Breaking primary checkpoint inhibitor resistance with intermittent alkylating chemotherapy in patients with metastatic melanoma: results of a multicentre phase II trial

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BACKGROUND: Patients with BRAF wildtype metastatic melanoma who exhibit primary resistance to immune checkpoint inhibitors (ICIs) have a poor prognosis. Chemotherapy has been shown to induce genetic mutations, modify the tumour microenvironment and microbiome, and influence immune system activity. OBJECTIVES: To investigate in a prospective multicentre phase II trial whether two applications of an alkylating agent (dacarbazine) can sensitize patients with metastatic melanoma who are nonresponsive to ICIs to the same checkpoint inhibitor regime. METHODS: The PROMIT trial (NCT04225390) enrolled patients with histologically confirmed BRAF wildtype metastatic melanoma who exhibited primary resistance to ICI therapy. Following radiological evidence of primary resistance to ICI (ipilimumab + nivolumab or pembrolizumab) upon the first staging after initiation, patients received two doses of dacarbazine at 850 mg m-2 intravenously on days 1 and 21. Subsequently, 1 week after application of the second dose of dacarbazine, patients were rechallenged with the same ICI therapy to which they had previously shown progressive disease. RESULTS: In total, 53 patients were enrolled across four German skin cancer centres. Of these patients, 38 were evaluable for efficacy, having received at least one dose of ICI re-exposure. The overall objective response rate was 18% (95% confidence interval 0.08-0.34), with 7 of 38 patients achieving a partial response. The disease control rate was 37%. Therapy was well tolerated, with treatment-related ≥ grade 3 CTCAE adverse events occurring in 10% of patients. No new safety signals were observed. CONCLUSIONS: The study indicates that short-term chemotherapy followed by ICI rechallenge can overcome primary ICI resistance in patients with melanoma, supporting its potential as a new therapeutic option in clinical practice.

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