Botensilimab (AGEN1181) in combination with balstilimab (AGEN2034) induced durable responses in patients with platinum-resistant or -refractory ovarian cancer, in the ongoing phase Ib C-800 study presented at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer by Bruno Bockorny, MD, Assistant Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center.1
In 24 patients with platinum-resistant or -refractory ovarian cancer, the novel doublet elicited an overall response rate of 33%, which included one (4%) complete response. With eight patients achieving stable disease, the disease control rate was 67%. At a median follow-up of 6.9 months, the responses appeared durable, with a median duration of response not reached at the time of analysis, Dr. Bockorny reported, noting that some patients had “very prolonged clinical benefit.”
Bruno Bockorny, MD
Patients with ovarian cancer are part of a much larger evaluation of botensilimab with or without balstilimab in a variety of solid cancers. Botensilimab is an Fc-engineered recombinant human immunoglobulin G1 monoclonal anti–CTLA-4 antibody, and balstilimab is a PD-1 antibody.
Compared with first-generation anti–CTLA-4 agents, botensilimab is multifunctional, “with enhanced T-cell priming, memory formation, and Treg depletion,” Dr. Bockorny said. Its activating Fc engineering lends it greater ability to bind to activating Fc gamma receptors on antigen-presenting and natural killer cells. Botensilimab has shown activity in “cold” and immunotherapy-refractory tumors.
“The novelty here, with botensilimab, as compared with the first-generation anti–CTLA-4 agents…is that it is a multifunctional CTLA-4 agent. In addition to binding the CTLA-4, botensilimab also has point mutations in the Fc region; that’s the back end of the molecule that increases the binding to some receptors in the antigen-presenting cells and natural killer cells,” Dr. Bockorny explained. “These receptors are called activating Fc gamma receptors, but by engaging other immune cells, the drug tightens the immune synapse and triggers better immune responses, which we don’t have with other first-generation CTLA-4 agents.”
About the Study
Patients with platinum-resistant or -refractory, metastatic disease received botensilimab at 1 or 2 mg/kg every 6 weeks plus balstilimab at 3 mg/kg every 2 weeks. Patients were allowed to have received prior immunotherapy, and crossover from prior botensilimab monotherapy was allowed.
This was a very heavily pretreated cohort; patients had received a median of four prior regimens. A total of 19 patients (79%) received prior bevacizumab, and 5 (21%) received prior immunotherapy. Most patients had biomarkers associated with a poor response to immunotherapy: 90% had a low tumor mutational burden, and more than half were PD-L1–negative by immunohistochemistry.
The doublet had a manageable toxicity profile, according to Dr. Bockorny, although 41% of patients experienced a grade 3 or 4 treatment-related adverse event; for 21%, this was grade 3 immune-mediated diarrhea or colitis (21%). There were no cases of pneumonitis, hypophysitis, or myocarditis of any grade and no treatment-related deaths. This is consistent with the larger data sets of botensilimab and balstilimab, where high-grade visceral toxicity outside of the gastrointestinal has been uncommon, he said.
“The combination of botensilimab and balstilimab in platinum-resistant ovarian cancer shows promise for a substantial improvement in efficacy compared to existing therapies, which typically yield single-digit response rates,” Dr. Bockorny commented. “The remarkable efficacy and manageable tolerability profile of this combination suggest a transformative potential for patients with ovarian cancer.”
Paul DiSilvestro, MD
During the discussion, Paul DiSilvestro, MD, asked whether the occurrence of grade 3 colitis was associated with improved outcomes, to which Dr. Bockorny responded: “That’s a great question. In a larger data set of botensilimab/balstilimab, with 300-plus patients treated, we are seeing some correlation between immune-mediated adverse events like colitis, skin toxicity, and endocrinopathies and better response. I think that’s generally a trend we are seeing with other checkpoint inhibitors.” Dr. DiSilvestro is Director of the Program in Women’s Oncology for Women & Infants Hospital of Rhode Island and Care New England Health System and Division Director for Gynecologic Oncology at The Warren Alpert Medical School of Brown University.
Following up with The ASCO Post, Dr. DiSilvestro said there is interest in exploring combinations of anti–CTLA-4 and anti–PD-1/L1 agents in ovarian cancer. “We’ve seen some promise but unfortunately also some toxicity. Here, there was a 21% rate of grade 3 colitis, but those patients may have responded very well. We’re trying to balance the benefits of therapy relative to toxicity.”
DISCLOSURE: Dr. Bockorny has served as a consultant to Blueprint Medicines and BiolineRx; and has received research funding from Agenus and NanoView Biosciences. Dr. DiSilvestro has served as a consultant to AstraZeneca, GSK/Tesaro, and Immunogen.
1. Bockorny B, Matulonis UA, O’Day SJ: Botensilimab, a novel innate/adaptive immune activator, plus balstilimab (anti–PD-1) in patients with recurrent platinum refractory/resistant ovarian cancer (NCT03860272). Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 27, 2023.