Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results

Abstract

Purpose: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma.

Methods: Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses.

Results: In 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided P = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; P = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; P = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02.

Conclusion: The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.

FIG 1.

CONSORT diagram. ^aThe PIVOT IO 001 study did not meet its primary end points of ORR and PFS by BICR and OS. BICR, blinded independent central review; ITT, intent-to-treat; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

FIG 2.

Kaplan-Meier estimates of (A) PFS per BICR and (B) OS in all patients. Database lock: February 1, 2022. The follow-up time is calculated relative to LPLV of November 19, 2021. The alpha allocated for PFS was .03, and that for OS was .019. Interim OS was tested using the group sequential testing procedure with O'Brien-Fleming alpha spending function. PFS was assessed by the primary definition of PFS per BICR, defined as the time between the date of random assignment and the date of first documented tumor progression, based on BICR assessment (per RECIST 1.1), or death because of any cause, whichever occurs first, before subsequent therapy. Statistical model for HR and P value: stratified Cox proportional hazards model and stratified log-rank test. The information fraction of events of OS is approximately 53%. BEMPEG, bempegaldesleukin; BICR, blinded independent central review; HR, hazard ratio; LPLV, last patient last visit; NIVO, nivolumab; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 3.

On-treatment longitudinal changes in ALC and sCD25. ^asCD25 was not measured in the NIVO monotherapy arm. ALC, absolute lymphocyte count; BEMPEG, bempegaldesleukin; C, cycle; D, day; NIVO, nivolumab; sCD25, soluble CD25.

FIG A1.

Subgroup analysis of ORR by BICR. Database lock: February 1, 2022. The median follow-up is 19.3 months (range, 6.0-37.4) for the ORR population. The alpha allocated for ORR was .001. ^aTwo-sided 95% CI for unweighted difference was calculated using the Newcombe method. ^bSubset categories with <10 patients per treatment group are not included as ORR differences were not computed. BEMPEG, bempegaldesleukin; BICR, blinded independent central review; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; M, metastatic; NIVO, nivolumab; ORR, objective response rate; ULN, upper limit of normal.

FIG A2.

Waterfall plot of best % change from baseline in the sum of diameters of target lesions, per BICR—all response evaluable patients in the ORR population for (A) BEMPEG plus NIVO and (B) NIVO. Patients with target lesion at baseline and at least one postbaseline tumor assessment were included. Best change is maximum reduction in sum of diameters of target lesions (negative value means true reduction, and positive value means increase only observed over time). The horizontal reference line indicates the 30% reduction consistent with a RECIST 1.1 response. The asterisk symbol represents responders. The rectangle symbol represents % change truncated to 100%. BEMPEG, bempegaldesleukin; BICR, blinded independent central review; NIVO, nivolumab.

FIG A3.

Subgroup analysis of PFS by BICR. Database lock: February 1, 2022. The median follow-up is 11.6 months (range, –0.9 to 37.4) for the ITT population. The follow-up time is calculated relative to LPLV of November 19, 2021. The alpha allocated for PFS was .03. ^aBy the primary definition of PFS per BICR, defined as the time between the date of random assignment and the date of first documented tumor progression, on the basis of BICR assessment (per RECIST 1.1), or death because of any cause, whichever occurs first, before subsequent therapy. ^bHR and median are not computed for any subset category with <10 patients per treatment arm. BEMPEG, bempegaldesleukin; BICR, blinded independent central review; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ITT, intent-to-treat; LDH, lactate dehydrogenase; LPLV, last patient, last visit; M, metastatic; mPFS, median progression-free survival; NIVO, nivolumab; PFS, progression-free survival; ULN, upper limit of normal.

FIG A4.

(A) Linear and (B) logarithmic linear plot of the mean (+SD) BEMPEG concentration profile versus time: PIVOT IO 001 extensively sampled PK subset versus the treated population of the PIVOT-02 trial. BEMPEG, bempegaldesleukin; PK, pharmacokinetic; SD, standard deviation.

FIG A5.

Box plot comparison of BEMPEG concentrations after administration of BEMPEG plus NIVO in PIVOT IO 001 and PIVOT-02 from all pharmacokinetics-evaluable patients at nominal times of (A) 0.5 hours, (B) 24 hours, (C) 48 hours, (D) 96 hours, and (E) 168 hours. BEMPEG, bempegaldesleukin; NIVO, nivolumab.