Balstilimab Monotherapy, Combination Shows Promise in Recurrent/Metastatic Cervical Cancer

Balstilimab as a single agent and combined with zalifrelimab demonstrated promising objective response rates, regardless of PD-L1 expression, and a tolerable safety profile in patients with recurrent or metastatic cervical cancer.

Findings of 2 independent phase 2 trials presented during the 2020 ESMO Virtual Congress indicated that the investigative PD-1 inhibitor balstilimab (AGEN2034) as a single agent and combined with the CTLA-4 inhibitor zalifrelimab (AGEN1884) demonstrated promising objective response rates (ORRs), regardless of PD-L1 expression, and a tolerable safety profile in patients with recurrent or metastatic cervical cancer.1

In the modified intent-to-treat (ITT) population, single-agent balstilimab brought about a 14% ORR, which included 3 complete responses (CRs) and 20 partial responses (PRs); when explored in combination with zalifrelimab, the ORR increased to 22%, with 8 CRs and 23 PRs. Additionally, the median duration of response (DOR) was 15.4 months (1.1+ to 15.4) with balstilimab monotherapy and was not reached (1.3+ to 16.6+) when used in combination.

“This is, by far, the largest reported study of checkpoint inhibitors in [patients with] recurrent/metastatic cervical cancer reported to date. We demonstrated responses in both PD-L1–positive and PD-L1–negative tumors in patients treated with single-agent balstilimab and with the combination of balstilimab/zalifrelimab,” lead investigator David O’Malley, MD, professor of obstetrics and gynecology at The Ohio State University College of Medicine, said in a virtual presentation during the meeting. “These results demonstrate that both single-agent balstilimab and the balstilimab/zalifrelimab combination are effective and well tolerated in the second-line treatment of [patients with] recurrent/metastatic cervical cancer.”

The presentation follows a September 2020 announcement from the manufacturer of balstilimab, Agenus Inc., which stated that a rolling submission of a biologics license application to the FDA has been initiated for single-agent balstilimab for the treatment of patients with recurrent/metastatic cervical cancer.2

One of the phase 2 trials, both of which were parallel, single-arm studies, evaluated single-agent balstilimab at 3 mg/kg every 2 weeks (NCT03104699), while the second explored the PD-1 inhibitor at the same dosage in combination with zalifrelimab at a dose of 1 mg/kg every 6 weeks (NCT03495882), both in patients with recurrent/metastatic cervical cancer. Imaging was conducted every 6 weeks for 2 years.

To be eligible for enrollment, patients must have had histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix that had relapsed following platinum-based therapy, measurable baseline disease, and an ECOG performance status of 0 or 1.

The primary end point of the trial was ORR via RECIST v1.1 criteria, as assessed by an independent review committee; secondary end points were progression-free survival, overall survival, DOR, and safety. PD-L1 positivity was defined as a combined positive score (CPS) of 1% or higher.

In the single-agent trial, 161 patients comprised the safety population, and 160 were in the modified ITT population; 138 patients had received 1 or more prior line of chemotherapy. The median age was 53 years, and 47% of patients had an ECOG performance status of 0. A total 62% of patients had a CPS of 1% or higher, 63% had squamous cell histology, and 37% had adenocarcinoma/adenosquamous histology.

In the combination trial, 155 patients were in the safety population, and 119 had received 1 or more lines of chemotherapy. A total 143 patients comprising the modified ITT population with baseline measurable disease. The median age was 50 years, and 57% of patients had an ECOG performance status of 0. Fifty-five percent of patients had a CPS of 1% or higher, and 70% had squamous histology. Thirty percent of patients had adenocarcinoma/adenosquamous histology.

In patients who received 1 or more lines of prior chemotherapy, the ORR in the single-agent balstilimab trial was 13%, with 3 CRs and 15 PRs. For those who received the combination and prior chemotherapy, the ORR was 20%, with 6 CRs and 18 PRs.

When stratified by histology, the ORR was higher in patients with squamous cell carcinoma who received the combination (27%) versus the single agent (18%), suggesting a predictor of response, O’Malley explained. For the adenocarcinoma/adenosquamous/other histology, the ORRs were 8% for those on single-agent balstilimab and 5% for patients on the combination.

Moreover, on the monotherapy study, the ORRs were 19%, 10%, and 0% for those with PD-L1–positive disease, PD-L1–negative disease, and unknown PD-L1 status, respectively. In the combination study, these rates were 27%, 11%, and 21%, respectively.

Regarding safety, the treatment was found to be well tolerated in both studies and no new safety signals were identified, with all-grade endocrine disorders more common with the combination compared with single-agent balstilimab (20.6% vs 9.3%, respectively).

The combination trial also saw more immune-related adverse effects (irAEs) than the single-agent study, O’Malley noted. Specifically, gastrointestinal (GI) disorders occurred in 8.4% and 5.6% of the combination and monotherapy arms, respectively, as well as laboratory abnormalities (11.6% vs 5.6%) and endocrine disorders (18.7% vs 5.0%). Grade 3 or higher immune-related treatment-related adverse effects were GI disorders (2.6% with the combination vs 3.1% with balstilimab alone), laboratory abnormalities (3.9% vs 1.2%, respectively), and skin and subcutaneous tissue disorders (1.9% vs 0.6%).

“Given the limited treatments available for our patients with recurrent/metastatic cervical cancer, both single-agent balstilimab and the combination of balstilimab/zalifrelimab present important treatment options for our patients,” O’Malley concluded.


1. O’Malley DM, Oaknin A, Monk B, et al. Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): Preliminary results of two independent phase II trials. Presented at: 2020 ESMO Congress; September 19-21, 2020; virtual. Abstract LBA34.

2. Agenus initiates rolling BLA submission of balstilimab for recurrent/metastatic cervical cancer. News release. Agenus Inc. September 18, 2020. Accessed September 18, 2020.