Second-Line Balstilimab Plus Zalifrelimab Yields Durable Clinical Activity in Recurrent/Metastatic Cervical Cancer

Findings from a phase 2 study demonstrated encouraging clinical activity and a manageable safety profile when patients with advanced cervical cancer were treated with second-line balstilimab and zalifrelimab.

The second-line combination of anti–PD-1 agent, balstilimab, and CTLA-4 agent, zalifrelimab (AGEN1884), produced durable clinical activity while maintaining a tolerable safety profile when treating patients with recurrent and/or metastatic cervical cancer who relapsed after a prior platinum-based therapy, according to results from a phase 2 study (NCT03495882) published in the Journal of Clinical Oncology.1

With a median follow-up of 21 months, the confirmed objective response rate (ORR) for patients treated with the combination was 25.6% (95% CI, 18.8%-33.9%), including 10 complete responses and 22 partial responses.

“Thanks to screening, most cervical cancers are detected in early or pre-cancerous stages that are very treatable. For women with an advanced or recurrent cancer, however, there are still limited medical therapies that provide durable cancer control,” corresponding author David O’Malley, MD, a gynecologic oncologist at Ohio State University Comprehensive Cancer Center – The James, said in a news release.2 “This data suggests the combination of balstilimab and zalifrelimab is an effective and durable new option for treating advanced or recurrent cervical cancers — particularly in patients whose tumors express PD-L1.”

Patient enrollment occurred from August 27, 2018, to May 7, 2020, at 45 sites in the United States, Europe, South America, and Australia. Patient eligibility required confirmed diagnosis of recurrent and/or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix in order enroll. Additional requirements included being 18 years of age or older, having an ECOG performance status of 0 or 1, and having adequate hematologic, renal, and hepatic function. Patients also had to have at least 1 measurable lesion by RECIST 1.1 and relapsed following treatment with a first-line, platinum-based therapy.

In terms of dosing, balstilimab was administered intravenously at 3 mg/kg once every 2 weeks plus 1 mg/kg zalifrelimab intravenously once every 6 weeks during a 6-week cycle. Treatment continued until disease progression, unacceptable toxicities, or investigator and/or patient decision.

The primary end point was ORR assessed by independent review committee. Secondary end points included duration of response (DOR), disease control rate (DCR), duration of stable disease, safety and tolerability, and survival.

A total of 155 patients were enrolled on the study and received treatment with balstilimab and zalifrelimab. Patients had a median age of 50 years (range, 24-76). The majority of patients were White (95.5%), had squamous cell carcinoma (70.3%), and previously received radiotherapy (89%). Most patients also had an ECOG performance status of 0 (57.4%) and PD-L1–positive tumors (55.5%).

The median DOR was not reached (NR) for the population of patients (95% CI, 9.7-NR), the median time to response was 2.7 months (95% CI, 1.3-15.8), and the DCR was 52% (95% CI, 43.3%-60.6%). The median progression-free survival (PFS) was 2.7 months (95% CI, 1.5-3.7) and the 12-month PFS rate was 21.3% (95% CI, 14.1%-29.4%). The median overall survival (OS) was 12.8 months (95% CI, 8.8-17.6). The 6-month OS rate was 69.2% (95% CI, 60.1%-76.7%) and the 12-month OS rate was 53.3% (95% CI, 43.8%-61.9%).

The subset analyses yielded an ORR of 32.8% (95% CI, 22.8%-44.7%) among patients with PD-L1–positive tumors and 9.1% for PD-L1–negative tumors.

Common any-grade treatment-related adverse effects (TRAEs) for the overall cohort included hypothyroidism (16.8%), diarrhea (14.2%), fatigue (11.6%), and nausea (9.0%). Grade 3 or higher TRAEs were observed in 20.0% of patients, with commonly reported TRAEs including alanine transaminase increase (2.6%) and diarrhea (1.9%).

“The high proportion of complete responders and activity irrespective of tumor PD-L1 status or histology were particularly promising outcomes that confirm the feasibility of dual targeted immunotherapy for this disease. Given the lack of effective therapies and poor prognosis for patients in this setting, the findings suggest that this novel regimen may provide meaningful clinical benefit in this difficult-to-treat population and further evaluation of the combination is warranted,” the investigators concluded.


  1. O'Malley DM, Neffa M, Monk BJ, et al. 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. J Clin Oncol. Published online December 21, 2021. doi:10.1200/JCO.21.02067
  2. Targeted two-drug therapy effective to treat advanced cervical cancer. News release. Ohio State University Comprehensive Cancer Center. January 4, 2022. Accessed January 5, 2022.