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

[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.