The nature and management of acquired resistance to PD1-based therapy in melanoma.

Abstract

10014 Background: Anti-PD1 therapy (PD1), either alone or in combination with anti-CTLA4, has high initial response rates, but 20% of patients (pts) with complete response (CR) and 60% with partial response (PR) experience disease progression by 5 years. The nature and best management of this acquired resistance (AR) remains unknown. Methods: Consecutive pts from 16 centers who achieved CR or PR to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics, nature of progression and subsequent treatments were examined. Results: 300 pts were identified, median age was 64y, 133 (44%) BRAF mutant and 55 (18%) had target therapy (TT) prior to PD1-based therapy. 173 (58%) received PD1 alone, 114 (38%) PD1+CTLA4 and 13 (4%) PD1 + an investigational drug. 89 (30%) pts had CR, 210 (70%) pts had PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2) and 142 (47%) progressed while still on drug. Most pts (N = 194, 65%) progressed in a single organ site, and in a solitary lesion (N = 154, 51%). 38 (25%) progressed in the brain only. AR was in new lesion in 136 (45%), existing lesions in 106 (35%), and both new and existing lesions in 58 (19%). For those with solitary lesion progression, 51 (33%) had local (L) treatment alone, 54 (35%) had local and systemic (L+ST), 46 (30%) had systemic therapy alone (ST) and 3 (2%) had no further treatment (BSC). If progression was non-solitary, 89 (61%) had ST, 33 (23%) L+ST, 17 (12%) L alone and 7 (5%) BSC. For those who received ST after AR, first ST (ST1) was PD1 alone in 130 (51%) [53, 41% continuation, 77, 59% reinduction], PD1+CTLA4 in 31 (12%), CTLA4 alone in 15 (6%), targeted therapy in 49 (19%) and investigational drugs in 29 (11%). Median follow-up from AR was 20 mo (95% CI 18-22). The ORR to ST1 was 46% for PD1 alone (56% continuation, 42% reinduction), 56% for PD1+ CTLA4, 0% for CTLA4 alone, 20% for investigational drugs and 67% for TT. Median OS from AR was 38 mo (95% CI, 34.6-NR). 2y-OS was 69% in those with solitary progression compared to 55% for the pts that had a non-solitary progression (p < 0.001). There was no difference in OS by ST1 class. Detailed analyses including nature and management of AR while on PD1 or after discontinuation will be presented, as will site-specific AR outcomes. Conclusions: Acquired resistance to PD1-based therapy in melanoma is usually oligometastatic, occurring approximately one year after PD1 start. Most pts with isolated progression have local therapy, and the most frequent subsequent systemic therapy is PD1-alone. Patients with AR can have meaningful survival, with median OS over 3 years from AR.