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Purpose: Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR -mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837)., Methods: Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS., Results: Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients., Conclusion: Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Introduction: In France, 40% of patients diagnosed with lung cancer are ≥70 years old, but these are under-represented in clinical trials. Using data from the French Epidemiological Strategy and Medical Economics (ESME) platform on Lung Cancer (LC), the objective is to provide an overview of the management and the prognosis of older patients with advanced or metastatic non-small cell lung cancer (AM-NSCLC) in a real-world context., Materials and Methods: From the ESME-LC database, we selected patients with AM-NSCLC (stage IIIB, IIIC, and IV), diagnosed between 2015 and 2019, and who received first-line systemic treatment. Demographics, tumour characteristics, and treatment received were described in patients ≥70, and compared to younger ones. Real-world progression-free survival (rwPFS) and overall survival (OS) were evaluated using the multivariable Cox model., Results: Among 10,002 patients with AM-NSCLC, the median age was 64 years, with 2,754 (27.5%) aged ≥70. In comparison with patients <70, older patients were more often male, with worse performance status and more comorbidities, but they were less underweight and more often non-smokers. The proportion of EGFR mutated non-squamous NSCLC was higher in older patients (25.0% vs 12.8%, p < 0.001), particularly among smokers and former smokers (12.7% vs 7.3%, p < 0.001). Among patients ≥70, 76.6% received first-line chemotherapy (including 67.0% treated with a platinum-based doublet), 15.0% received only targeted therapy, and 11.0% received immunotherapy (alone or in combination). Median first-line rwPFS was 5.1 months (95% confidence interval [CI] = [4.8;5.4]) for patients ≥70 and 4.6 months (95%CI = [4.4;4.8]) for patients <70, but age was not associated with rwPFS in multivariable analysis. Median OS was 14.8 months (95%CI = [13.9;16.1]) for patients ≥70 and 16.7 months (95%CI = [15.9;17.5]) for patients <70, with a significant effect of age in multivariable analysis for patients treated with chemotherapy and/or with targeted therapy, but not for patients treated with immunotherapy (alone or in combination with chemotherapy)., Discussion: In this real-world cohort of patients with AM-NSCLC, age was not associated with first-line rwPFS regardless of treatment received, nor with OS for patients receiving immunotherapy. However, OS was significantly shorter for patients aged ≥70 treated with chemotherapy or with targeted therapy alone., Competing Interests: Declaration of Competing Interest Mathilde Cabart reports non-financial support from Janssen, non-financial support from Pfizer, outside the submitted work. Loïc Mourey reports personal fees and non-financial support from Sanofi, personal fees from Astellas, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from BMS, personal fees and non-financial support from Ipsen, personal fees and non-financial support from Astra-Zeneca, personal fees and non-financial support from Pfizer, personal fees from Merck, outside the submitted work. David Pasquier has nothing to disclose. Sophie Schneider has nothing to disclose. Hervé Léna reports personal fees and non-financial support from Roche, personal fees from Astrazeneca, personal fees and non-financial support from MSD, personal fees and non-financial support from Novartis, personal fees and non-financial support from Takeda, personal fees from BMS, personal fees and non-financial support from Pfizer, non-financial support from Lilly, personal fees and non-financial support from Amgen, outside the submitted work. Nicolas Girard reports grants and personal fees from AstraZeneca, personal fees from Daiichi, grants and personal fees from Roche, grants and personal fees from MSD, grants and personal fees from BMS, grants and personal fees from Pfizer, grants and personal fees from Janssen, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Takeda, grants and personal fees from Novartis, grants and personal fees from Sanofi, outside the submitted work; and Family Member employee of AstraZeneca. Christos Chouaid reports grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants, personal fees and non-financial support from GSK, grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Sanofi Aventis, grants, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from Lilly, grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Pfizer, grants, personal fees and non-financial support from Takeda, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from Viatris, grants, personal fees and non-financial support from Chugai, grants, personal fees and non-financial support from Pierre Fabre, grants, personal fees and non-financial support from Amgen, outside the submitted work. Roland Schott reports personal fees and non-financial support from Roche, non-financial support from Takeda, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Pfizer, non-financial support from IPSEN, personal fees and non-financial support from BMS, outside the submitted work. Sandrine Hiret reports non-financial support from Roche, non-financial support from Novartis, other from Sanofi, other from Astra Zeneca, other from Takeda, other from BMS, outside the submitted work. Didier Debieuvre has nothing to disclose. Xavier Quantin has nothing to disclose. Anne Madroszyk has nothing to disclose. Pascale Dubray-Longeras reports personal fees from MSD, personal fees from AstraZeneca, personal fees and non-financial support from Takeda, non-financial support from Pfizer, outside the submitted work. Eric Pichon reports personal fees and non-financial support from Takeda, personal fees from AstraZeneca, personal fees from MSD, outside the submitted work. Anne Baranzelli has nothing to disclose. Grégoire Justeau has nothing to disclose. Maurice Pérol reports personal fees and non-financial support from Takeda, personal fees from Janssen, personal fees and non-financial support from AstraZeneca, outside the submitted work. Lise Bosquet has nothing to disclose. Bastien Cabarrou has nothing to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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 .Although the CNS activity of selpercatinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC) has been previously described, the ability of potent RET inhibition to prevent new CNS metastases from developing has been challenging to measure without randomized data. Serial CNS scans were studied from LIBRETTO-431, a randomized phase III trial of selpercatinib versus platinum/pemetrexed ± pembrolizumab whose primary results have been previously disclosed. Intracranial outcomes were assessed by neuroradiologic blinded independent central review in patients with baseline and ≥1 postbaseline CNS scans. Of the 192 patients within the intention-to-treat pembrolizumab population with baseline CNS scans, 150 patients were without baseline CNS metastases. The cumulative incidence of CNS progression in these patients was reduced with selpercatinib versus chemotherapy + pembrolizumab (cause-specific hazard ratio [HR], 0.17 [95% CI, 0.04 to 0.69]). The HR for intracranial progression-free survival (PFS) was 0.46 (95% CI, 0.18 to 1.18). Among the 42 patients with baseline CNS metastases, similar trends were observed in the cumulative incidence of CNS progression (cause-specific HR, 0.61 [95% CI, 0.19 to 1.92]) and intracranial PFS (HR, 0.74 [95% CI, 0.28 to 1.97]). These data demonstrate that selpercatinib effectively treats existing CNS disease and prevents or delays the formation of new CNS metastases. These results reinforce the importance of identifying RET fusions in first-line patients with NSCLC and treating with selpercatinib.

Aim: To investigate changes in treatment patterns in extensive-stage small-cell lung cancer (ES-SCLC) in France, Germany, Italy, Spain and the UK (EU5) between 2018 and 2021. Methods: Cross-sectional data from an oncology database were analyzed retrospectively. Results: Of 5832 eligible patients, 88.4% had stage IV disease at diagnosis. Among patients receiving first-line treatment, 91.8% (1079 /1176) received the platinum-etoposide (PE) combination in 2018 which decreased to 42.3% (509/1203) by 2021. Usage of the PE-atezolizumab combination increased from 0 to 41.2% during the same timeframe. Topotecan monotherapy remained the most widely used second-line treatment regardless of patients' platinum sensitivity. Conclusion: The first-line standard of care for ES-SCLC has evolved in EU5 with the PE-atezolizumab/durvalumab combination gradually superseding PE usage.