Balstilimab Plus Zalifrelimab Displays Strong Efficacy, Survival Benefits in Recurrent/Metastatic Cervical Cancer


The anti-PD-1 antibody balstilimab in combination with the anti-CTLA-4 antibody zalifrelimab exhibited impressive response rates, duration of response, and overall survival in patients with previously treated recurrent/metastatic cervical cancer.

David O'Malley, MD

David O'Malley, MD

The anti-PD-1 antibody balstilimab in combination with the anti-CTLA-4 antibody zalifrelimab (AGEN1884) exhibited impressive response rates, duration of response (DOR), and overall survival (OS) in patients with previously treated recurrent/metastatic cervical cancer, according to data from a single arm phase 2 trial (NCT03495882) presented at the 2021 ESMO Annual Congress.1

Among the 125-patient efficacy evaluable population, the combination elicited an overall response rate (ORR) of 25.6%. Ten (8.8%) responders experienced a complete response (CR). Among the 67-patients with a positive PD-L1 status, the ORR was 32.8% compared with 9.1% in the PD-L1-negative subgroup (n = 33).

Notably, the median duration of response (DOR) was not reached (range, 9.3 months-not reached). The 6-month DOR rate was 86.4% and the 12-month rate was 66.7%.

“There remains a significant unmet medical need for patients with recurrent or metastatic cervical cancer who progress after platinum-containing chemotherapy,” explained David O'Malley, MD, the director of the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine in Columbus.

“We know that single agent PD-1 activity is modest while CTLA-4 inhibition demonstrates limited to no activity in patients with cervical cancer,” he added. “Combining anti-PD1 and anti-CTLA-4 [agents] is now an established treatment paradigm across a broad spectrum of solid tumors. In this phase 2 study design, we report the largest trial to date combining PD-1 and CTLA-4 in patients with cervical cancer.”

In order to be eligible for the trial, patients needed to have histologically confirmed squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix that relapsed after platinum-based treatment. Patients also had to have measurable disease and an ECOG performance status of 0 or 1.

The primary end point of the trial was ORR by RECIST v1.1 per an independent review committee. Secondary end points included OS, DOR, and progression-free survival. The trial enrolled a total of 155 patients in Europe, Australia, South America, and the United States.

The median age of the total population was 50 (range, 24-76). Most patients (70.3%) had squamous cell carcinoma, 27.1% had adenocarcinoma, and 2.6% had adenosquamous histology.ECOG performance status was well balanced, 57.4% registered a 0 and 42.6% were at 1. A majority of patients (56.8%) had positive PD-L1 tumor expression status, defined as a combined positive score of at least 1%. The most common prior therapy exposures, besides platinum-containing (99.4%), were taxane (78.7%) and bevacizumab (32.9%).

Balstilimab was administered at a dose of 3 mg/kg every 2 weeks. Zalifrelimab 1 mg/kg was given every 6 weeks. Treatment lasted for up to 24 months and follow-up imaging occurred every 6 weeks through 2 years.

At a median follow-up of 21 months, the median PFS was 2.7 months (95% CI, 1.5-3.7). The median OS was 12.8 months (95% CI, 8.8-17.6). In the PD-L1-positive subset, the median OS improved to 15.7 months (95% CI, 7.6-21.1).

“The response rates [for this combination] nearly double currently achieved with approved agents in the second-line setting, including single agent PD-1 antibodies,” noted O’Malley. “Beyond response rate, the distinguishing feature of combining CTLA-4 and PD-1 antibodies are improved depth and durability of responses as well as survival outcomes. Longer follow-up will hopefully confirm this exciting trend and establish long-term survival as an achievable goal in advanced/recurrent cervical cancer.”

In terms of safety, 71.0% of the 155-patient safety population experienced a treatment-related adverse event (TRAE) of any grade. Common TRAEs of any grade included hypothyroidism (16.8%), diarrhea (14.2%), and fatigue (11.6%). TRAEs of at least grade 3 occurred in 20.0% of patients and included increased alanine transaminase (2.6%) and diarrhea (1.9%). TRAEs that lead to dose interruption were reported in 12.3% of patients and TRAEs leading to dose discontinuation occurred in 7.7% of patients.

Immune-mediated AEs were less commonly observed (44.5%), and included hypothyroidism (14.2%), hyperthyroidism (7.1%), diarrhea (7.1%), and puritis (4.5%).

“[This was] the largest study to date evaluating dual PD-1/CTLA-4 checkpoint blockade in patients with recurrent/metastatic cervical cancer,” concluded O’Malley. “With a median follow-up of almost 2 years, the balstilimab and zalifrelimab combination showed high response rates, durable clinical activity, and promising overall survival results. Advocacy outcomes were particularly impressive in the PD-L1 positive patients, but also broadly seen in subgroups with poor risk features. A confirmatory randomized phase 2 study comparing balstilimab and zalifrelimab with balstilimab alone is actively enrolling.”


  1. O’Malley DM, Neffa M, Monk BJ, et al. Balstilimab (anti-PD-1) in combination with zalifrelimab (anti-CTLA-4): Final results from a phase II study in patients (pts) with recurrent/metastatic (R/M) cervical cancer (CC). Presented at: 2021 European Society for Medical Oncology Congress. September 16-21, 2021; virtual. Abstr 724MO.
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