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Background: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC.Methods: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival.Results: After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%).Conclusions: In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .). [ABSTRACT FROM AUTHOR]

Introduction: Lenvatinib plus pembrolizumab was found to have antitumor activity and acceptable safety in previously treated metastatic NSCLC. We evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in metastatic NSCLC in the LEAP-007 study (NCT03829332/NCT04676412)., Methods: Patients with previously untreated stage IV NSCLC with programmed cell death-ligand 1 tumor proportion score of at least 1% without targetable EGFR/ROS1/ALK aberrations were randomized 1:1 to lenvatinib 20 mg or placebo once daily; all patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary end points were progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival (OS). We report results from a prespecified nonbinding futility analysis of OS performed at the fourth independent data and safety monitoring committee review (futility bound: one-sided p < 0.4960)., Results: A total of 623 patients were randomized. At median follow-up of 15.9 months, median (95% confidence interval [CI]) OS was 14.1 (11.4‒19.0) months in the lenvatinib plus pembrolizumab group versus 16.4 (12.6‒20.6) months in the placebo plus pembrolizumab group (hazard ratio = 1.10 [95% CI: 0.87‒1.39], p = 0.79744 [futility criterion met]). Median (95% CI) PFS was 6.6 (6.1‒8.2) months versus 4.2 (4.1‒6.2) months, respectively (hazard ratio = 0.78 [95% CI: 0.64‒0.95]). Grade 3 to 5 treatment-related adverse events occurred in 57.9% of patients (179 of 309) versus 24.4% (76 of 312). Per data and safety monitoring committee recommendation, the study was unblinded and lenvatinib and placebo were discontinued., Conclusions: Lenvatinib plus pembrolizumab did not have a favorable benefit‒risk profile versus placebo plus pembrolizumab. Pembrolizumab monotherapy remains an approved treatment option in many regions for first-line metastatic NSCLC with programmed cell death-ligand 1 tumor proportion score of at least 1% without EGFR/ALK alterations., Competing Interests: Disclosure Dr. Yang reports receiving funding to institution for serving on advisory or consultancy services for Daiichi Sankyo, Eli Lilly, Merck KGaA, Darmstadt, Germany, Merck Sharp & Dohme, Novartis, Roche, Genentech, Takeda Oncology, Yuhan Pharmaceuticals, Janssen Pharmaceuticals, Puma Technology, Gilead Sciences Inc., GlaxoSmithKline, BeiGene, Blueprint Medicines Corporation, Regeneron Pharmaceutical, and Taiho Pharmaceutical; receiving grant from Roche/Genentech; and having advisory or consultancy services from Ono Pharmaceuticals and Pfizer. Dr. Han reports receiving study funding to the institution from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, to support study conduct. Dr. Jiménez reports receiving study funding to the institution from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, to support study conduct. Dr. Lee reports receiving study funding to the institution from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, to support study conduct. Dr. Koralewski reports receiving study funding to the institution from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, to support study conduct. Dr. Karadurmus reports receiving study funding to the institution from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, to support study conduct. Dr. Sugawara reports receiving grants or contracts to their institution from AnHeart, AstraZeneca, Chugai Pharma, MSD, Daiichi Sankyo, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Ono Pharmaceuticals, AbbVie, Amgen, Taiho Pharmaceutical, Takeda, and Clinipace; payment or honoraria from AstraZeneca, Chugai Pharma, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly and Company, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck Biopharma Japan, Amgen, AbbVie, Otsuka, Thermo Fisher Scientific, and Towa Pharmaceutical. Dr. Livi reports receiving study funding to the institution from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, to support study conduct. Dr. Basappa reports receiving grants or contracts from Ipsen; receiving payment or honoraria from Bayer, Astellas, and Janssen; receiving support for attending meetings from Eisa, Ipsen, and Janssen; having participation on data safety monitoring board or advisory board with Eisai, Ipsen, Pfizer, Bristol-Myers Squibb, Roche, Janssen, AstraZeneca, EMD Serono, Bayer, Astellas, and MSD. Dr. Quantin reports receiving payment or honoraria to their institution from Sanofi, Bristol-Myers Squibb, and AstraZeneca; receiving support for attending meetings from Janssen Cilag, Sanofi, and Pfizer; and having participation on data safety monitoring board or advisory board with Bristol-Myers Squibb. Dr. Dudnik reports receiving study funding to the institution from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, to support study conduct. Dr. Moran reports receiving support for present manuscript from MSD; grants or contracts from Abbott; consulting fees from Bristol-Myers Squibb and MSD; honoraria from Bristol-Myers Squibb, MSD, AstraZeneca, GlaxoSmithKline, Novartis, and Bayer; support for attending meetings from Tecnofarma, Roche, Pfizer, Bayer, and Janssen; and having participation on data safety monitoring board or advisory board with MSD. Dr. Mekhail reports receiving payment for speakers bureau from MSD. Drs. Okpara and Dutcus are employees of Eisai Ltd., Hatfield, UK. Drs. Zimmer, Samkari, and Bhagwati are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, and own stock in Merck & Co., Inc., Rahway, New Jersey. Dr. Csőszi reports receiving study funding to the institution from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, to support study conduct., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC., Methods: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m 2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m 2 for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB., Results: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively)., Conclusions: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.B. reports advisory roles with AbbVie, AstraZeneca, Bayer, BMS, Causalis, Merck Serono, MSD, Novartis, Roche, and Takeda and receiving research funding from Immunai, OncoHost, MSD, and AstraZeneca. D.R.A. reports personal fees/honoraria for consultancy or advisory roles and lectures from Roche, Genentech, AstraZeneca, Bristol Myers Squibb, Boehringer Ingleheim, MSD, Merck Serono, Eli Lilly, Gilead, Sanofi, Regeneron, Incyte, Pfizer, Takeda, and Novartis; and travel expenses from Roche, Bristol Myers Squibb, MSD, Sanofi, Regeneron, and Novartis. E.F. reports personal fees or honoraria for advisory roles from Abbvie, Amgen, AstraZeneca, Bayer, Bergen Bio, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman-La Roche, GSK, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point; speaker’s bureau fees from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, F. Hoffman-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, and Touch Oncology; and independent board membership with Grifols. M.P. reports lecture fees, honoraria, or other fees from Bristol Myers Squibb, Roche, MSD, AstraZeneca, Takeda, Eli Lilly and Company, F. Hoffman-La Roche, Janssen, and Pfizer; and research funds from MSD, AstraZeneca, Roche, Boehringer Ingleheim, and Bristol Myers Squibb. D.R.C. reports lecture fees, honoraria or other fees from Roche and AstraZeneca. S.M.T, J.K., and E.J.D. report employment with MSD. M.A. reports employment and stock ownership with MSD. N.H. reports advisory or consultancy roles and stock ownership with Curve Biosciences. R.Mc. and B.J. report employment with Grail LLC. R.Ma reports employment with Grail LLC and stock ownership with Illumina. D.B. reports employment with GRAIL LLC and stock ownership with Illumina. E.E., S.P.A., M.G., A.R., A.F., S.B.R., G.S., T.C. have no conflicts of interest to disclose., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly ( p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604., Methods: Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ-Lung Cancer Module 13. Two-sided, nominal p values are reported., Results: A total of 439 patients completed at least one QLQ-C30 and QLQ-Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3-12.1) for pembrolizumab plus EP and 4.2 (0.9-7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2-8.7], p  = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9-not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56-1.14], p  = 0.208)., Conclusions: First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC., (© 2023 The Authors.)

Background Gadopiclenol is a macrocyclic gadolinium-based contrast agent (GBCA) with higher relaxivity compared with standard GBCAs, potentially allowing gadolinium dose reduction without decreasing efficacy. Purpose To investigate whether gadopiclenol at 0.05 mmol/kg is noninferior to gadobutrol at 0.1 mmol/kg for lesion visualization in body MRI. Materials and Methods A randomized, double-blind, crossover, phase 3 study was conducted between August 2019 and December 2020 at 33 centers in 11 countries. Adults with at least one suspected focal lesion in one of three different body regions (head and neck; breast, thorax, abdomen, or pelvis; or musculoskeletal system) underwent two contrast-enhanced MRI examinations, randomized to start with either gadopiclenol or gadobutrol. MRI examinations were read by three blinded expert readers for each respective body region. Readers rated border delineation, internal morphologic characteristics, and visual contrast enhancement. Three additional blinded readers assessed reader preference. For safety analysis, adverse events were recorded. The differences between gadopiclenol- and gadobutrol-enhanced MRI in terms of lesion visualization were analyzed with a generalized linear mixed model using a two-sided paired t test. Results Among 273 participants (mean age, 57 years ± 13 [SD]; 162 women) who underwent both gadopiclenol- and gadobutrol-enhanced MRI and had at least one correlating lesion, 260 participants without major protocol deviations were analyzed for noninferiority. Gadopiclenol was noninferior to gadobutrol for all qualitative visualization parameters and for all readers (lower limit 95% CI of the difference of at least -0.10, which was above the noninferiority margin [-0.35]; P < .001). For most participants (75%-83% [206-228 of 276]), readers reported no preference between gadopiclenol- and gadobutrol-enhanced images. Adverse events did not differ in frequency, intensity, type, or association with GBCA injection (12 of 288 participants receiving gadopiclenol and 16 of 290 receiving gadobutrol). Conclusion Gadopiclenol at 0.05 mmol/kg was comparable with gadobutrol at 0.1 mmol/kg for lesion evaluation at contrast-enhanced body MRI and had a similar safety profile. Clinical trial registration no. NCT03986138 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Bashir and Thomas in this issue.

Background: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer., Methods: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting., Findings: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group)., Interpretation: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population., Funding: HUTCHMED., Competing Interests: Declaration of interests AD reports support for the present manuscript from HUTCHMED; grants or contracts from HUTCHMED, Guardant Health, Natera, AAA/Novartis, Eisai, and Crinetics; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from HUTCHMED, Personalis, AAA/Novartis, Crinetics, and Voluntis. SL reports support for the present manuscript from HUTCHMED; grants or contracts from Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol Myers Squibb; consulting or advisory fees from Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, and MSD; and speakers' bureau fees from Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen, and MSD. RG-C reports support for the present manuscript to their institution from HUTCHMED; grants for investigator-initiated clinical trials from Pfizer, Bristol Myers Squibb, and MSD; consulting fees from AAA/Novartis, Advanz Pharma, Amgen, Bayer, Bristol Myers Squibb, Boerhringer Ingelheim, Esteve, HUTCHMED, Ipsen, Merck, Midatech Pharma, MSD, Pierre Fabre, Roche, and Servier; and support for attending meetings or travel from AAA/Novartis, Esteve, Ipsen, Merck, MSD, and Roche. EE reports grants or contracts to their institution from Amgen, Array Biopharma, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX SAS, HUTCHMED, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, and Taiho Pharma USA; consulting fees and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, Bayer, Hoffmann-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; support for attending meetings or travel from Amgen, Array BioPharma, Bristol Myers Squibb, Merck Serono, Roche, Sanofi, and Servier; participation on a data safety monitoring or advisory board for Amgen, Bayer, F Hoffmann-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; and a paid or unpaid leadership or fiduciary role with the American Society of Clinical Oncology, European Society for Medical Oncology, and Sociedad Española de Oncología Médica. TY reports grants or contracts to their institution from Ono Pharmaceutical, Sanofi, Daiichi Sankyo, PAREXEL International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex Corporation, Chugai Pharmaceutical, and Nippon Boehringer Ingelheim; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD. ASo reports consulting fees and attending meetings or travel support from HUTCHMED; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, Servier, MSD, Bristol Myers Squibb, Amgen, Merck, Bayer, Sanofi, and Pierre Fabre; and participation on a data safety monitoring or advisory board for Bristol Myers Squibb, Pierre Fabre, Amgen, HUTCHMED, MSD, and Servier. JY reports support for the present manuscript and consulting fees from HUTCHMED, Ipsen, Crinetics, Amgen, Chiasma, Advanced Accelerator Applications, and Novartis. PG-A reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events; and support for attending meetings or travel from and participation on a data safety monitoring or advisory board for Amgen, Merck, Roche, Sanofi, Servier, Lilly, and Pierre Fabre. AS-B reports lecture or educational event fees from Amgen, Bayer, Guardant Health, Merck, Sanofi, and Servier; and advisory board fees from Amgen, Bayer, Novartis, and Servier. TS reports grants or contracts from Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Daiichi Sankyo, Chugai Pharmaceutical, and Yakult Honsha; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, and Daiichi Sankyo. VR reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, Servier, and Pierre Fabre; and meetings or travel support from Merck, Bayer, Amgen, Vifor Pharma, and Accord Healthcare. JTo reports consulting fees and honoraria for lectures and presentations from Eisai, Roche, Merck, Servier, Amgen, Novartis, MSD, and Bristol Myers Squibb. GC reports consulting fees to their institution from and participation on a data safety monitoring or advisory board for Bristol Myers Squibb; support for attending meetings or travel from HUTCHMED; and research funding to their institution from HUTCHMED, Servier, Bayer, Isofol, Merck Serono, Bristol Myers Squibb, AstraZeneca, Pharmacyclics, Regeneron, Morphosys, and Incyte. ASP reports support for the present manuscript to the institution from HUTCHMED; grants or contracts for clinical trials to their institution from Ipsen, Bristol Myers Squibb, Exelixis, HUTCHMED, Taiho, Lilly, AstraZeneca, Incyte, Deciphers, G1 Therapeutics, Zentalkis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, Bayer, Sotio, and Innovations Cellular Therapeutics; educational event fees from Ideo Oncology, and MJH Life Sciences; travel support from Pfizer; participation on a data safety monitoring or advisory board for Amgen, Bristol Myers Squibb, Eisai, Ipsen, AAA, Exelixis, Pfizer, QED, Lilly, Mirati, HUTCHMED, Astellas, Incyte, AADi, Stromatis, EMD, and Serono; holding stock or stock options in Aptose, Actinium, and Alexion; and payment for medical writing services from Bayer, Ipsen, HUTCHMED, and Exelixis. TM reports grants or contracts to the institution from MSD, Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Health Clinical, Boehringer Ingelheim, Pfizer, Cimic Shift Zero, and Eli Lilly; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Lilly Japan, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, and Bristol Myers Squibb. CC reports consulting fees from Merck, Pierre Fabre, Servier, Amgen, and Nordic Pharma; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Roche, Servier, MSD, Merck, and Pierre Fabre; payment for expert testimony from Bayer, Servier, Pierre Fabre, and Merck; support for attending meetings or travel from Amgen; and participation on a data safety monitoring or advisory board for Amgen and Mirati. FG reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events to their institution from AstraZeneca, Roche, and MSD; and support for attending meetings or travel from MSD. ASh reports grants or contracts to their institution from HUTCHMED, Merck, INHIBRx, Verastem Oncology, Turning Point Therapeutics, Gritstone, Bolt Therapeutics, Bristol Myers Squibb, Pfizer, Astellas, Oncologie, Macogenics, Seattle Genetics, Amgen, Daiichi Sankyo, Lilly, and Jacobio; advisory board fees from Regeneron/Sanofi, Pfizer, and Catalyst Pharmaceuticals; and speaker fees from OncLive, OSCO/ASCO Direct, ACPMP, Cholangiocarcinoma Summit, Cholangiocarcinoma Foundation, and ASCO Advantage. HSH reports consulting fees from Merck, Processa, and TRIGR; lecture fees from Natera; and participation on a data safety monitoring or advisory board for Genentech and Seattle Genetics. JKr reports support for the present manuscript to their institution from Syneos Health/HUTCHMED; grants or contracts to their institution from Genentech, Bristol Myers Squibb, Amgen, Isofol Medical, Novartis, Tempest Therapeutics, MedImmune/AstraZeneca, AbbVie, MedImmune, Icon, and Turning Point Therapeutics; and participation on a data safety monitoring board for Amgen (Codebreak 300 trial, NCT05198934). MD reports support for the present manuscript from HUTCHMED; research grants from Roche, Keocyt, and Bayer; advisory board consulting fees from Boehringer, Roche, Merck Serono, Daiichi Sankyo, Rafael, Bayer, Agenus, Terumo, Pierre Fabre, and Servier; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, Merck Serono, Bayer, Amgen, Pierre Fabre, Servier, Roche, Merck Serono, and MSD; support for attending meetings from Servier, Pierre Fabre, and Roche; participation on a data safety monitoring or advisory board for Roche and Pancan; and a personal conflict of interest with Sandoz. AE reports payments for advisory boards from Amgen, Merck, and Ewopharma; and lectures or educational events from Amgen, Merck, Ipsen, and Ewopharma. SK reports personal and institutional grants or contracts from Bristol Myers Squibb, Lilly, and Roche; consulting fees and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Amgen, Servier, Lilly, Merck Serono, Roche, MSD, and Pierre Fabre; consulting fees from Novartis and Incyte; support for attending meetings or travel from Pierre Fabre, Lilly, Amgen, Bristol Myers Squibb, Roche, and Merch Serono; and participation on a data safety monitoring board or advisory board for Novartis. EVC reports grants or contracts to their institution from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Novartis, Roche, and Servier; and consulting fees from AbbVie, ALX, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, and Zymeworks. DA reports support for the present manuscript from his institution; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Roche, Sanofi, Servier, Sirtex, and Terumo; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Roche, Sanofi, Servier, Sirtex, Terumo, and CME providers Art Tempi, PriME Oncology, Medscape, and TRM Oncology; congress travel support from AstraZeneca; remunerated advisory board fees from Sanofi; non-remunerated advisory board fees from Oncolytics; and a paid or unpaid role with the European Society for Medical Oncology, European Organisation for Research in Treatment of Cancer, and Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society. SN, ZY, WRS, and MK report employment and holding stock or stock options with HUTCHMED. JTa reports consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, HUTCHMED, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; educational collaboration fees from Imedex/HMP, Medscape Education, MJH Life Sciences, and PeerView Institute for Medical Education and Physicians Education Resource; and holding stock or stock options in Oniria Therapeutics. CE reports support for the present manuscript from HUTCHMED; grants or contracts from Elevar, Merck, Pfizer, and Gritstone; and consulting fees from Bayer, GlaxoSmithKline, Halio Dx, and Boston Scientific. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients., Methods: IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting)., Findings: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%)., Interpretation: IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests All authors report editorial support from F Hoffmann-La Roche. EF received advisory or consulting fees from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, GlaxoSmithKline, Janssen, Medical Trends, Merck Sharp & Dohme (MSD), Merck Serono, Peptomyc, Pfizer, Puma, Regeneron, Sanofi, Syneos Health, and Takeda; received honoraria from Amgen, AstraZeneca, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, Janssen, Medscape, Medical Trends, MSD, Merck Serono, Peervoice, Pfizer, Springer, and Touch Medical; and is an independent member of the board for and has received personal fees from GRIFOLS. NA received grants or contracts from AstraZeneca, the National Cancer Institute, New York Genome Center P1000 and LC200388 the US Department of Defense; and received honoraria from AstraZeneca and Regeneron. CZ received honoraria from Lilly China, Sanofi, Boehringer Ingelheim, Roche, MSD, Qilu, Hengrui, Innovent, C-Stone, LUYE Pharma, TopAlliance Bioscience, and Amoy Diagnostics; and participated in a data safety monitoring board or advisory board for Innovent Biologics, Hengrui, Qilu, and TopAlliance Bioscience. AM-M received personal fees and travel expenses from Bristol–Myers Squibb, F Hoffmann-La Roche, MSD, Pfizer, Boehringer Ingelheim, MSD Oncology, and AstraZeneca, outside the submitted work. HK received research funding from Chugai Pharmaceutical, Novartis Pharma KK, Daiichi-Sankyo, AstraZeneca KK; and received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly KK, Kyowa Hakko Kirin, Bristol–Myers Squibb, MSD, Novartis Pharma KK, Daiichi-Sankyo, AstraZeneca KK, Pfizer, and Taiho Pharma. SS received honoraria from Chugai Pharma. DV, YD, and MM are employed by Genentech. FW is employed by Roche (China). JY, EB, and BG are employed by Genentech and have stock ownership of F Hoffmann-La Roche. HW received research funding (to institution) from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bristol–Myers Squibb, Celgene, Clovis Oncology, Genentech/Roche, Merck, Novartis, Pharmacyclics, SeaGen, Xcovery, and Eli Lilly; received honoraria from Novartis and AstraZeneca; received compensation for advisory boards from AstraZeneca, Xcovery, Janssen, Daiichi Sankyo, Blueprint, Mirati, and Helsinn; served in an uncompensated role for advisory boards for Merck, Takeda, Genentech/Roche, and Cellworks; and reports an uncompensated leadership role with the International Association for the Study of Lung Cancer. All other authors have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after Week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared to placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after Week 5 were significantly reduced with trilaciclib vs placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared to placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Supportive care interventions used to manage chemotherapy-induced myelosuppression (CIM), including granulocyte colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib., Methods: Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1-4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated., Results: The use of G-CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p < 0.0001; 3.3% vs. 11.8%, p = 0.0254; and 14.6% vs. 26.1%, p = 0.0252, respectively). Compared with placebo, trilaciclib significantly reduced DSN and SN, irrespective of G-CSF administration. RBC transfusions and ESAs were most often administered in patients with grade 3/4 anemia; however, patients typically received RBC transfusions over ESA administration., Conclusions: By improving CIM and reducing the need for associated supportive care, trilaciclib has the potential to reduce the burden of myelosuppression on patients receiving myelosuppressive chemotherapy for the treatment of ES-SCLC., Trial Registration: ClinicalTrials.gov (NCT02499770; NCT03041311; NCT02514447)., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS)., Methods: Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point., Results: Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure., Conclusion: Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%., Competing Interests: Martin ReckConsulting or Advisory Role: Lilly, MSD Oncology, Merck Serono, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, Abbvie, Amgen, Mirati Therapeutics, Samsung BioepisSpeakers' Bureau: Roche/Genentech, Lilly, MSD Oncology, Merck Serono, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics Delvys Rodríguez-AbreuConsulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, AstraZeneca Spain, NovartisSpeakers' Bureau: Roche, Bristol Myers Squibb, MSDTravel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD Andrew G. RobinsonHonoraria: MerckConsulting or Advisory Role: AstraZeneca, Merck, AmgenResearch Funding: AstraZeneca, Merck, Bristol Myers Squibb, Roche Canada Rina HuiHonoraria: Merck Sharp & Dohme, Novartis, Roche, AstraZeneca, Bristol Myers Squibb, Lilly, Pfizer, SeagenConsulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Roche, Bristol Myers Squibb, Novartis, Lilly, Pfizer, SeagenResearch Funding: AstraZeneca, Lilly, Novartis, MSD, Roche, Seagen, OncoSecTravel, Accommodations, Expenses: Novartis Tibor CsősziConsulting or Advisory Role: NovartisSpeakers' Bureau: Ipsen, Janssen-CilagTravel, Accommodations, Expenses: Sanofi, Pfizer Andrea FülöpResearch Funding: MSD, AstraZeneca, Janssen Nir PeledHonoraria: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Pfizer, Roche, TakedaConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, MSD, Novartis, Pfizer, RocheResearch Funding: MSD Oncology, Roche/Genentech, AstraZeneca, Takeda, Merck Serono, NovartisTravel, Accommodations, Expenses: Roche/Genentech, MSD Oncology, AstraZeneca, Pfizer Sinead CuffeTravel, Accommodations, Expenses: MSD Oncology, Roche, Pfizer, Bristol Myers Squibb Mary O'BrienHonoraria: Merck, Merck Serono, Abbvie, Bristol Myers SquibbConsulting or Advisory Role: MerckTravel, Accommodations, Expenses: Bristol Myers Squibb Suman RaoHonoraria: Merck, AstraZenecaConsulting or Advisory Role: Galvanize TherapeuticsSpeakers' Bureau: AstraZenecaTravel, Accommodations, Expenses: Merck Katsuyuki HottaHonoraria: AZD, MSD Oncology, Pfizer, Lilly, Taiho Pharmaceutical, Chugai Pharma, TakedaResearch Funding: MSD, Chugai Pharma, Lilly Japan, Bristol Myers Squibb, AZD Ticiana A. LealConsulting or Advisory Role: BeyondSpring Pharmaceuticals, Bristol Myers Squibb, Merck, Takeda, Genentech, InvisionFirst Lung, Novocure, Jazz Pharmaceuticals, AstraZeneca, Bayer, EMD Serono, Boehringer Ingelheim, Blueprint Medicines, Daiichi Sankyo/Lilly, Debiopharm Group, Genentech, LillyTravel, Accommodations, Expenses: Takeda, Abbvie, Bristol Myers Squibb, Genentech, Mirati Therapeutics, AstraZeneca, MerckUncompensated Relationships: Mirati Therapeutics Jonathan W. RiessConsulting or Advisory Role: Medtronic, Boehringer Ingelheim, Novartis, Blueprint Medicines, Genentech, EcoR1 Capital, Teladoc, Daiichi Sankyo, EMD SeronoResearch Funding: Merck, AstraZeneca/MedImmune, Spectrum Pharmaceuticals, Boehringer Ingelheim, Novartis, Revolution Medicines, GlaxoSmithKline Erin JensenEmployment: MerckStock and Other Ownership Interests: Merck Bin ZhaoEmployment: Merck Sharp & DohmeStock and Other Ownership Interests: Merck Sharp & Dohme M. Catherine PietanzaEmployment: MerckStock and Other Ownership Interests: Merck Sharp & Dohme Julie R. BrahmerHonoraria: Roche/GenentechConsulting or Advisory Role: Bristol Myers Squibb, Lilly, Merck, Amgen, Genentech, GlaxoSmithKline, AstraZeneca, Regeneron, SanofiResearch Funding: Bristol Myers Squibb, AstraZeneca, Spectrum Pharmaceuticals, Revolution, RAPT Therapeutics, Genentech/RocheTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche/GenentechOther Relationship: Bristol Myers Squibb, Merck, Janssen OncologyNo other potential conflicts of interest were reported.

Background: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma., Methods: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m 2 ] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m 2 ] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305., Findings: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group., Interpretation: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma., Funding: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA., Competing Interests: Declaration of interests TP reports honoraria and research funding from Merck Sharp and Dohme (a subsidiary of Merck, Kenilworth, NJ, USA), AstraZeneca, and Roche; honoraria from BMS, Seattle Genetics, Ipsen, Merck Sharp and Dohme, Novartis, and Pfizer; fees for a consultant or advisory role for AstraZeneca, BMS, Exelexis, Incyte, Ipsen, Merck Sharp and Dohme, Novartis, Pfizer, and Seattle Genetics; and travel expenses and accommodations from AstraZeneca and Roche. TC reports research funding from Merck Sharp and Dohme. MO reports research funding from Merck Sharp and Dohme; personal honoraria from Roche, Sanofi Aventis, and Astellas; institutional honoraria from Janssen; fees for a consultant or advisory role for Janssen, Sanofi Aventis, and Astellas; speaker bureau or expert testimony role for AstraZeneca; and travel expenses and accommodations from BMS, Janssen, and AstraZeneca. NM reports research funding from Merck Sharp and Dohme, Astellas, Chugai, Eli Lilly, Janssen, Pfizer, and Taiho; and fees for a consultant or advisory role for Chugai, Janssen, Merck Sharp and Dohme, and Sanofi Aventis. LG reports research funding from Merck Sharp and Dohme; fees for a consultant or advisory role for Janssen, Merck Sharp and Dohme, and Pfizer; and travel expenses and accommodations from Janssen, and Pfizer. SY-SC reports research funding from Merck Sharp and Dohme; and fees for a consultant or advisory role for AstraZeneca, BMS, and Merck Sharp and Dohme. YF reports research funding from Merck Sharp and Dohme, Tersera, Janssen, Astellas, and IMV; fees for a consultant or advisory role for AstraZeneca, Merck Sharp and Dohme, Sanofi Aventis, and Tersera; and fees for travel for Sanofi Aventis, and Tersera. SO reports research funding from Merck Sharp and Dohme, BMS, Sanofi Aventis, Pfizer, Novartis, Bayer, and Ipsen; personal honoraria from BMS, Merck, Sanofi Aventis, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen; institutional honoraria from Bayer and Pfizer; and travel expenses and accommodations from BMS, Merck, Sanofi Aventis, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen. CV reports research funding from Merck Sharp and Dohme, and Leo Pharma; fees for a consultant or advisory role for AstraZeneca, Merck Sharp and Dohme, GSK, Astellas, Ipsen, Roche, and BMS; and travel expenses and accommodations from Roche. RMB reports research funding from Merck Sharp and Dohme; honoraria from Sanofi Aventis, Roche, and Merck Sharp and Dohme; fees for a consultant or advisory role for Sanofi Aventis, Bayer, Janssen, AstraZeneca, Merck Sharp and Dohme, Roche, and Asofarma; and travel expenses and accommodations from Roche, Sanofi Aventis, Astellas, Janssen, Merck Sharp and Dohme, Bayer, Pharmacyclics, Clovis, and Eli Lilly. AF reports research funding from Merck Sharp and Dohme; honoraria from Merck Sharp and Dohme, AstraZeneca, Pfizer, and Seattle Genetics; and travel expenses and accommodations from Merck Sharp and Dohme, AstraZeneca, Pfizer, and Seattle Genetics. SG reports research funding from Merck Sharp and Dohme, and travel expenses and accommodations from Roche. YL reports research funding from Merck Sharp and Dohme, Sanofi Aventis, and Janssen; personal honoraria from Roche, Astellas, Janssen, Seattle Genetics, AstraZeneca, BMS, Merck Sharp and Dohme, Pfizer, Sanofi Aventis, and Ipsen; institutional honoraria from Janssen and Pfizer; and travel expenses and accommodations from Roche, Janssen, AstraZeneca, Merck Sharp and Dohme, and Sanofi Aventis. AR-V reports research funding from Merck Sharp and Dohme, Pfizer, and Takeda; honoraria from Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Roche, Ipsen, and Sanofi Aventis; fees for a consultant or advisory role for Astellas, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Ipsen, Clovis, and Roche; and travel expenses and accommodations from Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Roche, Ipsen, and Sanofi Aventis. RM reports research funding from Merck Sharp and Dohme; honoraria from MedLearning and Flatiron; and fees for a consultant or advisory role for Roche, Seattle Genetics, and Astellas. EYY reports research funding from Merck Sharp and Dohme, Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Pharmacyclics, Seattle Genetics, and Taiho; and fees for a consultant or advisory role for Abbvie, Advanced Accelerator Applications, Bayer, Clovis, Janssen, Merck Sharp and Dohme, and Sanofi Aventis. KN, KI, and BHM are employees of Merck Sharp and Dohme and report stock ownership. AA reports research funding from Merck Sharp and Dohme, Clovis, BMS, AstraZeneca, Bayer, Progenics, Janssen, Genentech, Esanik, Ionis, Arcus Biosciences, and Prometheus; honoraria from Merck Sharp and Dohme, BMS, and AstraZeneca; fees for a consultant or advisory role for Merck Sharp and Dohme, BMS, AstraZeneca, Pfizer, and Merck Serono; speaker bureau or expert testimony role for AstraZeneca; and travel expenses and accommodations from Merck Sharp and Dohme, BMS, and AstraZeneca., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: The neoadjuvant use of pertuzumab and trastuzumab with chemotherapy improves the pathologic complete response (pCR) in early HER2+ breast cancer. The aim of this study was to determine the pCR rate obtained with dual HER2 blockade in routine clinical practice. The secondary and tertiary objective was to investigate the impact of neoadjuvant systemic therapy (NST) on performing breast-conserving surgery and survival data. Methods: This was a multicentre, retrospective, observational study in patients with stage II and III HER2+ early breast cancer who received pertuzumab and trastuzumab-based NST. Data were collected from patients' medical records. Results: Eighty-two patients were included in the study treated in 8 cancer centers in Hungary between March 2015 and January 2020. The study included women with a median age of 50.3 years. The majority of the patients (95%) received a sequence of anthracycline-based chemotherapy followed by docetaxel. pCR was achieved in 54% of the cases. As a result of NST a significant increase of conservative breast surgeries (33% vs. 3.6% planned, p = 0.0001) was observed. Ki67 expression and neutrophil-to-lymphocyte ratio (NLR) significantly predicted pCR. None of the variables were independent predictors of DFS. Conclusion: The pCR rate achieved in our study demonstrates the reproducibility of trial data in a real-world population. The rate of breast-conserving surgery was significantly increased., Competing Interests: The authors declare that there are no known conflicts of interest associated with this publication and there was no significant financial support for this work that could have influenced its outcome. The authors state that the following financial relationships were not in any respect related to the present study. KB received consulting fees from Pfizer, Novartis, Eli Lilly, and Roche. ZH has received speaker honorarium from Roche, Pfizer, Eli-Lilly, Novartis, AstraZeneca, Amgen, Swixx, Bayer, Sandoz, Merck, Abbvie, Amicus, Egis, TEVA, Boeringer, BMS, Med-Gen Sol, and Oncompass. ZK received consulting fees from AstraZeneca EGIS, Pfizer, Novartis, Eli Lilly, Richter, and Roche. LL received consulting fees from Roche. GR received consulting fees from Pfizer, Novartis, Eli Lilly, and Roche. AR, TC, KM and BB declares no conflict of interest., (Copyright © 2021 Boér, Kahán, Landherr, Csőszi, Máhr, Ruzsa, Horváth, Budai and Rubovszky.)

Purpose: Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC., Methods: Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS., Results: Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%., Conclusion: Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.

Introduction : Authors present their 7-year experience since the introduction of minimal-invasive (VATS) lobectomies for lung cancer in regard to their surgical technique, results and oncological follow-up. Method: 173 VATS lobectomies were performed between June 2011 and December 2017, 105 men and 68 women. The mean age of patients was 64.1 years. Duration of surgery was 130 minutes on average. Results: Conversion to thoracotomy was required in 8 cases (3 bleedings, 3 pulmonary vessel lymph node infiltrations, 2 bronchial suture insufficiencies). Twenty persistent air leaks developed postoperatively, requiring 10 re-drainages and 10 re-operations: 7 re-VATS and 3 thoracotomies. Two hematomas were evacuated by re-VATS, 1 postoperative atrial fibrillation required cardioversion. There were no perioperative deaths. The 164 malignant cases were: 110 adenocarcinomas, 32 squamous cell carcinomas, 6 small cell neuroendocrine carcinomas, 4 undifferentiated carcinomas, 4 carcinoid tumours, 1 synchronous adenocarcinoma and squamous cell carcinoma, 1 synchronous adenocarcinoma and small cell carcinoma, 1 carcinosarcoma and 5 metastasis from other primary tumours. 118 patients received adjuvant chemotherapy. Tumour staging distribution was: IA 40, IB 53, IIA 29, IIB 16 and IIIA 21 cases. During an average follow-up time of 19.5 months, 9 local tumour recurrence and 27 distant metastasis evaluated, of which 11 were pulmonary (3 multiplex), 10 bone, 6 cerebral, 3 hepatic (1 multiplex), and 3 suprarenal gland. Conclusion: Our results correlate with published literature. During the period of this review, VATS lobectomies became a routine surgical technique in our department. Our experience proved that axillary thoracotomy is an advantage to learn the anterior VATS lobectomy technique.

Purpose: In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab., Patients and Methods: Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator's choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting., Results: Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively)., Conclusion: With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.

Background: Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors., Methods: BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, were recruited from 200 trial centres in 22 countries. Eligible patients were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Randomisation was stratified by visceral disease status. The primary endpoint was progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat). Safety was analysed in all patients who received at least one dose of treatment and at least one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01633060, and is ongoing but no longer enrolling patients., Findings: Between Jan 15, 2013, and March 31, 2016, 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups. Median progression-free survival was significantly longer in the buparlisib versus placebo group (3·9 months [95% CI 2·8-4·2] vs 1·8 months [1·5-2·8]; hazard ratio [HR] 0·67, 95% CI 0·53-0·84, one-sided p=0·00030). The most frequent grade 3-4 adverse events in the buparlisib versus placebo group were elevated alanine aminotransferase (63 [22%] of 288 patients vs four [3%] of 140), elevated aspartate aminotransferase (51 [18%] vs four [3%]), hyperglycaemia (35 [12%] vs none), hypertension (16 [6%] vs six [4%]), and fatigue (ten [3%] vs two [1%]). Serious adverse events were reported in 64 (22%) of 288 patients in the buparlisib group versus 23 (16%) of 140 in the placebo group; the most frequent serious adverse events (affecting ≥2% of patients) were elevated aspartate aminotransferase (six [2%] vs none), dyspnoea (six [2%] vs one [1%]), and pleural effusion (six [2%] vs none). On-treatment deaths occurred in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group; most deaths were due to metastatic breast cancer, and two were considered treatment-related (cardiac failure [n=1] in the buparlisib group and unknown reason [n=1] in the placebo group)., Interpretation: The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations., Funding: Novartis Pharmaceuticals Corporation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs)., Methods: In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients., Findings: Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and -0·9 (-4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44-0·97; two-sided nominal p=0·029)., Interpretation: Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC., Funding: Merck & Co., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1)., Methods: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety., Results: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%)., Conclusions: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).

Objective: To describe the incidence of febrile neutropenia (FN) and use of pegfilgrastim in cancer patients with high overall risk of FN and to investigate the relationship between granulocyte-colony stimulating factor (G-CSF) guideline adherence and chemotherapy delivery in Central and Eastern Europe (CEE) and Austria., Methods: Dose Intensity Evaluation Program and Prophylaxis (DIEPP) was a multicentre, prospective, and observational study of adult patients with breast cancer, lymphoma, lung cancer, gastric cancer, and ovarian cancer, who received chemotherapy with pegfilgrastim support and who had an overall risk of FN ≥ 20 %. Physicians assessed patient risk factors and reported their reasons for administering pegfilgrastim., Results: Patients were enrolled from 113 centres in CEE and Austria between August 2010 and July 2013, and data were analysed from 1072 patients. The most common tumour types were breast cancer (50 %) and lymphoma (24 %). FN incidence was 5 % overall. FN occurred in 3 % of patients (28/875) who received pegfilgrastim as primary prophylaxis (PP) and 13 % of patients (19/142) who received it as secondary prophylaxis (SP); 79 % of FN events in SP patients occurred in the first cycle before pegfilgrastim was administered. The three most frequently chosen reasons for using pegfilgrastim were planned chemotherapy with high FN risk, female gender, and advanced disease. Overall, 40 % of patients received > 90 % of their planned chemotherapy dose within 3 days of the planned schedule., Conclusion: FN incidence was relatively low with pegfilgrastim PP in patients with a physician-assessed overall FN risk of ≥ 20 %. The most important reasons for pegfilgrastim use were consistent with the investigators' risk assessment and international guidelines.