153P - BRAF variants and therapy outcomes in melanoma

Background

BRAF mutated (BRAFmut) melanoma accounts for 40-50% of melanomas. Recent evidence suggests that immune checkpoint inhibition (ICI) should be the preferred first-line therapy (1L) over targeted therapy (TT) with BRAF/MEK inhibitors. However, little data exists regarding BRAF mutated melanoma patients (pts) who achieved CR/PR under both therapeutic options.

Methods

We included pts diagnosed with stage IV melanoma, known BRAF mutation status, between 2010 and 2018 and treated with 1L ICI or TT. We aimed to assess long term outcomes and identify predictive biomarkers, focusing on BRAFmut melanoma pts achieving CR/PR under 1L TT or ICI.

Results

We included 181 pts with BRAFmut melanoma; 74 (41%) treated with 1L ICI and 107 (59%) with 1L TT. Response rate (RR) to ICI was 50% (13.5% CR) and 65.7% (14.3% CR) for TT (TT response: OR=1.9, p=0.022). RR to ICI for V600E was 40% (10% CR) and 69.3% (17% CR) to TT (OR=3.3, p=0.0001), for V600K RR to ICI was 69% (23% CR) and 58.3% (0% CR) to TT; for V600R RR to ICI was 50%. There were no CR/PR to TT in pts with V600R and class II mutations. The 2y progression free survival (PFS) for V600E melanomas was 30% for ICI and 18% for TT and 50% under ICI and 0% under TT for V600K melanomas. For BRAFmut pts, duration of response (DoR) to TT was shorter than DoR to ICI (log rank test; CR under ICI vs TT, p=0.044; PR under ICI vs TT, p=0.004). Median overall survival (OS) for pts with CR under TT and ICI was not reached. Median OS for PR under TT was 25 months, and 43 months under ICI. At therapy start involvement of less than 3 organs was positively associated with TT response (logistic regression, p=0.037), LDH and brain metastasis were associated with worse prognosis for TT and ICI.

Conclusions

In BRAFV600E melanoma, 1L TT leads to higher RR but shorter PFS and DoR than ICI. Melanoma with other BRAF variants has higher RR and better PFS with ICI. Our study supports ICI as 1L therapy for BRAF mutated pts. However since median OS was not reached in pts with CR under ICI or TT, discriminatory personalized biomarkers are needed to identify V600E melanoma pts less likely to respond to ICI and with higher chance of achieving CR under TT, for which TT could be an option upfront.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

T. Sinnberg: Financial Interests, Institutional, Funding: Novartis, Pierre Fabre, Neracare, Skyline DX, Pascoe GmbH.U. Leiter-Stoppke: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Invited Speaker: MSD, Novartis, Sun Pharma, Allmiral Hermal, Sanofi; Financial Interests, Institutional, Advisory Board: Sun Pharma, MSD, Novartis, Allmiral Hermal, Sanofi; Non-Financial Interests, Personal, Member ADO. L. Flatz: Financial Interests, Institutional, Research Grant: Hookipa Pharma, SAKK/Immunophotonics, Mundipharma; Financial Interests, Personal, Research Grant: DFG, Philogen; Financial Interests, Institutional, Advisory Role: Philogen, Sanofi, Novartis, BMS; Financial Interests, Institutional, Member of Board of Directors: Data Safety Board University of Basel; Financial Interests, Personal, Stocks/Shares: Hookipa Pharma. T.M.S. Amaral: Financial Interests, Personal, Invited Speaker: CeCaVa, BMS, Novartis, Pierre Fabre; Financial Interests, Institutional, Funding: Novartis, Neracare, Sanofi, Skyline-Dx; Financial Interests, Institutional, Research Grant: Novartis, iFIT; Financial Interests, Institutional, Invited Speaker: IO Biotech, MSD, University Hospital, Essen, Roche, Unicancer; Non-Financial Interests, Personal, Member: Portuguese Society for Medical Oncology, ASCO; Other, Personal, Other, Clinical expert: Infarmed. All other authors have declared no conflicts of interest.