Abstract 538P
Background
BRAF mutations are observed in several cancer histotypes at low frequency (<5%). Vemurafenib is active in BRAF-V600-mutated melanoma. Non-melanoma BRAF-V600-mutated cancers were also reported to respond to BRAF inhibitors. The ACSE program launched by the French National Cancer Institute (INCa) aimed to provide controlled access to targeted therapies outside their label. Here we report the final analysis of efficacy endpoint of the ACSE Vemurafenib study (cf ESMO2016, #55PD).
Methods
BRAF mutational status (exons 11 and 15) was assessed by direct sequencing or NGS within the INCa molecular genetic platforms network. Patients with various BRAF (V600 or non V600) mutated cancers (e.g., lung, ovarian, bladder, thyroid, prostate cancers, cholangiocarcinoma, sarcoma/GIST, multiple myeloma, chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL)) and progressing after ≥1 standard treatment, were included in dedicated cohorts to receive vemurafenib 960 mg BID. A Bayesian approach allowed sequential analyses in each cohort and early stopping using an inefficacy boundary for objective response rate (ORR) of 10%. ORR was assessed every 8 weeks using RECIST v1.1 criteria for solid tumors and specific criteria for myeloma, CLL and HCL.
Results
From Oct. 2014 to May. 2019, 216 out of 2500+ screened patients were included at 116 centers. Median age was 66 years [18-85], 51% were males. Table: 538P
| Included N=216 | Median duration of treatment (months) | Analyzed for response(a) N=212 | Best overall response | Bayesian estimation of mean ORR | ||||||
| CR | PR | SD | PD | NE | ||||||
| V600 mutated | NSCLC | 101 | 3.4 | 100 | 43 | 22 | 15 | 20 | 45% | |
| cholangiocarcinoma | 9 | 5.5 | 9 | 1 | 6 | 2 | 1/9 | |||
| Thyroid | 6 | 1.8 | 6 | 4 | 2 | 0/6 | ||||
| Ovary | 6 | 5.2 | 6 | 3 | 2 | 1 | 3/6 | |||
| Sarcoma | 3 | 23 | 3 | 1 | 1 | 1 | 2/3 | |||
| Bladder | 2 | 0.9 | 2 | 1 | 1 | 0/2 | ||||
| Multiple myeloma | 2 | 5.5 | 2 | 1 | 1 | 1/2 | ||||
| HCL | 27 | 2.2 | 27 | 13 | 12 | 2 | 90% | |||
| Miscellaneous: V600 mutated Non-V600 mutated | 33 27 | 5.7 1.6 | 32 25 | 3(b) 0 | 11(c) 1 | 5 4 | 6 14 | 7 6 | 14/32 1/25 |
(a) Minimum follow-up of 16 weeks. (b) 2 histiocytosis and 1 glioma. (c) 2 histiocytosis, 3 ganglioglioma, 2 xantho astrocytoma, 2 glioblastoma, 1 appendix, 1 unknown primary.
Conclusions
Antitumor activity of vemurafenib was important in V600-mutated NSCLC, HCL, sarcoma, ovarian cancer, brain tumors, histiocytosis and gangliogliomas. Importantly, Non-V600 mutated tumors derived no benefit.
Clinical trial identification
NCT02304809.
Editorial acknowledgement
Legal entity responsible for the study
UNICANCER.
Funding
Foundation ARC; Institut National du Cancer; UNICANCER; Roche.
Disclosure
P. Tomasini: Research grant/Funding (institution), Non-remunerated activity/ies: Roche; Research grant/Funding (institution), Non-remunerated activity/ies: AZ; Research grant/Funding (institution), Non-remunerated activity/ies: BI; Research grant/Funding (institution), Non-remunerated activity/ies: BMS; Research grant/Funding (institution), Non-remunerated activity/ies: Takeda; Research grant/Funding (institution), Non-remunerated activity/ies: Novartis. J. Mazieres: Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): AstraZenca; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Hengruii; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Boehringer; Advisory/Consultancy: Takeda. D. Malka: Leadership role: Member of the steering committee of The Prodige intergroup; Honoraria (self): Amgen; Honoraria (self): Bayer; Honoraria (self): MSD; Honoraria (self): Merck Serono; Honoraria (self): Servier; Honoraria (self): Agios; Honoraria (self): Incyte; Honoraria (self): Novartis; Honoraria (self): SANOFI; Honoraria (self): Roche; Honoraria (self): Haliodx; Honoraria (self): Pierre Fabre Oncology. I.L. Ray-Coquard: Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Agenus; Honoraria (self), Advisory/Consultancy: Advaxis; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy: PharmaMar; Honoraria (self), Advisory/Consultancy: Genmab; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZenca; Honoraria (self), Honoraria (institution), Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Roche/Genentech; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: GSK; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy: Deciphera; Honoraria (self), Advisory/Consultancy: Mersena; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sereno; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Tesaro; Honoraria (self), Advisory/Consultancy: Clovis; Non-remunerated activity/ies: Gineco; Non-remunerated activity/ies: ENGOT; Non-remunerated activity/ies: GCIG; Non-remunerated activity/ies: European Community; Non-remunerated activity/ies: ESMO; Non-remunerated activity/ies: ASCO; Non-remunerated activity/ies: ESGO; Non-remunerated activity/ies: IGSC; Non-remunerated activity/ies: Inca ; Non-remunerated activity/ies: Swiss, Italian, Belgium and German health authorities.. J-Y. Blay: Honoraria (self), Honoraria (institution), Research grant/Funding (self), Research grant/Funding (institution): Roche; Honoraria (self), Honoraria (institution), Research grant/Funding (self), Research grant/Funding (institution): Novartis ; Honoraria (self), Honoraria (institution), Research grant/Funding (self), Research grant/Funding (institution): GSK. All other authors have declared no conflicts of interest.