Phase I/IIa dose finding study of triplet regimen of relatlimab (RELA) ipilimumab (IPI), and nivolumab (NIVO) in first-line therapy of metastatic melanoma (MM) (TRINITY).

TPS9603 Background: Approved immune checkpoint blockade (ICB) agents for the treatment (tx) advanced, unresectable metastatic melanoma (MM) include NIVO (anti-PD1) alone or in combination with IPI (anti-CTLA-4) or RELA (anti-LAG3) and have transformed outcomes for patients with this disease. While doublet combinations induce higher rates of durable disease control and modestly improved survival vs single agent, higher doses of IPI induce higher objective response rates (ORR) also increase grade ≥3 immune-related adverse events. Notably, there is no established dose-response relationship for NIVO or RELA. IPI has a demonstrated role in expanding the T-cell receptor (TCR) repertoire, modulating suppressive T cell populations. NIVO+RELA regulates exhaustion of activated T cells, improving effector function. Together, these suggest potential synergy with triplet ICB. Results reported in RELATIVITY-048 (NIVO 480 mg Q4W + RELA 160 mg Q4W + IPI 1 mg/kg Q8W) demonstrated impressive efficacy (ORR 59%) and seemingly improved progression free and overall survival (PFS, OS) over previously reported doublet tx. The RELATIVITY-048 study design did not include dose escalation (DE) of IPI. Our team seeks to identify the optimal dose and schedule if IPI to combine with NIVO+RELA, identify the recommended phase II dose (RP2D) for this triplet ICB treatment and, ultimately, seeking to maximize the clinical benefit while maintaining a toxicity profile comparable to approved doublet regimens. Methods: In this single center, investigator initiated, PhI/IIa study, our team is evaluating triplet ICB (NCT06683755) in untreated, unresectable MM pts. Pts will receive NIVO 480mg + RELA 160mg IV Q4W (FDA approved dose). IPI DE will begin at 0.5mg/kg Q4W, escalating to 2mg/kg Q4W x4 induction doses. Pts will receive maintenance tx with NIVO+RELA Q4W at the approved dose. The maximum tolerated dose and the RP2D will be determined using a Bayesian optimal interval design, accruing 12-18 pts in DE. An additional 12-18 pts will be enrolled at RP2D to determine the ORR (primary objective) by RECIST 1.1. Secondary objectives include PFS, OS, and correlative analysis. Non IPI containing prior adjuvant or neoadjuvant tx is allowed if the last dose has been >6 months. Pts with asymptomatic brain metastasis on ≤10mg corticosteroids are allowed. Safely biopsiable lesions are required for pts enrolled in the PhII portion. By optimizing the dose and schedule of IPI in combination with NIVO+RELA, we seek to maximize clinical benefit while maintaining a toxicity profile comparable to approved regimens. This study is currently accruing at MD Anderson Cancer Center. Clinical trial information: NCT06683755 .