Balstilimab, a novel, fully human monoclonal immunoglobulin G4 (IgG4) designed to block PD-1 (programmed cell death protein 1) from interacting with its ligands PD-L1 and PD-L2 shows an objective response rate (ORR) of 20% with and median duration of response not reached with 14.6 month median follow-up in PD-L1+ tumors. Responses for the investigational agent, previously known as AGEN2034 and being developed by Agenus, were seen across all histology subgroups including populations of patients unresponsive to other therapies.[1]

Balstilimab is being investigated for the treatment of metastatic or locally advanced solid tumors, including second line cervical cancer, one of the most common female genital tract malignancy and fourth leading cause of cancer mortality in women worldwide. The prognosis for patients diagnosed with recurrent and/or metastatic disease is particularly poor, as evidenced by a 5-year overall survival (OS) rate of 17% [2]

Beyond palliative platinum-based chemotherapy, available treatment options for patients diagnosed with recurrent and/or metastatic disease are limited and typically administered without expectation of cure. Further, optimal second-line and later regimens for the management of advanced, relapsed disease are yet to be established. [3]

Earlier this week, results from the a global phase 2 trial of balstilimab monotherapy in recurrent/metastatic cervical cancer were published online in the international peer reviewed journal Gynecologic Oncology.[1]

The trial was an open-label, single-arm, global Phase 2 clinical trial conducted at 60 sites throughout the United States, Europe, South America, and Australia. Patients were enrolled from November 20, 2017, to April 16, 2020, and received intravenous balstilimab at a dose of 3 mg/kg once every two weeks, given as a 60-minute infusion. Treatment was permitted for up to 24 months, or until disease progression, intolerable toxicity, or investigator/patient decision

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Significant achievement
“Publication of these data marks another significant achievement toward our objective to provide effective therapeutic options to those battling cancer,” said Steven O’Day, MD, Chief Medical Officer of Agenus.

“These data are drawn from the largest Phase 2 study to date evaluating PD-1 inhibition in advanced cervical cancer patients who have progressed on or after first-line chemotherapy; the results indicate balstilimab’s potential as an effective new therapy,” O’Day added.

Study results
Among the 140 evaluable patients participating in the study, the objective response rate (ORR) in patients with PD-L1 positive tumors was 20.0% and included 3 patients (3/85, 3.5%) with a complete response and 14 patients (14/85, 16.5%) with a partial response. The median duration of response (DoR) was not reached after a 14.6-month median follow-up. Responses were also observed in the PD-L1 negative population with an ORR of 7.9%.

The confirmed ORR for both PD-L1 positive and negative tumors was 15.0% and included 5 patients (3.6%) with a complete response and 16 patients (11.4%) with a partial response. The median DoR was 15.4 months and the disease control rate was ~50%. Notably, responses were observed across histologies, with responses in the squamous cell histology (ORR 17.6%) and in the more difficult to treat adenocarcinoma histology (ORR 12.5%).

The study results demonstrated that =the safety profile was manageable and consistent with that of currently approved anti-PD-1 antibodies; it also compared favorably to the safety profiles of chemotherapies used in this population. Data from this trial continue to mature.

These data suggest that balstilimab may be a differentiated anti-PD-1 antibody as compared to currently approved PD-1 inhibitors. In the KEYNOTE-158 trial of pembrolizumab, an anti-PD-1 antibody, in the same setting, an ORR of 14.6% was observed in the PD-L1 positive population and no responses were observed in the PD-L1 negative population. In addition, the noted 12.5% response rate of balstilimab in patients with cervical adenocarcinoma is significant as this subpopulation typically does not respond to immunotherapy and represents a growing proportion of advanced cervical cancer cases. Balstilimab thus provides the potential for therapeutic benefit to patient populations that do not typically respond to currently-available immunotherapy, both alone and in combination with other therapies, such as Agenus’ anti-CTLA-4 antibodies zalifrelimab and AGEN1181.

Final results from a Phase 2 trial of balstilimab in combination with zalifrelimab in advanced cervical cancer will be presented in a Mini Oral Session at the European Society for Medical Oncology (ESMO) Congress 2021 on September 19 from 11:35 – 11:40am ET by David O’Malley, MD.

“The efficacy and safety of balstilimab provides additional evidence of the importance of immune checkpoint blockade in the treatment of recurrent, advanced cervical cancer patients,” said David O’Malley, MD, Professor, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine; Director, Division of Gynecologic Oncology, OSUCCC – James; and lead author on the publication.

“Furthermore, responses to balstilimab were seen in patients who were PD-L1 positive, PD-L1-negative, bevacizumab pre-treated, and squamous cell and adenocarcinoma histologies. Balstilimab clearly provides clinical benefit in a broad range of cervical cancer patients,” O’Malley concluded.

Regulatory development
Agenus announced it had submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) on April 19, 2021, for use in patients with recurrent or metastatic cervical cancer, and the application is under priority review with a target action date of December 16, 2021.

Clinical trial
Phase 1 / 2 Study of AGEN2034 in Advanced Tumors and Cervical Cancer – NCT03104699

Highlights of Prescribing Information
Pembrolizumab (Keytruda®; Merck & Co) [Prescribing Information]

[1] O’Malley DM, Oaknin A, Monk BJ, Ortuzar Feliu W, Ancukiewicz M, Ray-Coquard I, et all. Phase II study of the safety and efficacy of the anti-PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer. Published:August 25, 2021 DOI:10.1016/j.ygyno.2021.08.018 [Article]
[2] Cancer stat facts: cervical cancer/ National Cancer Institute – 2020 – NCI website.
[3] Boussios S, Seraj E, Zarkavelis G, Petrakis D, Kollas A, Kafantari A, Assi A, Tatsi K, Pavlidis N, Pentheroudakis G. Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review. Crit Rev Oncol Hematol. 2016 Dec;108:164-174. doi: 10.1016/j.critrevonc.2016.11.006. Epub 2016 Nov 15. PMID: 27931835.

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