Research support: Amgen, Abbvie, BMS. DP: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer; Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer. CME, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene. Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo. Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. NC: Sponsored Research at Gustave Roussy Cancer Center BMS fondation, GSK, Sanofi, advisory role and lectures: AstraZeneca. These are outside the scope of this work. GL: Research support Merck serono, BMS, Pfizer, AstraZeneca, Blueprint medicines. KA: Consultant for Astrazeneca and Iovance Biotherapeutics. Her institution has received non-monetary research support from Takeda and Novartis on her behalf. BB: Sponsored Research at Gustave Roussy Cancer Center Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown., Methods: Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants., Results: Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation., Conclusions: Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)