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. 2023 Dec;8(6):102038.
doi: 10.1016/j.esmoop.2023.102038. Epub 2023 Nov 1.

Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma

J Y Blay  1 , C Cropet  2 , S Mansard  3 , Y Loriot  4 , C De La Fouchardière  2 , J Haroche  5 , D Topart  6 , D Tougeron  7 , B You  8 , A Italiano  9 , V Le Brun-Ly  10 , J M Ferrero  11 , N Penel  12 , M Fabbro  13 , X Troussard  14 , D Malka  15 , I Ray-Coquard  16 , S Leboulleux  4 , A Fléchon  2 , E Maubec  17 , J Charles  18 , S Dalle  19 , S Taieb  20 , G C T E Garcia  4 , A M Mandache  2 , N Colignon  21 , M Gavrel  4 , F Nowak  22 , N Hoog Labouret  22 , C Mahier Aït Oukhatar  23 , C Gomez-Roca  24
Affiliations

Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma

J Y Blay et al. ESMO Open. 2023 Dec.

Abstract

Background: BRAF inhibitors are approved in BRAFV600-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 BRAFV600-mutated melanoma and NSCLC.

Patients and methods: Patients with advanced tumours other than BRAFV600E 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 BRAFV600 mutations and 10 with BRAFnonV600 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.

Trial registration: ClinicalTrials.gov 02304809.

Keywords: BRAF(V600) mutations; efficacy; objective response rate; overall survival; progression-free survival; safety; vemurafenib.

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Conflict of interest statement

JYB reports research support and honoraria from Roche, Novartis, MSD, BMS, PharmaMar, and GSK; travel grants from OSE; support from Unicancer, Institut National du Cancer, and Fondation ARC; is a supervisory board member for Transgene and Innate Pharma; and is on the advisory board for Deciphera. YL reports consulting for AstraZeneca, Clovis Oncology, Seattle Genetics, Janssen, Roche, Merck Sharp & Dohme, Nektar, Bristol-Myers Squibb, Tahio, Merck KGaA, and Pfizer; research funding from Janssen, Merck Sharp & Dohme, Sanofi, Roche, and Celsius; speaking activities for Janssen, Pfizer, Astellas Pharma, Merck Sharp & Dohme, and Bristol-Myers Squibb; travel support from AstraZeneca, Seattle Genetics, Janssen, Merck Sharp & Dohme, and Bristol-Myers Squibb; is a clinical study investigator for Gilead, AstraZeneca, Clovis Oncology, Seattle Genetics, Pfizer, Merck KGaA, Janssen, Incyte, Roche, Astellas Pharma, Merck Sharp & Dohme, Nektar, Basilea, and Bristol-Myers Squibb. JH is the co-principal investigator of an academic French trial on the efficacy of cobimetinib on histiocytoses (NCT04007848). DTop reports research support and honoraria from MSD, BMS, Janssen, and Ipsen. DTou reports research support and honoraria from MSD, BMS, AstraZeneca, Servier, Sanofi, AMGEN, Bayer, Novartis, Roche, and Pierre Fabre. AI reports research grant from AstraZeneca, Bayer, BMS, GSK, Merck, MSD, and PharmaMar; honoraria from AstraZeneca, Bayer, Daiichi Sankyo, MSD, Epizyme, Lilly, Novartis, Parthenon, and Pfizer. VLB-L reports travel grants from PharmaMar and MSD. NP reports research grant from Roche, Bayer, Novartis, and PharmaMar; honoraria from Astellas, Bayer, MSD, PharmaMar, Ipsen, and Janssen. MF reports honoraria from AstraZeneca and GSK. XT is a consultant for AbbVie, BeiGene, Deciphera, and AstraZeneca. IRC reports honoraria (self) from AbbVie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, 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 and AstraZeneca and GSK. EM reports research support and/or honoraria from MSD, Novartis, Pierre Fabre, and Sanofi. CGR reports receiving research support (institutional) from Roche/Genentech and BMS; honoraria from BMS, Roche, Pierre Fabre, Macomics, and Eisai.CC, SM, CDLF, BY, JMF, DM, SL, AF, JC, SD, ST, GCTEG, AMM, NC, MG, FN, NHL, and CMAO have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Best reduction in tumour measurement from baseline in solid tumours. The line at −30% represents the threshold for a partial response, according to RECIST version 1.1. The line at +20% demarcates disease progression. Bars show maximum reduction from baseline sum of diameters by the best confirmed response. Evaluable measurements for RECIST criteria were available for 45 patients.
Figure 2
Figure 2
Vemurafenib treatment duration and activity. For hairy cell leukaemia (HCL), vemurafenib is prescribed for two cycles (first assessment) and possibly for two additional cycles if a complete response is not achieved at cycle 2. In total, treatment is stopped at day 112 (maximum) whatever the response. OR, objective response; PD, progressive disease.
Figure 3
Figure 3
Overall survival and progression-free survival (PFS). (A and B) in the global cohort and (C and D) in hairy cell leukaemia, glioblastoma, cholangiocarcinoma, and Erdheim–Chester disease, and histiocytosis cohorts. CI, confidence interval; ECD, Erdheim–Chester disease; NE, not evaluable.
Figure 3
Figure 3
Overall survival and progression-free survival (PFS). (A and B) in the global cohort and (C and D) in hairy cell leukaemia, glioblastoma, cholangiocarcinoma, and Erdheim–Chester disease, and histiocytosis cohorts. CI, confidence interval; ECD, Erdheim–Chester disease; NE, not evaluable.
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