Agenus Withdraws BLA for Balstilimab in Metastatic Cervical Cancer


The immuno-oncology company Agenus has made the decision to withdraw its biologic license application for the use of the PD-1 inhibitor balstilimab in patients with recurrent or metastatic cervical cancer who experienced disease progression on, or after, chemotherapy.

The immuno-oncology company Agenus has made the decision to withdraw its biologic license application (BLA) for the use of the PD-1 inhibitor balstilimab in patients with recurrent or metastatic cervical cancer who experienced disease progression on, or after, chemotherapy.1

The decision follows the full approval of pembrolizumab (Keytruda) on October 13, 2021, for use as a single agent in patients with recurrent or metastatic cervical cancer with disease progression on, or after, chemotherapy and whose tumors have a PD-L1 combined positive score of 1 or higher, as determined by a FDA-approved test.2 In light of this decision, the FDA no longer considered it appropriate to review the balstilimab application for accelerated approval and recommended that Agenus withdraw.

The application was supported by data from a phase 2 trial (NCT03894215), which showed that balstilimab elicited a confirmed objective response rate (ORR) of 15% (95% CI, 10.0%-21.8%; n = 21/140); this included a complete response (CR) rate of 3.6%, a partial response (PR) rate of 11.4%, and a stable disease rate of 36.4%. Forty percent of patients had progressive disease.3

Moreover, in patients with PD-L1 positivity (n = 85), balstilimab induced an ORR of 20.0%; in those with PD-L1 negativity (n = 38), the ORR with the agent was 7.9%.

“While the commercial market for balstilimab monotherapy in second-line cervical cancer is always anticipated to be small, Agenus’ priority remains developing balstilimab as a necessary component of highly effective and affordable combination therapies, both with its own portfolio and with partners, including in combination with Agenus’ next-generation CTLA-4, AGEN1181,” Garo Armen, chief executive officer and chairman of Agenus, stated in a press release.

The open-label, single-arm, global phase 2 trial enrolled patients with a pathologically confirmed diagnosis of squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix, with metastatic, persistent, or recurrent disease.

To be eligible for enrollment, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and acceptable hematologic, renal, and hepatic function. Patients also needed to have at least one measurable lesion per RECIST v1.1 criteria, disease that had relapsed following a first-line, platinum-based regimen. Notably, patients were enrolled irrespective of PD-L1 expression status.

If patients previously received immune checkpoint inhibitor therapy, known hypersensitivity to humanized monoclonal antibodies, or if they received more than 1 systemic regimen for advanced cervical cancer, they were excluded.

Study participants were given intravenous balstilimab at a dose of 3 mg/kg once every 2 weeks, given as a 60-minute infusion. This dose was determined to be the recommended phase 2 dose based on findings from the run-in phase 1 dose-escalation portion of the trial. Treatment continued for up to 24 months or until progressive disease, unacceptable toxicity, or investigator or patient decision.

The primary end point of the trial was ORR per independent end point review committee in accordance with RECIST v 1.1 criteria. Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival, and overall survival. An exploratory end point was focused on the association of PD-L1 expression and clinical response.

The median age of the 161 patients enrolled was 53 years (range, 25-81) and 52.2% had an ECOG performance status of 1. The distribution of histology was squamous cell carcinoma (62.7%), adenocarcinoma (32.3%), and adenosquamous carcinoma (4.3%). All patients were previously exposed to platinum treatment and 29.2% received bevacizumab (Avastin) as part of a prior regimen.

Moreover, 61.5% of patients had tumors with PD-L1 positivity and 26.7% had PD-L1 negativity. The rest of the cases, or 11.8%, were not evaluable for PD-L1 expression or did not have that information available. Among those with PD-L1–positive tumors, 23.2% previously received bevacizumab.

The median duration of follow-up was 14.6 months (range, 9.9-38.8). The median DOR with balstilimab was 15.4 months (95% CI, 5.7–not reached). The 6-month response rate was 12%; at 9 months and 12 months, these rates were 8% and 6%, respectively. The DCR with balstilimab was 49.3% (95% CI, 41.1%-57.5%).

Responses were observed across all histologic subtypes, including tumor responses that were reported in 12.5% if those with cervical adenocarcinomas. Moreover, 33.6% of patients previously received bevacizumab and 5 of these patients responded to treatment with balstilimab; this included 1 CR and 4 PRs and translated to an ORR of 10.6%.

Regarding safety, the most common any-grade treatment-related toxicities included asthenia (23%), diarrhea (12.4%), pruritis (11.8%), and fatigue (10.6%). The majority of the effects were grade 1 or 2 in severity. The incidence of grade 3 or higher treatment-related adverse effects (TRAEs) was 11.8%, with 3.1% of patients experiencing immune-mediated enterocolitis.

Moreover, 7.5% of patients experienced at least 1 serious TRAE, the most common of which was immune-mediated enterocolitis. Twenty-three patients experienced a TRAE that resulted in dose interruption and 7 patients had a TRAE that led to discontinuation. One death was determined to be potentially related to treatment; the patient died of an unknown cause.

Agenus announced plans to discontinue the ongoing confirmatory phase 3 BRAVA trial (NCT04943627), which is examining balstilimab monotherapy or investigator’s choice of chemotherapy, which could include gemcitabine, irinotecan, pemetrexed, vinorelbine, or topotecan, in patients with recurrent, persistent, or metastatic cervical cancer who have progressed following platinum-based chemotherapy.

However, due to the clinical benefit reported with the immunotherapy, the company announced plans to launch expanded access programs to provide patients and providers with access to the agent in several countries, including the United States, following regulatory processes.

“Balstilimab has demonstrated meaningful clinical activity and an excellent safety profile in second-line cervical cancer, including in PD-L1–negative patients, who are ineligible to receive standard-of-care anti–PD-1 therapy, which makes the decision to withdraw so difficult for us,” Steven O’Day, MD, chief medical officer of Agenus, stated in the press release. “Balstilimab remains a critical component of our combination regimens, including with our next-generation CTLA-4 agent, AGEN1181. Concomitant with the presentation of new data at SITC next month, we continue to accelerate development of AGEN1181 in combination with balstilimab in trials designed to rapidly support full or accelerated approval in multiple tumor types.”


  1. Agenus provides update on balstilimab development. News release. Agenus. October 22, 2021. Accessed October 22, 2021.
  2. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. News release. FDA. October 13, 2021. Accessed October 22, 2021.
  3. O’Malley DM, Oaknin A, Monk BJ, et al. Phase II study of the study and efficacy of the anti-PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer. Gynecol Oncol. Published online August 24, 2021. doi:10.1016/j.ygyno.2021.08.018

This article was originally published on OncLive®.

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