Phase 1b Study of Tovorafenib, Plozalizumab or Vedolizumab Plus Standard-of-Care Immune Checkpoint Inhibitors in Patients with Advanced Melanoma

<b>Background:</b> Novel advanced melanoma therapy combinations may increase treatment efficacy and reduce treatment-related toxicities. <b>Methods:</b> This open-label, nonrandomized, multicenter, phase 1b, 3-arm, umbrella study enrolled patients with advanced melanoma eligible for standard-of-care checkpoint inhibitor therapy. There were 3 phases: dose escalation; Part 1 limited cohort expansion; Part 2 additional expansion. Arms (A) 1, 2, and 3 investigated tovorafenib plus nivolumab, plozalizumab plus nivolumab, and vedolizumab plus nivolumab plus ipilimumab, respectively. In the dose-escalation plus Part 1 limited cohort expansion phase, the primary endpoint was dose-limiting toxicities. <b>Results:</b> Twenty-two patients (A1=1; A2=9; A3=12) were enrolled before premature study termination. A1 was closed due to lack of enrollment. A2 enrollment was closed due to lack of clinical benefit (6/9 patients discontinued due to disease progression), and A3 enrollment was closed due to meeting prespecified stopping criteria (grade 3 diarrhea/colitis in 2 patients). One patient (A2) experienced dose-limiting toxicities. Grade ≥3 adverse events were reported in the single patient from A1, 3 (33.3%) patients from A2, and 10 (83.3%) patients from A3. <b>Conclusion:</b> Study design allowed early termination after initial results suggested unlikely clinical benefit. Efficacy remains inconclusive for tovorafenib plus nivolumab and vedolizumab plus nivolumab plus ipilimumab in advanced melanoma. Trend review in this small population suggests a limited effect of investigated vedolizumab regimens as primary prophylaxis against nivolumab plus ipilimumab gastrointestinal toxicity.