Abstract 1043P
Background
Three genomic subtypes of BRAF wildtype (WT) cutaneous melanoma (CM) include NRAS mutant (mut), NF1 mut, triple wildtype (tWT). NF1 mut melanoma have a high tumor mutation burden and have been associated with increased responsiveness to immune checkpoint inhibitors (ICI) in some retrospective studies. We evaluated whether the NF1 subtype was associated with improved ICI outcomes in our population.
Methods
This is a single center retrospective cohort study including patients (pts) with BRAF V600 WT unresectable/ metastatic melanoma, who received anti-PD1 +/- anti-CTLA4 between 2012-2021. Next Generation Sequencing (NGS) was performed in tumor samples for NF1 and NRAS mut. Mucosal, uveal or acral-lentiginous melanomas were excluded. ICI treatment response was determined by investigator assessment of clinical and radiologic parameters. X2, Fisher’s exact and U-Mann Whitney tests were used to compare groups. Log-rank tests and Kaplan Meier curves were used to assess clinical progression free survival (cPFS) and overall survival (OS).
Results
Our cohort included 68 pts, 43 (64.2%) were male and median age was 68 (30 to 93). Combination ICI was given to 31 (45.6%) and anti-PD1 monotherapy to 37 (54.4%) pts. Median follow-up was 10.6 months. NGS revealed 17 (25%) NF1-only pathogenic variants, 28 (41.2%) NRAS mut and 3 (4.4%) NF1/NRAS co-mutation (4.4%). There were no significant differences in gender, age, LDH, M stage or ICI regimen between NF1-only mut versus NRAS mut and tWT pts. Treatment responses were seen in 82.4% (14/17) NF1 mut pts and in 49% (25/51) NRAS/tWT pts treated with ICI (p=0.016). NF1 mut pts had longer median cPFS (not reached, >21 months) compared to NRAS/tWT pts (15.2 months) (p=0.040). Median OS was not reached in either group, but there was a trend toward longer median OS in NF1 mut pts versus NRAS/tWT pts (HR: 0.373 95%CI 0.11-1.26 p=0.113).
Conclusions
Our data provide external validation to independent observations that NF1 mut are associated with improved ICI outcomes in pts with BRAF V600 WT metastatic cutaneous melanoma. Prospective validation of NF1 mut as complementary biomarker of responsiveness is warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
University of Toronto - Hold'em for Life Charity Challenge.
Disclosure
A. Rose: Financial Interests, Personal, Advisory Board: Pfizer. M.O. Butler: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: IOVANCE; Financial Interests, Personal, Advisory Board: Instil Bio; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Adaptimmune; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Immunocore; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Sun Pharma; Financial Interests, Personal, Advisory Board: Immunovaccine; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Takara Bio. S. Saibil: Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Sanofi Genzyme. D. Hogg: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Merck Serono. A. Spreafico: Financial Interests, Personal, Advisory Board, Compensated: Merck; Financial Interests, Personal, Advisory Board, Compensated: Bristol-Myers Squibb ; Financial Interests, Personal, Advisory Board, Compensated: Oncorus; Financial Interests, Personal, Advisory Board, Compensated: Janssen; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Novartis; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Symphogen AstraZeneca/Medimmune; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Merck; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Bayer; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Surface Oncology; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Northern Biologics; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Janssen Oncology/Johnson & Johnson; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Roche; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Regeneron; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Alkermes; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Array Biopharma/Pfizer; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: GSK; Financial Interests, Institutional, Research Grant, Funding paid to Dr Spreafico Institution to support clinical trials: Treadwell. All other authors have declared no conflicts of interest.