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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: BRAF inhibitors are approved in BRAF V600 -mutated metastatic melanoma, non-small-cell lung cancer (NSCLC), Erdheim-Chester disease (ECD), and thyroid cancer. We report here the efficacy, safety, and long-term results of single-agent vemurafenib given in the AcSé vemurafenib basket study to patients with various BRAF-mutated advanced tumours other than BRAF V600 -mutated melanoma and NSCLC., Patients and Methods: Patients with advanced tumours other than BRAF V600E melanoma and progressing after standard treatment were eligible for inclusion in nine cohorts (including a miscellaneous cohort) and received oral vemurafenib 960 mg two times daily. The primary endpoint was the objective response rate (ORR) estimated with a Bayesian design. The secondary outcomes were disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and vemurafenib safety., Results: A total of 98 advanced patients with various solid or haematological cancers, 88 with BRAF V600 mutations and 10 with BRAF nonV600 mutations, were included. The median follow-up duration was 47.7 months. The Bayesian estimate of ORR was 89.7% in hairy cell leukaemias (HCLs), 33.3% in the glioblastomas cohort, 18.2% in cholangiocarcinomas, 80.0% in ECD, 50.0% in ovarian cancers, 50.0% in xanthoastrocytomas, 66.7% in gangliogliomas, and 60.0% in sarcomas. The median PFS of the whole series was 8.8 months. The 12-, 24-, and 36-month PFS rates were 42.2%, 23.8%, and 17.9%, respectively. Overall, 54 patients died with a median OS of 25.9 months, with a projected 4-year OS of 40%. Adverse events were similar to those previously reported with vemurafenib., Conclusion: Responses and prolonged PFS were observed in many tumours with BRAF mutations, including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas. Although not all cancer types responded, vemurafenib is an agnostic oncogene therapy of cancers., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status., Patients and Methods: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis., Results: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms., Conclusions: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure., Competing Interests: Disclosure IRC reports honoraria (personal) from AbbVie, Agenus, Advaxis, Bristol Myers Squibb (BMS), PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GlaxoSmithKline (GSK), Merck Sharp & Dohme (MSD), Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis; honoraria (institution) from GSK, MSD, Roche, and BMS; advisory/consulting fees from AbbVie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis; research grant/funding (self) from MSD, Roche, and BMS; research grant/funding (institution) from MSD, Roche, BMS, Novartis, AstraZeneca, and Merck Sereno; and travel support from Roche, AstraZeneca, and GSK. AL reports grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria/reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GSK, Medscape, Merck Serono, MSD, TouchCongress, and Zentalis; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. SP reports honoraria from AstraZeneca, Roche, MSD, Pfizer, Tesaro, Clovis Oncology, GSK, and PharmaMar; and research funding (institution) from Roche, MSD, AstraZeneca, and Pfizer. AGM reports advisory/consultancy fees (personal) from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Eisai, Genmab, GSK, Hedera Dx, Illumina, ImmunoGen, MSD, Macrogenics, Mersana, Novartis, Oncoinvent, PharmaMar, Roche, Regeneron, Sotio, and Sutro; speaker bureau fees (personal) from AstraZeneca, Roche, GSK, MSD, Novocure, Takeda, Zai Lab, and Clovis; research grant/funding (institution) from Roche, Novartis, GSK, and Aravive; and steering committee member (personal) for MSD. CM reports honoraria/consulting fees (personal) from Roche, Novartis, Amgen, MSD, PharmaMar, AstraZeneca, GSK, and Seagen; participation on an advisory board from Roche, Novartis, Amgen, MSD, PharmaMar, AstraZeneca, GSK, and Seagen; and travel expenses from Roche and AstraZeneca. SN reports honoraria (self) from AstraZeneca, Chugai, Mochida, MSD, Takeda, and Terumo; and research grant (self) from AstraZeneca. IV reports consulting fees from Agenus, Akesobio, AstraZeneca, BMS, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Sanofi, Seagen, Sotio, Verastem Oncology, and Zentalis; contracted research funding (via KULeuven) from Oncoinvent AS; corporate sponsored research funding from Amgen and Roche; and accommodation and travel expenses from Karyopharm. NC reports research grants from AstraZeneca, PharmaMar, and Roche; honoraria for lectures from AstraZeneca, Tesaro, Novartis, Clovis Oncology, MSD, GSK, and Eisai; honoraria for advisory boards from Roche, PharmaMar, AstraZeneca, Clovis Oncology, MSD, GSK, Tesaro, Pfizer, BIOCAD, ImmunoGen, Mersana Therapeutics, Eisai, and OncXerna Therapeutics; and is a steering committee member on ESMO clinical guidelines and a scientific committee chair for Acto Onlus. JM reports honoraria from AstraZeneca and GSK. FS reports honoraria from AstraZeneca, GSK Tesaro, MSD, Sandoz (Novartis), and Clovis Oncology; and institutional financial support from Roche, GSK Tesaro, AstraZeneca, Immunogen, MSD, Incyte, and Agenus. JS reports grants or contracts from Roche Pharma, AstraZeneca, Bayer, Clovis, GSK, Lilly, Tesaro, consulting fees from Tesaro, Merck, Pfizer, PharmaMar, Clovis Oncology, AstraZeneca, Roche Pharma, GSK, MSD, Eisai, Novocure, Oncoinvent, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Tesaro, GSK, PharmaMar, AstraZeneca, Clovis, Bayer, Roche, PharmaMar, Vifor Pharma, Hexal AG, Novartis Pharma. DL reports consultancy fees (personal) from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar, Novartis, and Seagen; membership on an advisory board (personal) from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; research funding (institutional) from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, and Seagen; and travel support from Roche, PharmaMar, AstraZeneca, Clovis Oncology, and GSK. EMGA reports consulting fees from AstraZeneca–MSD, Clovis Oncology, GSK–Tesaro, PharmaMar, and Roche; speaker bureau/expert testimony honorarium from AstraZeneca–MSD, PharmaMar, Roche, GSK–Tesaro, and Clovis Oncology; and travel support from Roche, GSK–Tesaro, and Baxter. GB reports consulting or advisory board roles for AstraZeneca, Roche, and GSK; and has received funding for medical conferences from AstraZeneca, Roche, and GSK. CLP reports advisory/consultancy honoraria from Pfizer, AstraZeneca, Roche, and Daiichi–Sanko; and other travel/accommodation/medical congress expenses from Roche, Novartis, Pfizer, Pierre Fabre, and MSD. PB reports honoraria from Roche, AstraZeneca, and GSK; and congress and travel support from GSK and PharmaMar. AL reports advisory board fees from AstraZeneca, MSD, and Tesaro; speaker honoraria from Clovis Oncology and Roche; and participation in a medical congress for Novartis, Pfizer, MSD, Lilly, and Roche. AB reports honoraria for lectures and advisory boards from AstraZeneca, Roche, and Tesaro. JM reports advisory board fees (personal) from Daiichi Sankyo, Gilead, and Eli Lilly; and non-financial traveling facilities from Pfizer. AEB reports advisory board fees from AstraZeneca, MSD, and GSK; speaker honoraria from AstraZeneca and Olympus; and participation in a medical congress for PharmaMar and AstraZeneca. MR reports advisory board fees (personal) from AstraZeneca, GSK, and Immunocore; advisory board fees and research grant (personal/institution) from MSD; and research grant (institution) from BMS. TWPS reports honoraria (advisory role, expert testimony and lectures, participation in clinical trials, other financial relationships, e.g. travel) from AstraZeneca, Daiichi-Sankyo, Exact Sciences, Gilead, GSK, Lilly, MSD, NCO, Novartis, Pfizer, Roche, and Seagen. CD reports participation on a data safety monitoring board or advisory board for MSD, Eisai, and AstraZeneca. DD reports consulting or advisory roles (personal) for AstraZeneca, GSK/Tesaro, Roche, Eisai Germany, and MSD Oncology; travel expenses from AstraZeneca; and honoraria from Roche, AstraZeneca, GSK/Tesaro, MSD, Intuitive Surgical, and KLS Martin. BY reports consulting fees (personal) from MSD, AstraZeneca, GSK–Tesaro, Bayer, Roche–Genentech, ECS Progastrin, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, SEAGEN, and Myriad. EPL reports lecture fees, speaker’s bureau fees, and travel support from AstraZeneca, Tesaro, and Roche; lecture fees from Clovis Oncology, Incyte, and Pfizer; and is employed by ARCAGY Research. PH reports honoraria from AstraZeneca, Roche, Clovis Oncology, Stryker, MSD Oncology, Zai Lab, Lilly, Sotio, Eisai, and GSK; consulting/advisory roles from AstraZeneca, Roche, Tesaro, Merck, GSK, Clovis Oncology, and Immunogen; and research funding (institution) from AstraZeneca, Roche, Genmab, GSK, Immunogen, and Clovis Oncology. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) agents have only moderate antitumor activity in some advanced solid tumors (AST), including breast cancer (BC), prostate cancer (PC), cervical cancer (CC), and head and neck cancer (HNC). Combining anti-PD-L1 with anti-cytotoxic T-lymphocyte-associated protein (CTLA) and chemotherapy may significantly improve efficacy., Patients and Methods: MOVIE is a multicohort phase I/II study examining the combination of anti-PD-L1 durvalumab (Durv; 1500 mg IV Q4W) plus anti-CTLA tremelimumab (Trem; 75 mg IV Q4W) with metronomic vinorelbine (MVino; 20-40 mg orally daily) in various AST resistant to conventional therapies. The primary objective of the phase I part was to determine the maximum tolerated dose (MTD) and recommended dose for phase II (RP2D)., Results: Among the 14 patients enrolled during phase I, including 13 women and 1 man, 9 had BC, 1 PC, 2 CC, and 2 miscellaneous cancers with high mutational loads. Median age was 53 years. A total of 12 patients were assessable for the dose-escalation part in which only one dose-limiting toxicity (DLT) was observed [one neutropenia without fever, grade (G) 4]. Two (14.3%), four (28.6%), and four (28.6%) patients had G ≥3 adverse events (AEs) related to MVino, Durv, and Trem, respectively. Treatment-related events included mostly clinical AEs with asthenia (eight G2; three G3), colitis (one G2, one G3), diarrhea (one G3), nausea (two G2), dry skin (two G2), maculopapular rash (one G3), and hyperthyroidism (three G2). No toxic death was reported. Preliminary data showed one patient (CC) who presented a complete response and four patients with stable disease (SD)., Conclusions: MTD was not reached and dose level 2 (MVino 40 mg, Durv 1500 mg, Trem 75 mg) was selected as RP2D. The safety profile of the combination was manageable and consistent with previous reports of Trem + Durv or MVino. Phase II is currently ongoing in BC, PC, CC, HNC, and miscellaneous cohorts., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The impact of the first coronavirus disease 2019 (COVID-19) wave on cancer patient management was measured within the nationwide network of the Unicancer comprehensive cancer centers in France., Patients and Methods: The number of patients diagnosed and treated within 17 of the 18 Unicancer centers was collected in 2020 and compared with that during the same periods between 2016 and 2019. Unicancer centers treat close to 20% of cancer patients in France yearly. The reduction in the number of patients attending the Unicancer centers was analyzed per regions and cancer types. The impact of delayed care on cancer-related deaths was calculated based on different hypotheses., Results: A 6.8% decrease in patients managed within Unicancer in the first 7 months of 2020 versus 2019 was observed. This reduction reached 21% during April and May, and was not compensated in June and July, nor later until November 2020. This reduction was observed only for newly diagnosed patients, while the clinical activity for previously diagnosed patients increased by 4% similar to previous years. The reduction was more pronounced in women, in breast and prostate cancers, and for patients without metastasis. Using an estimated hazard ratio of 1.06 per month of delay in diagnosis and treatment of new patients, we calculated that the delays observed in the 5-month period from March to July 2020 may result in an excess mortality due to cancer of 1000-6000 patients in coming years., Conclusions: In this study, the delays in cancer patient management were observed only for newly diagnosed patients, more frequently in women, for breast cancer, prostate cancer, and nonmetastatic cancers. These delays may result is an excess risk of cancer-related deaths in the coming years., Competing Interests: Disclosure JYB reports research support and honoraria from Troche, BMS, MSD, PharmaMar, Bayer, Deciphera, GSK, Novartis, and AstraZeneca. JPD reports institutional fees for advisory or speaker roles for Genentech, Roche, BMS, MSD, and Novartis, and institutional grants for research projects with Genentech, Roche, BMS, MSD, Debiopharm, and Astra Zeneca. JCS reports shares from AstraZeneca, Daiichi Sankyo, Gritstone, and is also a full-time employee of AstraZeneca from September 2017 to December 2019. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort., Patients and Methods: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS)., Results: Of the 118 patients enrolled, 101 presented with a BRAF V600 mutation and 17 with BRAF nonV600 mutations; the median follow-up was 23.9 months. In the BRAF nonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAF V600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications., Conclusion: Routine biomarker screening of NSCLC should include BRAF V600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAF V600 -mutated NSCLC but not those with BRAF nonV600 mutations., Trial Registration: ClinicalTrials.gov identifier: NCT02304809., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Twenty-five to 65% of patients suffer from chronic pain after breast cancer. The treatment combines analgesic drugs and psychophysical techniques., Hypothesis: Osteopathy improves the control of pain and the quality of life of patients., Methods: This randomized prospective single center study allocated patients to the initiation of a standard analgesic treatment exclusively (arm A) or associated to osteopathy (arm B) between from 1 to 12months after surgery., Main Objective: Intensity of pain (VAS at three months [j90])., Secondary Objectives: Pain (VAS) at 6 and 12 months, analgesic consumption, anxiety/depression (HADS), and Quality of life (QLQ-C30). Eighty patients were planned to observe a 2-point difference in VAS (5% bilateral alpha, 90% power)., Results: Twenty-eight patients (A: 14; B: 14, median age 50 years) were included from April 2011 to February 2014; the study was stopped due to a too slow recruitment. No difference in the VAS pain score between arms was observed at j90 (P=0.258), nor at 6 and 12 months. At j90, the HADS depression score was reduced in arm B (P=0.049). Improvement in the overall score of quality of life (P=0.015), and reduced pain sub-score (P=0.021) were observed at j90 in arm B., Discussion: Patients are strongly seeking complementary therapies. Few studies exist. Our study has encountered major recruitment difficulties therefore limiting the interpretation of the results. Despite the absence of difference in the main objective, some other scores (QOL, depression) are noteworthy in favor of osteopathy. Further multicentric studies are needed., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: The management of cancer in aging people remains a challenge for physicians. Specialists agree on the assistance provided by a multidimensional geriatric assessment (MGA) to guide the cancer treatment decision-making process. We aim to explore the use of MGA in treatment decision and to identify MGA parameters likely to influence the planned cancer treatment., Material and Methods: We conducted a single-site retrospective study in patients older than 65 years suffering from various types of cancer who underwent MGA before cancer treatment decision. Logistic regression analyses were used for identification of predictive variables., Results: In the 266 patients' population, the mean age was 75.8 ± 7.4 years and 155 (58%) patients were men. Patients had solid tumors (95.4%) or hematologic malignancies (4.6%). Most of patients were in advanced setting (57%). The MGA revealed malnutrition (47%), cognitive/mood impairment (48%), functional decline (53%), and led to adjust medical care through reinforcing health status and fostering successful completion of cancer treatment plan for 259 (97%) patients. The MGA changed cancer treatment in 47 (18%) patients. Functional and/or cognitive impairment, risk of falls, and polypharmacy were associated with treatment change in univariate analysis. No multivariate model was possible., Conclusions: MGA leads to modification of treatment in only few patients. However, MGA enables a better understanding of patients' strengths and weaknesses essential to improve care management. Further improvements with integration of innovative specific tools are warranted to help decision-process in the increasing complexity of treatment plans available in older adults., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Maintenance strategies beyond response or tumor stabilization with first-line chemotherapy in metastatic breast cancer (MBC) have not been extensively studied. Endocrine therapy combined with continued bevacizumab may be a helpful option for estrogen receptor (ER)-positive MBC., Patients and Methods: In this prospective, open-label, phase III study, patients with histologically confirmed ER-positive, HER2-negative MBC and non-progressive disease after 16-24 weeks of taxane plus bevacizumab (T + BEV) were randomized to continuation of T + BEV or maintenance bevacizumab plus exemestane (E + BEV). The primary end point was progression-free survival (PFS) from randomization. To have 80% power to detect an improvement in the 6-month PFS rate (PFS6m) from 50% to 65%, 186 assessable patients were needed for a total of 141 PFS events. An interim analysis was planned after 40% of the required events., Results: The interim analysis with 98 patients showed that the probability of reaching a statistically significant improvement in PFS by the end of the study was only 7%. This led the Independent Data and Monitoring Committee to recommend termination of patient enrollment. After a median of 21-month follow-up of all randomized patients (117 in total), PFS6m from randomization was 67.2% [95% confidence interval (CI) 53.6-77.7] with T + BEV and 55.2% (95% CI 41.5-66.9) with E + BEV [hazard ratio (HR): 1.0, 95% CI 0.7-1.5, P = 0.998]. Median PFS from BEV initiation was 12.5 and 12.3 months in the T + BEV and E + BEV arms, respectively. In the T + BEV arm, taxane was prematurely stopped for the majority of patients (94.9%), mainly due to toxicity (49.2%). Updated data after 35 months' median follow-up showed death rates of 44% and 55% in T + BEV and E + BEV arms, respectively., Conclusion: In this trial, maintenance therapy with E + BEV in ER-positive, HER2-negative MBC patients with no evidence of progression after first-line T + BEV did not achieve longer PFS compared with continuation of T + BEV., Clinicaltrialsgov: NCT01303679., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Lymphopenia is a predictive factor for hematological toxicity, progression and early death in advanced cancers including metastatic breast cancer (MBC). CYT107 is a recombinant interleukin 7 (IL-7) (Cytheris, now Revimmune), well tolerated and able to expand lymphocyte pool in humans. The aims of this study were to determine the optimal schedule to deliver CYT107 and to assess its effect on clinical end points., Patient and Methods: This placebo-controlled, double blind, phase IIa was conducted in MBC patients with <1500/µl lymphocytes treated with capecitabine. Using a 2-by-2 factorial design, 20 patients were randomly allocated to four arms to receive (i) before chemotherapy: CYT107 or placebo; then (ii) during chemotherapy: CYT107 or placebo. The primary end point was CD4+ count changes before and during chemotherapy. Secondary end points were hematological toxicity, safety, overall response, progression-free survival (PFS) and overall survival (OS). Quantification and functional competence of circulating immune cells were also assessed., Results: When administered before chemotherapy, CYT107 induced a significant increase of CD4+ [+148.1% in CYT107 versus +9.9% in placebo groups, (Wilcoxon, P = 0.002)] and CD8+ T-cell counts, including both naïve and memory subsets. When CYT107 was administered during chemotherapy, the magnitude of CD4+ and CD8+ increase was less important. No modulation of immune cell functional competence was observed. CYT107 was well tolerated with no related ≥grade 3 adverse events except 1 fatal suspected unexpected serious adverse reaction (SUSAR) of uncertain relationship. Of the 12 cases evaluable for response, 6 of 7 patients (86%) receiving CYT107 before chemotherapy achieved a response or stabilization, whereas two of five patients (40%) receiving placebo achieved the same result. No significant difference was observed for PFS or OS., Conclusion: In lymphopenic MBC, CYT107 increases CD4+ and other T-cell subset counts without altering their function. A larger clinical trial to demonstrate its impact on clinical outcome is warranted., Clinicaltrialsgov Identifier: NCT01362107., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial., Patients and Methods: Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells)., Results: A total of 55 primary tumor samples from the TAMRAD trial—25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group—were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6-34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient., Conclusions: A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Decrease of circulating tumor cells (CTC) during treatment is an independent prognostic factor in metastatic breast cancer (MBC). We specifically evaluated the impact of CTC on brain metastasis outcome., Methods: HER2-positive MBC with brain metastasis not previously treated with whole-brain radiotherapy received first-line combination of lapatinib and capecitabine in a phase II study. CTC were detected at baseline and day 21 (CellSearch)., Results: Median follow-up of the 44 analyzed patients was 21.2 months. The central nervous system objective response (CNS-OR) rate was 66%. At baseline, 20 of 41 assessable patients for CTC (49%) had ≥1 CTC (range 1-301, median 3) and 9 (22%) had ≥5 CTC. At day 21, 7 of 38 patients (18%) had ≥1 CTC (P = 0.006, versus baseline), and CTC had disappeared in 11 patients. CNS-OR rate was significantly higher in patients with no CTC at day 21 [25 of 31 (80%) versus 2 of 7 (29%), P = 0.01]. The 1-year overall survival rate was 83.9% in patients with no CTC at day 21 versus 42.9% in patients with ≥1 CTC (P = 0.02)., Conclusions: This is the first report showing a correlation between CNS metastasis response, outcome and early CTC clearance under targeted treatment of HER2+ MBC., Clinical Trials Number: NCT00967031.