Mutations in homologous recombination DNA damage repair genes and treatment outcomes to immune checkpoint inhibitors in melanomas.

Abstract

e21502 Background: Homologous recombination DNA damage repair (HR-DDR) gene mutations are frequently found in melanomas, and studies have shown the presence of mutations in HR-DDR may predict response to immune checkpoint inhibitors (ICI) in unresectable metastatic melanomas. We conducted this study to evaluate the treatment outcomes to anti-PD-1 ICI in both unresectable metastatic melanomas and resected stage III melanomas. Methods: We prospectively sequenced 174 melanoma patients treated at Inova Schar Cancer Institute using next-generation sequencing techniques including 440 cancer-related genes on formalin-fixed, paraffin-embedded tumor samples. Tumor Mutation Burden (TMB) is classified as high if >=20 mutations per megabase occurred. The patient demographics, tumor characteristics, treatments and outcomes were abstracted from electronic health records. RECIST1.1. was used for treatment response. Progression free survival (PFS) and overall survival (OS), recurrence free survival (RFS) was calculated from the start of ICI using Kaplan- Meier method. Results: 44 of 174 (25.3%) patients had at least one HR-DDR gene mutations including ARID2 (13.2%), ARID1A (4.6%), ARID1B, ATM, BRCA2, BRIP (1.7% each), CHEK2, FANCA, RAD50 (0.6% each). Patients with HR-DDR mutations were more likely to have thinner Breslow depth, melanoma on head and neck, and high TMB (Table). Sixty-five patients received anti-PD1 ICI (alone or in combination) for unresectable and/or metastatic melanoma. Patients with HR-DDR mutations were more likely to achieve complete response compared to those without (38.1% v 15.9%; p=0.047), however, there was no statistically significant difference in PFS or OS between HR-DDR present and absent. Eighty-nine patients received adjuvant anti-PD1 ICI with no significant difference in RFS and OS based on HR-DDR mutation status. Conclusions: Patients with HR-DDR mutations had similar RFS and PFS to patients without HR-DDR mutations for whom subsequent therapy options are needed. Clinical trial of PARP inhibitor combined with anti-PD1 for patients with HR-DDR mutations whose melanoma progressed on prior immunotherapy is currently undergoing (NCT04633902). Characteristics HR-DDR MutationPresent (n=44) HR-DDR MutationAbsent(n=130) Total(n=174) p-value Age in years, median (range) 66 (29-90) 62 (22-89) 63 (22-90) Male (%) 27 (61) 69 (53) 96 (55) 0.339 Primary site (%) Head and neck 18 (41) 27 (21) 45 (26) 0.008 Trunk 6 (14) 33 (25) 39 (22) 0.106 Extremities 17 (39) 52 (40) 69 (40) 0.873 Melanoma thickness in mm, mean (SD) 2.3 (1.8) 4.5 (4.1) 3.9 (3.8) 0.002 Ulceration present (%) 14 (32) 24 (19) 42 (24) 0.064 TMB High (%) 23 (52) 16 (12) 39 (22) 0.000