Toripalimab vs Dacarbazine as First-Line Therapy for Advanced Melanoma of Acral Subtype

Importance Programmed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear. Objective To evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype. Design, Setting, and Participants This multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023. Intervention Patients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m 2 , every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression. Main Outcomes and Measures Progression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1. Results The analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) months vs 6.9 (95% CI, 3.8-not evaluable) months, respectively, also favored toripalimab over dacarbazine. Grade 3 or worse treatment-related adverse events occurred in 36 patients (28.3%) receiving toripalimab, with the most common (≥3%) being increased lipase (11 patients [8.7%]), anemia (5 patients [3.9%]), increased γ-glutamyltransferase (4 patients [3.1%]), hyponatremia (4 patients [3.1%]), and increased blood triglycerides (4 patients [3.1%]). Conclusions and Relevance This phase 3 randomized clinical trial found that as a first-line treatment for advanced melanoma predominantly of acral subtype, toripalimab showed a significant PFS benefit over dacarbazine and an acceptable safety profile. Trial Registration ClinicalTrials.gov Identifier: NCT03430297