847P Precision oncology for resistant acral, mucosal and cutaneous melanomas: A prospective broad high throughput genomics feasibility study

Abstract

There are limited therapies for metastatic cutaneous, mucosal and acral melanomas (m) progressing after checkpoint (CPI) and BRAF/MEK (TKI) inhibitors. The Treat20 Plus study aimed to identify oncogenic drivers through high throughput genomics that could inform treatment recommendations ((Trec). From 1.2016 - 1.2019, 54 resistant m were prospectively subjected to a comprehensive molecular analysis (WGS, WES, RNA seq), that allowed a molecular tumor board to make individualized treatment recommendations. Primary sites: cutaneous (34), mucosal (16), acral (4), PS 1(0-3), abnormal LDH (37), # of therapies 5(2-22) (surgery 2(0-18), irradiation 1 (0-5), CPI 2(1-5), TKI 0 (0-2), chemo 0(0-2). No Trec in 10 p (low purity 7, early PD 3). Trec in 44 p (81%) with 4 (0-5) / p, for a total of 108 Trec including inhibitors of MEK 27%, CDK4/6 23%, TKI 7%, MET 6%, MTOR 6%, EGFR, FGFR, RAS 5 %, ALK 4%, NOTCH and PARP 2%, IGFR, NTRK, IDO and ER 1%. Treatment realization made in 21/44 p (48 %). Non-realization was early PD (14), still on CPI (6), on chemo (1), no druggable mutation (2). Among the 21 treated p 1 CR, 4 PR (RR: 24 %; 9 % of whole cohort (wc)), 3 SD (Clinical benefit: 38 %; 15% of wc) and 13 PD. Duration of the clinical benefit ranged from 147-678+ d. Resistance to prior TKI were observed in 8/9 BRAF V600E p by BRAF fusion (1), splicing (1), NRAS mutation (4), PTEN (2), RB1 (1), CDKN2A loss (2). CPI resistance mutations were shown in B2M (1), SOCS1 (1), MDM2 (1) and MDM2 focal amplification (2), and homozygous deletion in PTEN (4), but no relevant JAK1, JAK2, IRF1, IFNGR1/2, PIAS4, EGFR, MDM4, EZH2 alterations. Responding p had BRAF 599delinsTT (1), BRAF G469S (1), cKIT (2) mutations and NTRK fusion (1). Stabilization: IGFR (1) MET overexpression (1), CDKN2A loss (1). Among the seven p without BRAF V600E, NRAS and NF1 mutation (triple-negative profile) six had a clinical benefit. PFS for the treated p: 2.26 months (95%CI: 0.00-4.98) and the OS for the 54 p: 8.7 months (95 % CI: 1.56-15.97). For resistant acral, mucosal and cutaneous m, precision oncology was feasible with Trec in 81 % of p. It uncovered targetable alterations that led to a clinical benefit in 38 % of p mainly presenting with absence of BRAF V600E, NRAS and NF1 mutation.