Abstract Background Patients with BRAF wild type (wt) metastatic melanoma who exhibit primary resistance to immune checkpoint inhibitors (ICI) face a poor prognosis. Chemotherapy has been shown to induce genetic mutations, modify the tumor microenvironment and microbiome, and influence immune system activity. Objectives This prospective multicenter phase II trial investigates whether two applications of an alkylating agent (dacarbazine/DTIC) can sensitize ICI non-responsive patients with metastatic melanoma to the same checkpoint inhibitor regime. Methods The PROMIT trial (NCT04225390) enrolled patients with histologically confirmed BRAF wt metastatic melanoma who exhibited primary resistance to ICI therapy. Following radiologic evidence of primary resistance to ICI (ipilimumab plus nivolumab or pembrolizumab) upon the first staging after initiation, patients received two doses of DTIC at 850 mg/m² intravenously on days 1 and 21. Subsequently, 1 week after application of the second dose of DTIC, patients were re-challenged with the same ICI therapy to which they had previously shown progressive disease. Result In total, 53 patients were enrolled across four German skin cancer centers. Of these, 38 patients were evaluable for efficacy, having received at least one dose of ICI re-exposure. The overall objective response rate was 18.4% (95% CI 0.08-0.34), with 7 out of 38 patients achieving a partial response. The disease control rate was 36.8%. Therapy was well tolerated, with grade 3 CTCAE or higher adverse events occurring in 10.4% of patients, and no new safety signals were observed. Conclusions Study results indicate that short-term chemotherapy followed by ICI re-challenge can overcome primary ICI resistance in melanoma patients, supporting its potential as a new therapeutic option in clinical practice.
Haferkamp et al. (2025) studied this question.