Repurposing azacitidine and carboplatin to prime for anti-PDL1 re-challenge of immunotherapy-resistant melanoma

Drug repurposing offers the opportunity for approved chemotherapy agents to be used to re-establish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (Avelumab) in patients with advanced ICB-resistant melanoma. 20 participants with ICB resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB re-challenge with anti-PD-L1 avelumab. The overall response rate (ORR) determined after 2 × 4-week cycles of azacitidine and carboplatin priming was 10% (2/20) with 2 partial responses (PR). The ORR determined after priming followed by 6 cycles of avelumab (week 22) was 10%, with 2/20 participants achieving iPR. The clinical benefit rate (CBR) for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by 6 cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks (95% CI: 14.87 – 21.13 weeks) and the median OS was 47.86 weeks (95% CI: 9.67 – 86.06 weeks). Translational correlation analysis of tumour biopsies at baseline, after priming and after 6 cycles of avelmuab confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus showed a consistent decrease in methylation after priming and T-cells, in particular CD8+, showed the greatest increase in infiltration. Priming with azacitidine and carboplatin can induce disease stabilization and re-sensitisation to ICB for metastatic melanoma. One Sentence Summary Sequential azacitidine and carboplatin stabilises disease burden and re-establishes sensitivity to checkpoint immune blockade immunotherapy.