Multi-arm multi-stage clinical trials for time-to-event outcomes.

This paper investigates the use of a general multi-arm multi-stage (MAMS) approach for time-to-event outcomes that would streamline simultaneous comparison of a large number of promising therapies in clinical trials, thus significantly reducing the time and the number of patients needed to evaluate the treatment. Controlling type I error in this setting is different than regular clinical trials as this approach incorporates both multiple comparison between arms and multiple stages. Historically, pairwise (PWER) and familywise (FWER) type I error rates have been primarily used to regulate the type I error in such designs. This paper will focus on constructing the efficacy and futility boundaries for a MAMS clinical trial in two different scenarios. In the first, it is assumed that the same outcome is used throughout the clinical trial for both intermediate and final assessments. In this scenario, we propose using the generalized Dunnett procedure that controls FWER. In the latter scenario, where intermediate and final outcomes are different in nature, we propose modifications to the existing method that originally concentrated on controlling PWER and extend the method to include FWER in the design. We also explore the performance of the proposed MAMS design in a setting where the proportional hazard assumption is violated in the presence of a delayed treatment effect and demonstrate the loss of power because of that. An alternative test statistic that can help circumvent this problem to maintain the desired power is also suggested.

Nivolumab and Relatlimab in Patients With Advanced Melanoma That Had Progressed on Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy: Results From the Phase I/IIa RELATIVITY-020 Trial.

PURPOSE: Nivolumab and relatlimab activity in advanced melanoma with prior progression on anti-programmed death-1/programmed death ligand 1 (PD-(L)1)-containing regimens is under investigation. RELATIVITY-047 demonstrated significantly improved progression-free survival (PFS) for nivolumab and relatlimab over nivolumab in previously untreated advanced melanoma. METHODS: The phase I/IIa, open-label RELATIVITY-020 trial part D assessed efficacy and safety of nivolumab and relatlimab in advanced melanoma with progression during, or within 3 months of, 1 (D1) or ≥ 1 (D2) anti-PD-(L)1-containing regimens. Safety was a primary end point. Objective response rate (coprimary end point) and PFS by blinded independent central review (BICR) were assessed. RESULTS: Five hundred eighteen patients (D1 = 354; D2 = 164) received nivolumab and relatlimab. Among evaluable patients, the objective response rate by BICR was 12.0% (95% CI, 8.8 to 15.8) in D1 (n = 351) and 9.2% (95% CI, 5.2 to 14.7) in D2 (n = 163). Responses appeared to be enriched among patients with tumors expressing programmed death ligand 1 or lymphocyte activation gene 3; however, responses were observed regardless of programmed death ligand 1 and lymphocyte activation gene 3 expression (1%). The median duration of response was not reached (95% CI, 12.9 to not reached) in D1 and 12.8 months (95% CI, 6.9 to 12.9) in D2. The median PFS by BICR was 2.1 months (95% CI, 1.9 to 3.5) in D1 and 3.2 months (95% CI, 1.9 to 3.6) in D2; the 6-month PFS rate was 29.1% (95% CI, 24.2 to 34.1) and 27.7% (95% CI, 20.5 to 35.4), respectively. The grade 3-4 treatment-related adverse event incidence was 15.0% in D1 and 12.8% in D2. One case of grade 3 myocarditis and no treatment-related deaths occurred across part D. CONCLUSION: Nivolumab and relatlimab had a manageable safety profile and demonstrated durable clinical activity in a proportion of patients with heavily pretreated advanced melanoma with prior progression on anti-PD-(L)1-containing regimens.[Media: see text].