TrioMBM: A multicenter, phase II trial of relatlimab, nivolumab, and ipilimumab in patients with asymptomatic and symptomatic melanoma brain metastases.

Abstract

TPS9604 Background: Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients (pts) with advanced melanoma. Modern systemic therapies including immune checkpoint blockade (ICB) are insufficient at controlling MBM, particularly in patients with who are symptomatic and/or require corticosteroids. The CheckMate 204 study established nivolumab (NIVO) 1 mg/kg + ipilimumab (IPI) 3mg/kg followed by maintenance NIVO as the standard treatment (tx) for pts with MBM based on intracranial IC) objective response rate (ORR) of 55% and 6-month progression-free survival (PFS) of 64% in the asymptomatic cohort ( Tawbi et al. NEJM 2018 ). In symptomatic pts, intracranial benefit rate (iCBR) was only 22% and median PFS was 1.2 mos ( Tawbi et al. Neuro Oncol 2021 ). Triplet tx with the addition of LAG-3 inhibition with relatlimab (RELA) is now being explored as a mechanistically-driven means to improve efficacy of ICB. Arm 2B of RELATIVITY-048 (NIVO 480 mg Q4W + RELA 160 mg Q4W + IPI 1 mg/kg Q8W) reported promising efficacy (ORR 59%, 3y PFS 52%) and 2 of 3 (67%) pts with MBM had confirmed responses ( Ascierto et al. ASCO 2024 ) further justifying the need to explore this combination in this population. We hypothesize that triplet ICB will be more effective than NIVO+IPI for the tx of symptomatic and asymptomatic MBM. Methods: In this multicenter, investigator initiated, phase II study evaluating triplet ICB (NCT06712927) pts with MBM will be assigned to one of two cohorts: Cohort A (asymptomatic, n=40) and Cohort B (symptomatic, n=20) defined as having symptoms attributable to brain metastases and/or requiring steroids >10 mg prednisone/day or equivalent. All pts will receive NIVO 480mg + RELA 160mg IV Q4W (FDA approved dose) plus IPI 1mg/kg IV Q8W. Pts must have ≥1 untreated intracranial lesion (5-40mm) and no prior ICB for unresectable stage III/IV melanoma (>6 mo since neoadjuvant or adjuvant ICB). Primary endpoint is iCBR (CR+PR+SD ≥6 mo) determined by modified RECIST 1.1; secondary endpoints include safety, ORR, duration of response, and PFS. Extensive correlative analyses of peripheral blood mononuclear cells, plasma, tumors, and cerebrospinal fluid are planned. The study is currently enrolling at Stanford Cancer Center with multisite expansion underway. Clinical trial information: NCT06712927 .