623P - Phase II trial of vemurafenib (VEM) and cobimetinib (COB) in BRAF V600-mutated solid tumours and first-line (1L) non-small cell lung cancer (NSCLC): Australian molecular screening and therapeutics (MoST) substudy 12

Background

Class I BRAF mutations contribute to the oncogenesis of 4% of solid tumours and 3% of non-squamous NSCLC. While combined BRAF/MEK inhibition with VEM+COB has been established in melanoma management, its activity in other tumour types and 1L NSCLC treatment remains underexplored.

Methods

This multicentre phase 2 trial (ACTRN12620000861954), part of the MoST program and its NSCLC subprogram (ASPiRATION), assessed the activity of the VEM+COB in 2 patient (pt) groups with advanced BRAF V600 mutant cancers (refractory solid tumours and 1L NSCLC) identified through comprehensive genomic profiling. Pts received VEM 960 mg twice daily and COB 60 mg daily (days 1 to 21 every 28 days) until disease progression, withdrawal, or unacceptable toxicity. The primary objective was objective response rate (ORR) assessed by RECIST v1.1 or RANO criteria (primary brain tumours). Secondary objectives included overall and progression-free survival (OS and PFS), PFS rate at 6 months (mo), safety and tolerability. The activity threshold was defined as > 6 responses in 32 pts preplanned for each group; the Kaplan-Meier method was used for time-to-event analyses.

Results

This study enrolled 64 pts (36 solid, 28 1L NSCLC) with median follow-up of 13.1 and 14.7 mo, respectively (solid and 1L NSCLC groups). Both groups met the predefined threshold, achieving ORR of 50% (18 of 36, solid) and 42% (10 of 24 RECIST evaluable, 1L NSCLC). Confirmed responses were seen in 16 pts with NSCLC (across both groups, including 1 complete, CR), 2 each with biliary tract, unknown primary, salivary gland (1 CR), and papillary thyroid cancers, 1 each with glioblastoma, anal, pancreatic acinar carcinoma, and a malignant peripheral nerve sheath tumour. In the solid group, the median PFS and OS were 7.9 mo (95% CI: 5.6–15.9) and 15.9 mo (9.1–21.9). The 6-mo PFS rates were 68% (48–82%) and 67% (45–81%) for the solid and 1L NSCLC groups respectively. Ten pts (16%) discontinued treatment and 21 pts (33%) required dose adjustments due to adverse events.

Conclusions

VEM+COB is active in a range of advanced solid tumours and 1L NSCLC with a BRAF V600 mutation.

Clinical trial identification

ACTRN12620000861954.

Editorial acknowledgement

Legal entity responsible for the study

University of Sydney.

Funding

Australian Federal Government; Office for Health and Medical Research, New South Wales; Roche.

Disclosure

F.P. Lin: Non-Financial Interests, Institutional, Trial Chair: Roche, Amgen; Non-Financial Interests, Personal, Member, Editorial Board: ASCO. A. Mersiades, S. Thavaneswaran: Non-Financial Interests, Institutional, Trial Chair: Roche. R. Harrup: Non-Financial Interests, Other, Received monetary compensation for writing a case study: BeiGene. M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Professor of Clinical Cancer Research: University of Western Australia; Financial Interests, Personal, Full or part-time Employment, Medical Oncology Director: Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution: Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma, AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, IMPACT Therapeutics, Kinnate Biopharma, Rely Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Other, Scientific Advisory Committee member: Thoracic Oncology Group Australasia. J. Desai: Financial Interests, Personal, Invited Speaker: Pierre Fabre, Merck KGaA, Novartis; Financial Interests, Personal, Advisory Board: Bayer, Boehringer Ingelheim, Roche/Genentech, Pfizer, Amgen, Pierre Fabre, BeiGene, Axelia, Ellipses; Financial Interests, Coordinating PI: Roche/Genentech, BeiGene; Financial Interests, Local PI: Amgen, AstraZeneca, GSK, Novartis; Financial Interests, Steering Committee Member: Pfizer; Non-Financial Interests, Principal Investigator: BeiGene, Roche/Genentech, Amgen, Pfizer, Novartis, Boehringer, MapCure, Springworks, AstraZeneca, Vivace, Incyte; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Leadership Role: Australia New Zealand Sarcoma Association; Other, Not-for-profit. Director-uncompensated: Cancer Trials Australia. C.K. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Roche, Janssen, Gilead, MSD, GSK, Novartis, Merck kGA; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Amgen, Merck kGA, Novartis, Roche. B.J. Solomon: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Merck, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Amgen, Roche-Genentech, Eli Lilly, Takeda, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Employed as a consultant Medical Oncologist: Peter MacCallum Cancer Centre; Financial Interests, Personal, Member of Board of Directors: Cancer Council of Victoria, Thoracic Oncology Group of Australasia; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Steering Committee Member, Principal Investigator and Steering committee Chair: Roche/Genentech, Pfizer; Financial Interests, Institutional, Steering Committee Member: Novartis. All other authors have declared no conflicts of interest.