Patients whose ovarian cancer no longer responds to platinum-based therapy have limited treatment options and poor prognoses, emphasizing the need for alternative therapeutic approaches. This phase 1b investigation examined the tolerability and antitumor activity of botensilimab (BOT), an Fc-modified monoclonal antibody targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), administered with the programmed cell death protein 1 (PD-1) inhibitor balstilimab (BAL), in an expanded population of individuals with advanced, treatment-refractory ovarian malignancies. Eligible patients received intravenous BOT at either 1 mg/kg or 2 mg/kg every six weeks in combination with intravenous BAL at a dose of 3 mg/kg every two weeks, with treatment continuing for up to two years. Safety and tolerability constituted the primary study endpoints. Measures of antitumor efficacy included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS), evaluated using RECIST version 1.1 criteria. Overall survival (OS) was assessed exploratorily. Forty-four patients were included in the safety analysis, having received a median of three prior systemic regimens, with a median observation period of 9.6 months (range, 0.6–36.6 months). Thirty-five patients were evaluable for response. Gastrointestinal immune-related toxicity, particularly diarrhea or colitis, was the most frequently reported treatment-related adverse event, occurring in 43% of patients; grade 3 events were observed in 16%, and no deaths attributable to study therapy were reported. Confirmed radiographic responses were observed in 23% of evaluable patients (8 of 35; 95% CI, 10%–40%), comprising one complete remission and seven partial tumor regressions. Sustained disease control lasting at least 24 weeks, including responses and prolonged stable disease, was achieved in 31% of patients (95% CI, 17%–49%). The median DOR was 9.7 months, while median PFS was 2.8 months. Median OS reached 14.8 months, with an estimated 75% of patients alive at 12 months. Correlative immune analyses revealed that therapeutic benefit was associated with increased frequencies of FcγRIIIA⁺CD11c⁺ immune cells, elevated tumor PD-L1 expression, and the presence of pre-existing T-cell–inflamed tumor microenvironments. Distinct immune patterns were also noted among different histopathologic subtypes. Dual checkpoint inhibition with the Fc-engineered CTLA-4 antibody botensilimab and PD-1 blockade via balstilimab produced meaningful and durable clinical activity in a heavily pretreated ovarian cancer population lacking effective standard treatments. Traditional RECIST criteria underestimated the overall therapeutic impact, as a subset of patients experienced prolonged disease stabilization with clinical relevance. Adverse events were generally manageable and reversible. These findings, together with the observed immune biomarker associations, support continued clinical evaluation of this combination regimen.
