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Background: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC)., Methods: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review., Results: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib., Conclusions: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)., (Copyright © 2024 Massachusetts Medical Society.)

Objectives: IMbrella A is a Phase III extension study that allowed rollover from Roche/Genentech-sponsored atezolizumab trials, including IMpower133, a Phase I/III trial of first-line atezolizumab or placebo plus carboplatin/etoposide in extensive-stage small cell lung cancer. We report outcomes from an exploratory analysis of IMpower133 with extended time-to-event data for patients who rolled over to IMbrella A., Materials and Methods: IMpower133 patients could roll over to IMbrella A to receive atezolizumab 1200 mg intravenously every three weeks if they continued to receive atezolizumab at IMpower133 closure or were in survival follow-up after atezolizumab discontinuation. Overall survival and safety were assessed; only serious adverse events and AEs of special interest were collected in IMbrella A., Results: Eighteen of 26 eligible patients rolled over to IMbrella A. At clinical cutoff (March 16, 2023), median follow-up in the atezolizumab plus carboplatin/etoposide arm (IMpower133 and IMbrella A) was 59.4 months. The three-, four-, and five-year overall survival (95 % CI) estimates were 16 % (11 %-21 %), 13 % (8 %-18 %), and 12 % (7 %-17 %), respectively. In IMbrella A, serious adverse events occurred in three patients (16.7 %), and one adverse event of special interest was reported (grade two hypothyroidism)., Conclusion: This long-term analysis of patients from IMbrella A previously enrolled in IMpower133 provides the first report of five-year overall survival outcomes in patients with extensive-stage small cell lung cancer treated with first-line cancer immunotherapy and chemotherapy. While limited by small patient numbers and lack of long-term data for the IMpower133 control arm, exploratory overall survival analyses in patients treated with atezolizumab plus carboplatin/etoposide compared favorably with historical data with chemotherapy alone. NCT03148418., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report editorial support funded by the Sponsor. Martin Reck reports receiving consulting fees, honoraria and travel support from Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Lily, Novartis, Pfizer, Sanofi, Roche, and Regeneron; and participation on a data safety monitoring or advisory board for Sanofi and Daiichi Sankyo. Rafal Dziadziuszko reports receiving honoraria from Roche, AstraZeneca, Amgen, Novartis, MSD, Bristol Myers Squibb, Takeda, and Pfizer; and materials from Novartis. Shunichi Sugawara reports receiving grants (to institution) from AstraZeneca, Chugai Pharma, MSD, Bristol Myers Squibb, and Ono Pharmaceutical; and honoraria from AstraZeneca, Chugai Pharma, MSD, Bristol Myers Squibb, and Ono Pharmaceutical. Steven Kao reports receiving grants (to institution) from AstraZeneca; honoraria from AstaZeneca, Pfizer, MSD, Bristol Myers Squibb, Roche, Amgen, Beigene, and Boehringer Ingelheim; and travel support from MSD. Maximilian Hochmair reports receiving honoraria from MSD, Roche, Lilly, AstraZeneca, Takeda, Bristol Myers Squibb, and Amgen. Florian Huemer declares no conflict of interest. Gilberto de Castro, Jr reports receiving consulting fees from Daiichi-Sankyo; honoraria from AstraZeneca, Bristol Myers Squibb, Jannsen, Lilly, MSD, Novartis, Roche, Amgen, and Daiichi-Sankyo; travel support from Roche, Amgen, Daiichi-Sankyo, MSD, AstraZeneca, and Bristol Myers Squibb; and participation on a data safety monitoring or advisory board for GlaxoSmithKline, AstraZeneca, MSD, and Novartis. Libor Havel declares no conflict of interest. Reyes Bernabé Caro reports receiving an investigational grant from Roche; honoraria from Roche, Bristol Myers Squibb, Pfizer, MSD, Amgen, Takeda, and AstraZeneca; and participation in a data safety monitoring or advisory board for Takeda, Roche, Bristol Myers Squibb, and AstraZeneca. György Losonczy and Jong-Seok Lee declare no conflict of interest. Dariusz M. Kowalski reports participation on an advisory board and consultancy for Roche, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, MSD, Sanofi-Aventis, Takeda, Pfizer, and Johnson & Johnson. Zoran Andric declares no conflict of interest. Raffaele Califano reports receiving grants (to institution) from Roche and MSD; consulting fees from Roche, MSD, Bristol Myers Squibb, and AstraZeneca; and honoraria from Roche, MSD, and AstraZeneca; membership in the EORTC lung cancer group and ESMO educational publication working group; and stock or stock options in The Christie Private Care and Supportive Care UK. Andrea Veatch, Gregory Gerstner, and Marta Batus declare no conflicts of interest. Stefanie Morris reports employment with and stock or stock options in Roche. Monika Kaul, Vaikunth Cuchelkar, Huafei Li, Bradford J. Danner, and Barzin Y. Nabet report employment with Roche. Stephen V. Liu reports receiving grants from AbbVie, Alkermes, Elevation Oncology, Ellipses, Genentech, Gilead, Merck, Merus, Nuvalent, RAPT, and Turning Point Therapeutics; and consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; and participation on a data safety monitoring for Candel Therapeutics., (Copyright © 2024. Published by Elsevier B.V.)

Background: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups., Patients and Methods: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR)., Results: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]., Conclusions: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The current standard of care for patients with newly diagnosed limited-stage small-cell lung cancer (SCLC) is concurrent chemoradiotherapy (CCRT). The prognosis remains poor due to the aggressiveness and high risk of progression or relapse of SCLC even if an initial response is achieved. Therefore, there is an urgent unmet clinical need in this population. The multicenter, phase 3, randomized, placebo-controlled, double-blind KEYLYNK-013 study evaluates the addition of pembrolizumab to CCRT followed by pembrolizumab with or without olaparib in participants with previously untreated limited-stage SCLC. (ClinicalTrials.gov: NCT04624204)., Methods: Eligible participants aged ≥18 years with newly diagnosed, pathologically confirmed, limited-stage (ie, stage I-III) SCLC will be randomized 1:1:1 to CCRT (ie, etoposide plus carboplatin or cisplatin for 4 cycles and standard thoracic radiotherapy) plus pembrolizumab (Groups A and B) or CCRT plus placebo (Group C). In the absence of disease progression, participants will receive pembrolizumab plus placebo (Group A), pembrolizumab plus olaparib (Group B), or placebo (Group C). Dual primary endpoints are progression-free survival per RECIST version 1.1 by blinded independent central review and overall survival., Results: Enrollment began in December 2020 and is ongoing at approximately 150 sites., Conclusions: KEYLYNK-013 will provide valuable information on the efficacy and safety of pembrolizumab plus CCRT and pembrolizumab with or without olaparib post CCRT in participants with limited-stage SCLC., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: Pembrolizumab monotherapy is standard first-line therapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population., Methods: In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival., Results: Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo., Conclusion: Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population., Competing Interests: Michael BoyerHonoraria: AstraZenecaConsulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Bristol-Myers Squibb, JanssenResearch Funding: Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim, Lilly, Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Amgen, Ascentage Pharma, Novartis, Janssen, Merck SeronoTravel, Accommodations, Expenses: Merck Sharp & Dohme, Genentech/Roche Mehmet A. N. ŞendurResearch Funding: Merck Sharp & Dohme Delvys Rodríguez-AbreuConsulting or Advisory Role: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca Spain, NovartisResearch Funding: Merck Sharp & DohmeSpeakers' Bureau: Roche, Bristol-Myers Squibb, Merck Sharp & DohmeTravel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Merck Sharp & Dohme, Blueprint Medicines, Amgen, Merck KGaA, LOXO, Abbvie, Daiichi Sankyo, Boehringer Ingelheim, Johnson & Johnson, Eisai, Puma BiotechnologySpeakers' Bureau: Boehringer Ingelheim, AZDResearch Funding: AstraZeneca, Merck Sharp & Dohme Dae Ho LeeHonoraria: AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Chong Kun Dang Pharmaceutical, CJ Healthcare, Lilly, Janssen, Merck, Merck Sharp & Dohme, Mundipharma, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Samyang, ST Cube, Takeda, Abbvie, Menarini, Green CrossConsulting or Advisory Role: ST CubeResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Takeda, Blueprint Medicines Irfan ÇiçinConsulting or Advisory Role: Pfizer, Merck Sharp & Dohme, Roche, Novartis/Ipsen, Lilly, Bristol-Myers Squibb, SERVIER, Abdi Ibrahim, Nobelpharma, Abbvie, Teva, Janssen OncologyResearch Funding: Merck Sharp & DohmeSpeakers' Bureau: Novartis, Roche, Bristol-Myers Squibb, Pfizer, Abdi Ibrahim Perran Fulden YumukConsulting or Advisory Role: Takeda, Roche, Bristol-Myers SquibbSpeakers' Bureau: Novo Nordisk, Nestle Health Science, Bristol-Myers Squibb, Roche, AstraZenecaResearch Funding: Roche, Merck, Merck Sharp & Dohme, Novartis Francisco J. OrlandiHonoraria: Roche/GenentechConsulting or Advisory Role: AstraZeneca, Roche/Genentech, Bristol-Myers Squibb, Merck Sharp & Dohme, Lilly, Pfizer, Novartis, SanofiSpeakers' Bureau: AstraZeneca/MedImmune, RocheResearch Funding: AstraZeneca/MedImmune, Amgen, Genentech/Roche, Boehringer Ingelheim, Astellas Medivation, Merck Sharp & Dohme, Bristol-Myers Squibb, Celltrion, Pfizer, mAbxience, Nektar, SanofiTravel, Accommodations, Expenses: Pfizer, Merck Sharp & Dohme, AstraZeneca/MedImmune, Roche, Bristol-Myers Squibb, Genentech/Roche Ticiana A. LealConsulting or Advisory Role: Takeda, Abbvie, AstraZeneca, Genentech, Bayer, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb, Merck & Co, InvisionFirst Lung, NovocureTravel, Accommodations, Expenses: Takeda, Abbvie, Bristol-Myers Squibb, Genentech, Mirati Therapeutics, AstraZeneca, Merck & Co Olivier MolinierConsulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, TakedaResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Boehringer Ingelheim Nopadol SoparattanapaisarnResearch Funding: Merck Sharp & Dohme Adrian LanglebenResearch Funding: Merck Sharp & Dohme Raffaele CalifanoStock and Other Ownership Interests: The Christie Private CareHonoraria: AstraZeneca, Boehringer Ingelheim, Lilly Oncology, Roche, Pfizer, Merck Sharp & Dohme, BMS, Takeda, NovartisConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Lilly Oncology, Roche, Pfizer, Merck Sharp & Dohme, BMS, Takeda, NovartisSpeakers' Bureau: AstraZeneca, Roche, Pfizer, Merck Sharp & Dohme, BMS, Takeda, and NovartisResearch Funding: Roche, AstraZeneca, Pfizer, Clovis, Lilly Oncology, Merck Sharp & Dohme, BMS, Abbvie, Takeda, and NovartisTravel, Accommodations, Expenses: Roche, Lilly Oncology, Merck Sharp & Dohme, Takeda Balazs MedgyasszayResearch Funding: Merck Sharp & Dohme Te-Chun HsiaResearch Funding: Merck Sharp & Dohme Gregory A. OttersonConsulting or Advisory Role: Takeda, Novocure, Guardant Health, Bristol-Myers Squibb, AstraZenecaResearch Funding: Genentech/Roche, Pfizer, Bristol-Myers Squibb, Novartis, Merck, AstraZeneca, Celgene Lu XuEmployment: Merck Sharp & DohmeStock and Other Ownership Interests: Merck & Co, Inc, Kenilworth, NJ, USA Bilal PiperdiEmployment: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USAStock and Other Ownership Interests: Merck & Co, Inc, Kenilworth, NJ, USA Ayman SamkariEmployment: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USAStock and Other Ownership Interests: Merck & Co, Inc, Kenilworth, NJ, USA Martin ReckConsulting or Advisory Role: Lilly, Merck Sharp & Dohme, Merck Serono, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, Abbvie, Amgen, Mirati Therapeutics, Samsung BioepisResearch Funding: Merck Sharp & DohmeSpeakers' Bureau: Roche/Genentech, Lilly, Merck Sharp & Dohme, Merck Serono, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati TherapeuticsNo other potential conflicts of interest were reported.

Purpose: IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported., Patients and Methods: Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m 2 IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted., Results: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status., Conclusion: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.

The advent of PD-(L)1 and CTLA-4 immune check point inhibitors (CPIs) has dramatically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). For up to a quarter of patients with advanced NSCLC, CPIs have the potential to induce durable responses with long-term survival outcomes. Since the approval of first-line pembrolizumab for patients whose tumors express a PD-L1 ≥ 50%, several pivotal first-line CPI-based phase 3 studies have been conducted investigating combination treatments combining CPIs with chemotherapy (ChT) or combining different CPIs with or without ChT. As a result, there has been an increase in front-line treatment options for advanced NSCLC, and treatment algorithms are changing very quickly. In fit patients with advanced NSCLC, combination treatments including CPI and ChT are considered the new standard of care with improved clinical outcomes. CPI combination treatments are well tolerated and quality of life also seems to be better when CPIs are implemented in the first-line setting. The aim of this review is to provide a summary of the recently published first-line phase 3 studies investigating CPIs as monotherapy or in combination with other CPIs or ChT in advanced NSCLC, and to suggest possible treatment algorithms.

Background: CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial., Methods: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and disease progression during/after ≥1 systemic treatment (≥1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3-4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety., Results: Of 811 patients treated, 103 had ECOG PS 2; 278 were aged ≥70 years and 125 were ≥75 years of age. Minimum follow-up was ~18 months. Safety was similar across populations; the most frequent grade 3-4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged ≥70 and ≥75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2., Conclusion: These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population., Clinical Trial Registration: NCT02409368., Competing Interests: Conflict of interest statement E.F. reports receiving personal fees from AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, priME Oncology, Roche, Samsung, Springer, Takeda, and Touchtime, outside the submitted work. A.A. reports receiving personal fees from Boehringer Ingelheim, Eli Lilly, MSD, and Pfizer, grants from Celgene, and grants and personal fees from Bristol-Myers Squibb and Roche, outside the submitted work. T.C. reports receiving personal fees from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Janssen, MSD, Novartis/GSK, Pfizer, Roche, Sanofi, and Servier, outside the submitted work. M.C., K.L., M.S., E.C., M.A.G., D.I., and J.M. have nothing to disclose. R.C. reports receiving grants from Bristol-Myers Squibb during the conduct of the study, and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly Oncology, MSD, Novartis, Pfizer, Roche, and Takeda, outside the submitted work. R.G. reports receiving personal fees from Bristol-Myers Squibb, outside the submitted work. L. P-A. reports receiving personal fees from Amgen, Bayer, Blueprint, Eli Lilly, Incyte, Merck, MSD, Novartis, Roche, and Takeda, and grants and personal fees from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. R.D. reports receiving travel grants from Amgen and Roche, receiving travel grants and holding advisory position for Pfizer, and acting in an advisory role for Ely Lilly and Novartis, outside the submitted work. J.J. reports receiving personal fees from AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer, Roche, and Takeda, and receiving travel support from Roche, outside the submitted work. W.A. reports receiving non-financial support from Boehringer Ingelheim and Bristol-Myers Squibb, personal fees from AstraZeneca and Pfizer, personal fees and non-financial support from Amgen and Roche, outside the submitted work. J.P.V.M. reports receiving travel support from Bristol-Myers Squibb and institutional grants from Pfizer, outside the submitted work. J.W. reports receiving personal fees from AbbVie, AstraZeneca, Blueprint, Boehringer Ingelheim, Chugai, Eli Lilly, Ignyta, Loxo, Roche, and Takeda, and grants and personal fees from Bristol-Myers Squibb, Janssen, MSD, Novartis, and Pfizer, outside the submitted work. A.L. and A.A. were employees of Bristol-Myers Squibb during the conduct of the study and A.A. has received company stock from Bristol-Myers Squibb. S.P. reports receiving personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Elsevier, EMD Serono, Guardant Health, Medscape, MSD, Novartis, OncLive, Pfizer, Roche, Takeda, and Tesaro, outside the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We investigated selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective, allosteric MEK1/2 inhibitor, plus platinum-doublet chemotherapy for patients with advanced/metastatic non-small cell lung cancer., Methods: In this Phase I, open-label study (NCT01809210), treatment-naïve patients received selumetinib (50, 75, 100 mg BID PO) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. Primary objectives were safety, tolerability, and determination of recommended Phase II doses., Results: Fifty-five patients received treatment: selumetinib 50 or 75 mg plus gemcitabine/cisplatin (n=10); selumetinib 50 mg plus gemcitabine/carboplatin (n=9); selumetinib 50, 75 or 100 mg plus pemetrexed/carboplatin (n=21); selumetinib 75 mg plus pemetrexed/cisplatin (n=15). Most frequent adverse events (AEs) were fatigue, nausea, diarrhoea and vomiting. Grade ⩾3 selumetinib-related AEs were reported in 30 (55%) patients. Dose-limiting toxicities (all n=1) were Grade 4 anaemia (selumetinib 75 mg plus gemcitabine/cisplatin), Grade 4 thrombocytopenia/epistaxis and Grade 4 thrombocytopenia (selumetinib 50 mg plus gemcitabine/carboplatin), Grade 4 febrile neutropenia (selumetinib 100 mg plus pemetrexed/carboplatin), and Grade 3 lethargy (selumetinib 75 mg plus pemetrexed/cisplatin). Partial responses were confirmed in 11 (20%) and unconfirmed in 9 (16%) patients., Conclusions: Standard doses of pemetrexed/carboplatin or pemetrexed/cisplatin were tolerated with selumetinib 75 mg BID. The selumetinib plus gemcitabine-containing regimens were not tolerated.

Unlabelled: Small-cell lung cancer has a high chemotherapeutic sensitivity but with disappointing outcome results. Patients with “sensitive disease” are those who respond to treatment with a long relapse-free interval (RFI): in these cases rechallenge with first-line chemotherapy might represent a therapeutic opportunity. Our largest retrospective experience confirmed that rechallenge is feasible with interesting outcome results; there are no statistical differences between RFI and outcome., Introduction: Patients with small-cell lung cancer (SCLC) that progresses after first-line (FL) chemotherapy have a poor prognosis and second-line (SL) chemotherapy has limited efficacy. Patients whose disease relapses/progresses > 90 days after FL platinum-based treatment are considered platinum-sensitive and could be rechallenged with a similar regimen. We conducted a multicenter retrospective analysis to evaluate outcomes of SCLC patients rechallenged with platinum/etoposide., Patients and Methods: Records of all SCLC patients treated in 7 institutions between January 2007 and December 2011 were reviewed. The primary end point was overall survival from the time of rechallenge (OS-R); secondary end points were progression-free survival (PFS) and overall survival from the time of diagnosis (OS-D). Survival curves were calculated using the Kaplan-Meier method., Results: Of the 2000 SCLC patients identified, 112 (5.6%) had sensitive disease treated with rechallenge platinum/etoposide; 65% were men with a median age of 64 years. At the time of diagnosis, 44% of patients had limited disease, 82% had an Eastern Cooperative Oncology Group performance status of 0 to 1. A median of 4 cycles of rechallenge was administered. Tumor response was 3% for complete response and 42% for partial response, 19% of patients maintained stable disease, 27% progressive disease, and 9% were not evaluable. Median PFS from the time of rechallenge was 5.5 months (95% confidence interval [CI], 4.4-6.3). Median OS-R and OS-D were 7.9 months (95% CI, 6.9-9.7) and 21.4 months (95% CI, 19.8-24.1), respectively. Subgroup analysis according to relapse-free interval (90-119 vs. 120-149 vs. > 150 days) did not show any statistically significant difference in PFS or OS-R., Conclusion: The outcome for SL chemotherapy for SCLC is poor. Rechallenge platinum/etoposide is a reasonable option with potentially better outcomes than standard chemotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Small-cell lung cancer is an aggressive disease for which the mainstay of treatment is chemotherapy. Despite good initial responses most patients will relapse. Some will receive second-line therapy with clinical benefit, but for third-line chemotherapy there is little evidence to guide treatment decisions and the benefits of treatment are unknown. This study investigated the treatment of SCLC in the third-line setting., Patients and Methods: An international, multicenter retrospective analysis of patients who received at least 3 lines of chemotherapy for their SCLC was performed., Results: From 2000 to 2010, 120 patients were identified from 5 centers: median age 61, 40% (n = 72) limited stage, and 79% (n = 95) Eastern Cooperative Oncology Group performance status of 0 to 1. Only 22% of these patients received 3 distinct lines of chemotherapy. The remainder were rechallenged with a chemotherapy regimen used at least once previously. Six percent received platinum-based chemotherapy in all 3 lines. In third-line, response rate was 18% and median overall survival was 4.7 months. Factors associated with longer survival included normal baseline LDH levels and response to second-line chemotherapy. On multivariate analysis only normal baseline LDH retained statistical significance. Thirty-five patients went on to receive chemotherapy beyond the third line., Conclusion: Few SCLC patients receive 3 chemotherapy lines. Most patients were rechallenged with a similar regimen at least once. Response and survival in the third-line setting are modest. Lack of response to second-line chemotherapy and elevated baseline LDH level might predict lack of benefit from third-line treatment. This data set does not include patients receiving fewer lines for comparison., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The epidermal growth factor receptor (EGFR) mutation is the first recognized molecular target in non-small cell lung cancer that makes personalized therapy feasible. This molecular alteration has been demonstrated to be more frequent in Asians, non-smokers and patients with adenocarcinoma histology. Several retrospective and subgroup analyses of phase III trials have shown the single agent, erlotinib, to be associated with higher response rates and longer progression-free survival in patients harbouring an EGFR mutation. Two prospective randomized phase III studies from China and Europe have confirmed the role of first-line erlotinib in patients with the mutations. Erlotinib has also been evaluated in combination with chemotherapy in either a concurrent or intercalated regimen. Earlier trials were limited by little information on the EGFR mutational status of the enrolled patients, and an ongoing phase III trial with translational biomarker analysis will provide more comprehensive data on the combination.

Omitting elective nodal irradiation (ENI) in limited-stage disease small cell lung cancer (LD-SCLC) is expected to result in smaller radiation fields. We report on data from a randomised phase II trial that omitted ENI in patients receiving concurrent chemo-radiotherapy for LD-SCLC. 38 patients with LD-SCLC were randomised to receive once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy (RT). 3D-conformal RT was given concurrently with cisplatin and etoposide starting with the second cycle of a total of four cycles. The gross tumour volume was defined as primary tumour with involved lymph nodes (nodes ≥1 cm in short axis) identifiable with CT imaging. ENI was not used. Six recurrence patterns were identified: recurrence within planning target volume (PTV) only, recurrence within PTV+regional nodal recurrence and/or distant recurrence, isolated nodal recurrence outside PTV, nodal recurrence outside PTV+distant recurrence, distant metastases only and no recurrence. At median follow-up 16.9 months, 31/38 patients were evaluable and 14/31 patients had relapsed. There were no isolated nodal recurrences. Eight patients relapsed with intra-thoracic disease: 2 within PTV only, 4 within PTV and distantly and 2 with nodal recurrence outside PTV plus distant metastases. Rates of grade 3+ acute oesophagitis and pneumonitis in the 31 evaluable patients were 23 and 3% respectively. In our study of LD-SCLC, omitting ENI based on CT imaging was not associated with a high risk of isolated nodal recurrence, although further prospective studies are needed to confirm this. Routine ENI omission will be further evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563)., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

There is paucity of data in the literature regarding the safety of combining granulocyte colony stimulating factor (G-CSF) during chemo-radiotherapy (CTRT) in lung cancer patients. The ASCO 2006 recommendations advise against use of CSFs during concomitant mediastinal CTRT. The only randomised study evaluating CSFs in this context showed significant increase in grade 3/4 thrombocytopenia and an excess of pulmonary toxic deaths. In the context of a phase II trial, 38 patients with limited-stage small cell lung cancer were randomised to receive once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy. Radiotherapy (RT) was given concurrently with cisplatin and etoposide. G-CSF was given as primary or secondary prophylaxis or as a therapeutic measure during an episode of febrile neutropenia according to local protocols. Common terminology criteria for adverse events (CTCAE) v3.0 was used to record toxicity. Thirteen (34%) of 38 patients received G-CSF concurrently with RT. With a median follow-up of 16.9 months, there were no treatment related deaths reported. Seven (54%) patients experienced grade 3/4 thrombocytopenia and 5 (38%) experienced grade 3/4 anaemia. Thirty-one percent required platelet transfusions. No episodes of bleeding were observed. There were no cases of grade 3/4 acute pneumonitis. These data suggests that with modern three-dimensional (3D) conformal RT, G-CSF administration concurrently with CTRT does not result in the increase risk of pulmonary toxicity, but does increase the risk of thrombocytopenia. Whether the risks of thrombocytopenia are outweighed by the outcome of timely early concurrent CTRT is being evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563) in which G-CSF is permitted during thoracic irradiation., (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Patients with small-cell lung cancer (SCLC) that progress after first-line chemotherapy have a poor prognosis and the evidence of a benefit from second-line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy., Patients and Methods: We retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival., Results: The median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months. The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum-based chemotherapy. A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors., Conclusions: The outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment., Patients and Methods: Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells., Results: The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma., Conclusion: This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.

This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and

The universally accepted first-line treatment for advanced (stage IIIB effusion/IV) non-small-cell lung cancer in patients with a good performance status is a platinum drug in combination with one of gemcitabine, paclitaxel, vinorelbine or docetaxel. Although cisplatin is generally the favoured platinum agent, gemcitabine partnered with carboplatin is convenient to administer and has a favourable toxicity profile. Here, the pharmacology, preclinical and clinical data to support the use of this regimen for the treatment of advanced non-small-cell lung cancer is evaluated.