Breaking primary checkpoint inhibitor resistance: Interim analysis of a multicenter phase II study by intermittent application of an alkylating agent among patients with metastatic melanoma

9544 Background: Patients with BRAF wildtype (wt) metastatic melanoma with primary resistance to immune checkpoint inhibitors (ICI) have a dismal prognosis. Chemotherapy has been shown to induce mutations, alter the tumor microenvironment as well as the microbiome, and modulate the immune system. This prospective phase II trial investigates whether two applications of an alkylating agent (dacarbazine/DTIC) can render ICI non-responsive patients with metastatic melanoma responsive to the same checkpoint inhibitor regime. Methods: The PROMIT trial (NCT04225390) targets patients with histologically confirmed BRAFwt metastatic melanoma showing primary resistance to ICI therapy. Applying an optimal two-step design, the uninteresting responder rate was set to 5% with an expected rate of 20%. Response is defined as complete or partial response by week 14 according to RECIST 1.1. Design foresaw 29 assessable patients at first step and 38 patients overall (alpha one-sided 5%, 90% power).After showing primary resistance to ICI, patients received 2 doses of DTIC (850 mg/m 2 i.v.) on days 1 and 21, and were subsequently re-exposed to the same ICI therapy they had previously shown resistance to. Results: In total, 38 patients were screened at 4 skin cancer centers. Interim analysis was performed after 29 patients who had received at least one ICI re-exposure were assessable for efficacy. Overall response rate was 24% (90%CI 12-41%) with 7 out of 29 patients showing a partial response; disease control rate was 38%. Application was well tolerated with 16% grade 3 or more adverse events and no new safety signals. Conclusions: Interim analyses results indicate that this approach of a short-term chemotherapy can break resistance in a subgroup of patients and allows us to continue the phase II trial to assess relevance of this treatment approach for metastatic melanoma. Enrolment is ongoing. Clinical trial information: NCT04225390 .