The combination of gotistobart (BNT316; ONC-392), a pH-sensitive, CTLA-4–preserving antibody, and pembrolizumab (Keytruda) has shown encouraging antitumor activity in patients with platinum-resistant ovarian cancer. These findings were presented at the 2024 ESMO Congress from the phase 2 PRESERVE-004 trial (NCT5446298).
Efficacy Results
In the trial, patients treated with gotistobart at 1 mg/kg plus pembrolizumab (n = 32) achieved an objective response rate (ORR) of 25.0% (95% CI, 11.5%-43.4%), including a complete response (CR) rate of 3.1% and a partial response (PR) rate of 21.9%. Stable disease was observed in 21.9% of patients, while 40.6% experienced progressive disease. A separate cohort treated with gotistobart at 2 mg/kg plus pembrolizumab (n = 29) showed an ORR of 27.6% (95% CI, 12.7%-47.2%), with a 6.9% CR rate and a 20.7% PR rate. Stable disease occurred in 13.8% of these patients, and 44.8% had progressive disease.
Lead study author Dr. Joyce N. Barlin, from Women’s Cancer Care Associates, noted the preliminary efficacy results as encouraging during her presentation.
Safety Profile
The safety profile of the combination was manageable across both dose levels, with no new safety concerns emerging. In the 1-mg/kg cohort (n = 33), all patients experienced treatment-emergent adverse effects (TEAEs) of any grade, while 96.6% of patients in the 2-mg/kg cohort (n = 29) experienced similar effects. Grade 3 or higher TEAEs were reported in 75.8% and 86.2% of patients in the 1-mg/kg and 2-mg/kg groups, respectively. Serious TEAEs occurred in 54.5% of patients in the 1-mg/kg cohort and 72.4% in the 2-mg/kg cohort. TEAEs led to the discontinuation of gotistobart in 21.2% and 27.6% of patients, respectively.
Trial Design and Patient Characteristics
The PRESERVE-004 trial was a randomized, open-label, multicenter, phase 2 study. It enrolled patients aged 18 years and older with platinum-resistant high-grade serous ovarian cancer who had previously undergone hysterectomy and salpingo-oophorectomy. Participants were required to have received at least one prior systemic platinum-based regimen, exhibit platinum-resistant disease, have measurable lesions per RECIST 1.1 criteria, and possess an ECOG performance status of 0 to 1.
The trial initially randomized patients to receive either 3 mg/kg or 6 mg/kg of gotistobart combined with pembrolizumab at 200 mg every three weeks. However, due to dose reductions, the study continued with patients receiving either 1 mg/kg or 2 mg/kg of gotistobart plus pembrolizumab at 200 mg every three weeks. Treatment continued until confirmed CR, progressive disease, unacceptable toxicity, or a maximum of 35 cycles.
The primary endpoint was ORR per RECIST 1.1 criteria. Secondary endpoints included duration of response, disease control rate, best overall response, progression-free survival, and overall survival. Exploratory endpoints included pharmacokinetics, exposure-response, and treatment-related AE–related study discontinuation.
Patients in the 1-mg/kg cohort had a median age of 65.2 years, while those in the 2-mg/kg cohort had a median age of 63.5 years. The majority of patients in both groups were White (81.8% and 86.2%, respectively), had an ECOG performance status of 0 (57.6% and 51.7%, respectively), and had high-grade serous ovarian cancer (84.8% and 86.2%, respectively). Patients had received a median of 4.0 prior anticancer regimens (range, 2-9) in the 1-mg/kg cohort and 3.0 prior regimens (range, 1-8) in the 2-mg/kg cohort.
Additional Safety Details
TEAEs related to either drug occurred in 81.8% of patients in the 1-mg/kg group and 79.3% of patients in the 2-mg/kg group. Immune-related AEs (irAEs) of any grade were observed in 45.5% of patients in the 1 mg/kg cohort, with 24.2% experiencing grade 3 or higher effects. In the 2-mg/kg cohort, the rate of any-grade irAEs was 62.1%, with 37.9% experiencing grade 3 or higher effects.
Common TEAEs related to either drug (reported in ≥5% of patients) included fatigue, increased aspartate aminotransferase, increased alanine aminotransaminase, diarrhea, nausea, pruritus, colitis, hypothyroidism, maculopapular rash, increased blood alkaline phosphatase, headache, vomiting, adrenal insufficiency, hyperthyroidism, chills, increased blood bilirubin, increased blood creatinine, dizziness, dry mouth, and pyrexia.
