Abstract
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.
Competing Interest Statement
The healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.
Clinical Trial
ACTRN12618000053224
Funding Statement
This study was financially supported by Merck Healthcare Pty. Ltd., Macquarie Park, Australia, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer (AvdW and NAB); Calvary Mater Medical Oncology Research Fund (AvdW and NAB); Maitland Cancer Appeal Committee (MCG and NAB); Hunter Medical Research Institute and University of Newcastle (NAB).
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This study was approved by the Northern Sydney Local Health District Human Research Ethics Committee, reference number HREC/17/HAWKE/55 Australian clinical trial registry number: ACTRN12618000053224; registered 16th January 2018
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Data Availability
All data produced in the present study are available upon reasonable request to the authors