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Background: The use of first-line poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is increasing in advanced ovarian cancer. Understanding the efficacy of first subsequent therapy (FST) in patients experiencing disease progression in the first-line setting is important to optimize postprogression treatments. We evaluated the efficacy of FST in patients from PAOLA-1/ENGOT-ov25 (NCT02477644) who received first-line olaparib maintenance., Patients and Methods: This post hoc analysis evaluated the efficacy of subsequent chemotherapy following disease progression by assessing time from FST to second subsequent therapy (SST) according to whether progression occurred during versus after first-line olaparib maintenance and FST type. A multivariate Cox model was used in the olaparib plus bevacizumab arm to identify prognostic factors influencing the efficacy of subsequent chemotherapy., Results: Of 806 randomized patients, 544 (67.5%) progressed and received subsequent chemotherapy. The median time from FST to SST was shorter in patients in the olaparib plus bevacizumab arm who progressed during first-line olaparib maintenance (6.1 months) than in those who progressed after first-line olaparib maintenance (11.4 months). Multivariate analysis indicated that progression after (versus during) first-line olaparib maintenance influenced time from FST to SST (hazard ratio 0.65, 95% confidence interval 0.50-0.84; P = 0.0011) independently of platinum-free interval or clinical risk. Among patients who progressed and received platinum-based chemotherapy with a PARP inhibitor as FST, the efficacy of subsequent therapies was also dependent on whether progression occurred during versus after first-line olaparib maintenance., Conclusions: These results suggest that the timing of disease progression relative to first-line olaparib maintenance may impact the efficacy of subsequent platinum-based chemotherapy. Although results should be interpreted with caution, across all subgroups, including patients who received platinum-based chemotherapy with PARP inhibitor rechallenge as FST, the median time from FST to SST was longer if progression occurred after versus during first-line olaparib maintenance., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies has shown superiority over chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC), but data for older patients (aged ≥70 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or those with an ECOG performance status of 2 are scarce. We aimed to test the superiority of the PD-1 antibody nivolumab and the CTLA-4 antibody ipilimumab over platinum-based doublet chemotherapy as first-line treatment in patients with NSCLC aged 70 years or older or with an ECOG performance status of 2., Methods: This open-label, multicentre, randomised, controlled, phase 3 trial was done at 30 hospitals and cancer centres in France. Eligible patients had stage IV histologically proven NSCLC, with no known oncogenic alterations, and were either aged 70 years or older with ECOG performance status of 0-2 or younger than 70 years with an ECOG performance status of 2. Patients were randomly assigned (1:1) centrally, using a computer-generated algorithm stratified by age (<70 vs ≥70 years), ECOG performance status (0-1 vs 2), and histology (squamous vs non-squamous) to receive nivolumab plus ipilimumab or platinum-based doublet chemotherapy (carboplatin [area under the curve ≤700 mg] plus pemetrexed [500 mg/m 2 intravenous infusion every 3 weeks] or carboplatin [on day 1; area under the curve ≤700 mg] plus paclitaxel [90 mg/m 2 as intravenous infusion on days 1, 5, and 15, every 4 weeks]). The primary endpoint was overall survival; secondary endpoints included progression-free survival and safety. All efficacy analyses were performed in the intention-to-treat population, which included all randomly assigned patients. Safety was analysed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study treatment and who had at least one safety follow-up. The trial is registered with ClinicalTrials.gov, NCT03351361., Findings: The trial was stopped early for futility on the basis of a pre-planned interim analysis after 33% of the expected events had occurred. Between Feb 12, 2018, and Dec 15, 2020, 217 patients were randomly assigned, of whom 216 patients were included in the final analysis, with 109 patients in the nivolumab plus ipilimumab group and 107 in the chemotherapy group; median age was 74 years (IQR 70-78). Median overall survival was 14·7 months (95% CI 8·0-19·7) in the nivolumab plus ipilimumab group and 9·9 months (7·7-12·3) in chemotherapy group (hazard ratio [HR] 0·85 [95% CI 0·62-1·16]). Among patients aged 70 years or older with an ECOG performance status of 0-1 (median age 76 years [IQR 73-79]), median overall survival was longer in the nivolumab plus ipilimumab group than the chemotherapy group: 22·6 months (95% CI 18·1-36·0) versus 11·8 months (8·9-20·5; HR 0·64 [95% CI 0·46-0·96]). Among patients with an ECOG performance status of 2 (median age 69 years [IQR 63-75]), median overall survival was 2·9 months (95% CI 1·4-4·8) in the nivolumab plus ipilimumab group versus 6·1 months (3·5-10·4) in the chemotherapy group (HR 1·32 [95% CI 0·82-2·11]). No new safety signals were reported. The most frequent grade 3 or worse adverse events were neutropenia (28 [27%] of 103 patients) in the chemotherapy group and endocrine disorders (five [5%] of 105 patients), cardiac disorders (ten [10%] patients), and gastrointestinal disorders (11 [11%] patients) in the nivolumab plus ipilimumab group., Interpretation: The study showed no benefit of nivolumab plus ipilimumab combination in the overall study population. As a result of early stopping, the trial was underpowered for primary and secondary endpoints; however, the finding of better survival with nivolumab plus ipilimumab compared with platinum doublet in the subgroup of older patients with NSCLC with an ECOG performance status of 0-1 warrants further study., Funding: Bristol-Myers Squibb., Competing Interests: Declaration of interests HL reports support for attending meetings or travel from Roche, Sanofi, Amgen, Takeda, and Pfizer; and participation on a data safety monitoring board or advisory board for Roche, MSD, Sanofi, Takeda, Daiichi, Amgen, and Pfizer. LG reports grants or contracts to their institution from Bristol-Myers Squibb, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly, and Novartis; payment or honoraria for lectures or presentations from Bristol-Myers Squibb, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly and Novartis; support for attending meetings or travel from Pfizer, MSD, AstraZeneca, Takeda, and Amgen; and participation on a data safety monitoring board or advisory board for InhaTarget Therapeutics. OB reports consulting fees from Roche, Takeda, and AstraZeneca; and honoraria for lectures and presentations from MSD, Bristol-Myers Squibb, and Janssen. IM reports honoraria for educational events from Regeneron; and support for attending meetings or travel from Pfizer and MSD. AV reports consulting fees from Pierre Fabre, Amgen, and MSD; support for attending meetings or travel from Pierre Fabre and Amgen; and participation on a data safety monitoring board or advisory board for MSD, AstraZeneca, Sanofi, Amgen, and Pierre Fabre. PD reports support for attending meetings or travel from Takeda and Accord Healthcare; and participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb. FG reports consulting fees from Roche, Takeda, and AstraZeneca; honoraria for lectures or presentations from MSD, Bristol-Myers Squibb, and Janssen; and congress travel expenses from AstraZeneca and MSD. RC reports meeting presentations and participation on boards for Bristol-Myers Squibb. CCh reports consulting fees from AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, Bristol-Myers Squibb, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, and Amgen; and support for attending meetings or travel from AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, Bristol-Myers Squibb, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, and Amgen. CR reports consulting fees from Roche, Takeda, MSD, Bristol-Myers Squibb, Janssen, and Sanofi; honoraria for lectures or presentations from Sanofi, Takeda, and AstraZeneca; and support for attending meetings or travel from MSD and Sanofi. CCr, CAV, LF, MG, SH, and CL declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The MOVIE phase I/II trial (NCT03518606) evaluated the safety and antitumor activity of durvalumab and tremelimumab combined with metronomic oral vinorelbine in patients with advanced tumors. We present the results of the recurrent advanced cervical cancer cohort., Methods: Patients received tremelimumab (intravenously, 75 mg, every four weeks (Q4W); four cycles max) plus durvalumab (intravenously, 1,500 mg, Q4W; 26 cycles max) and metronomic oral vinorelbine (40 mg, every three weeks (3QW)) until disease progression. The primary efficacy endpoint was the clinical benefit rate (CBR) based on the Response Evaluation Criteria in Solid Tumors V.1.1, which was analyzed using a Bayesian approach RESULTS: A total of 31 patients were enrolled and treated in the cervical cancer cohort. The median number of previous lines of chemotherapy for advanced disease was 2 (0-6), with all (100%) and 12 (38.7%) patients pretreated with cisplatin and bevacizumab, respectively. At the data cut-off, the median follow-up duration was 12.8 (Q1-Q3, 6.1-34.6) months. The CBR was 53.1% (95% CI, 36.0% to 69.8%), using a non-informative prior distribution (beta(1, 1)). The overall response rate was 41.9%, five patients achieved a complete response (16.1%), and eight patients (25.8%) had a partial response irrespective of histological subtype or programmed death-ligand 1 (PD-L1) expression. Of the 31 patients, 28 (90.3%) experienced treatment-related adverse events (TRAEs), 13 (41.9%) reported grade ≥3 immune-related adverse events (AEs), and 13 (41.9%) reported grade ≥3 chemotherapy-related AEs. The definitive discontinuation rate due to TRAEs was 16.1%., Conclusions: Dual checkpoint blockade of PD-L1 and cytotoxic T-lymphocyte-associated antigen-4 combined with metronomic oral vinorelbine demonstrated meaningful and durable clinical activity in patients with previously treated advanced cervical cancer. Toxicity was significant but manageable., Competing Interests: Competing interests: J-SF reported consulting fees from AstraZeneca, GSK, Esai, MSD, Lilly, Pfizer, Novartis, Daichi Sankyon and Seagen; honoraria from AstraZeneca, GSK, Esai, MSD, Lilly, Pfizer, Novartis, Daichi Sankyon and Seagen; support for attending meetings from AstraZeneca, GSK, Esai, MSD, Lilly, Pfizer, Novartis, Daichi Sankyon and Seagen; and participant on advisory board from AstraZeneca, GSK, Esai, MSD, Lilly, Pfizer, Novartis, Daichi Sankyon and Seagen outside the submitted work. EB reported consulting fees from Egle Tx; honoraria from Eisai, MSD, Sandoz and Amgen; and support for attending meetings from Daiichi Sankyo, Eisai, Amgen, Sandoz, MSD, Bristol-Myers Squibb, Novartis, Pfizer and Roche outside the submitted work. EC reported honoraria from AstraZeneca, Pfizer, Ipsen, BMS, MSD and Janssen; and support for attending meeting from Novartis, AstraZeneca and Janssen outside the submitted work. TDLMR reported grants from MSD, Novartis, Pfizer and Seagen; consulting fees from AstraZeneca, GSK, Clovis oncology, Pfizer, Gilead, Seagen and Sanofi; honoraria from GSK and MSD; support for attending meetings from Pfizer, Gilead and Eisai; and participant on advisory board from MSD outside the submitted work. ES-B reported grants from Merck Serono and AstraZeneca; honoraria from Merck Serono and MSD; support for attending meetings from Merck Serono, MSD and Novartis outside the submitted work. RS reported grants from AstraZeneca; consulting fees from DSK, Eisai and MSD; honoraria from GSK, Pharmaand, MSD, Eisai, Seattle Genetics and Novartis; and support for attending meetings from Eisai, Novartis, GSK and MSD outside the submitted work. PL reported grants from Servier; honoraria from BMS, AstraZeneca, Sanofi and Astellas; supports for attending meetings from Daicho, Ipsen, Astellas, Sanofi, Janssen and Pfizer; and participant on advisory board from Daichi outside the submitted work. OLS reported grants from AstraZeneca and BMS; honoraria from GSK, Pharmaand and MSD; and support for attending meetings from AstraZeneca, Pfizer and Accord outside the submitted work. AG reported received payments to his institution for grants from Roche/Genentech, AstraZeneca, Daiichi Sankyo, MSD, Gilead and Novartis; received payments to his institution for consulting fees from Novartis, AstraZeneca, MSD and Gilead; received payments to his institution for honoraria from Novartis; support for attending meetings from Mylan and Menarini outside the submitted work. No other disclosures were reported., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)