PRIME002: Early phase II study of azacitidine and carboplatin priming for avelumab in patients with advanced melanoma who are resistant to immunotherapy

Abstract

Melanoma patients with checkpoint inhibitor immunotherapy resistance have limited treatment options. Azacitidine (aza) results in DNA-demethylation and increase in neoantigen expression. Carboplatin increases DNA-damage and cellular stress. This trial aims to test if sequential aza and carboplatin "primes" for checkpoint inhibitor therapy rechallenge. 2 cycles of aza 40 mg/m2 IVI/day × 5 days followed by carboplatin AUC 4.5 IVI D8/28 day cycle, followed by Avelumab 10 mg/kg IVI/2 weeks. RECIST 1.1 after 8 weeks and 22 weeks. Avelumab continued until iRECIST disease progression. Primary outcomes-complete response (CR), partial response (PR), stable disease (SD), objective response rate (ORR), disease control rate (DCR). A favourable response in 20% patients and minimal grade 4/persistent (>4 weeks) grade 3 treatment-related adverse events are required for continuation. 7 primary immunotherapy resistant metastatic melanoma patients were enrolled [median age, 64 (range, 63-76); 5M/2F; ECOG PS 0/1 (83%/17%)]. Pts received at least 6 cycles of prior pembrolizumab (median, 17.5; range, 6-44) or combination ipilimumab and nivolumab (4 cycles combo, 6-8 months nivolumab). All 7 pts received 2 cycles of aza/carbo and 6 doses of Avelumab. The ORR was 14.3% (1/7) and DCR was 100% (7/7) after aza/carbo. ORR was 28.6% (2/7) and DCR 71.4% (5/7) after 6 doses of Avelumab. Average follow-up 40 weeks (range = 62-26). 4 additional patients have enrolled. Pt 8 had SD in multiple intracranial metastases after 2 cycles of aza/carbo. Sequential azacitidine and carboplatin limits the burden of disease for immunotherapy resistant advanced melanoma which may allow for effective re-treatment with checkpoint inhibitor therapy. The results meet the criteria for continuation and expansion. The authors acknowledge the support provided by Merck KGaA.