Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study

Abstract

Purpose: Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte-associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy.

Patients and methods: Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival.

Results: In total, 155 women (median age, 50 years [range, 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1-positive and programmed death ligand-1-negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events.

Conclusion: Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte-associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.

FIG 1.

Antitumor activity of the balstilimab-zalifrelimab combination. (A) Maximum percentage change from baseline in the sum of tumor target lesion diameters according to RECIST, version 1.1. PD-L1 status is indicated by color coding of bars. (B) Kinetics of tumor burden over time presented as percentage change in RECIST sum in patients with confirmed responses to combination treatment. The dashed red line corresponds to the 30% decrease in tumor size. CR, complete response; PD-L1, programmed death ligand-1; PR, partial response.

FIG 2.

CRs to balstilimab-zalifrelimab combination therapy. (A) Computed tomography scans shown for a 59-year-old patient who received her first dose of the combination on January 22, 2019. Target lesions at baseline were an external iliac lymph node lesion (16 mm) and bladder lesion (23 mm). The first documentation of CR was on April 7, 2020, after 10 cycles of treatment, with regression of both target lesions. The patient remained cancer free and completed the study after 24 months, per protocol. (B) Scans for a 58-year-old patient, initially dosed on December 30, 2019, showing complete clearance of a large paraspinal muscle target lesion (49 mm) on May 1, 2020, after three cycles of treatment. CR, complete response.

FIG 3.

Kaplan-Meier estimates of survival outcomes in the efficacy population (n = 125). (A) PFS and (B) OS assessed by the independent review committee per RECIST v1.1. OS, overall survival; PFS, progression-free survival.

FIG A1.

Patient enrollment and disposition. CRT, chemoradiotherapy; ITT, intent-to-treat. ^aPatients who received ≥ 1 dose of study treatment, with measurable disease at baseline, and had prior line of platinum-based treatment in the metastatic, persistent, or recurrent setting (per Independent Review Committee).