Gotistobart Plus Pembrolizumab Shows Activity in Platinum-Resistant Ovarian Cancer

Treatment with the combination of the pH-sensitive, CTLA-4–preserving antibody gotistobart (BNT316; ONC-392) and pembrolizumab (Keytruda) led to antitumor activity with a manageable safety profile in patients with platinum-resistant ovarian cancer, according to data from the phase 2 PRESERVE-004 trial (NCT5446298) presented at the 2024 ESMO Congress.

Findings showed that evaluable patients treated with gotistobart at 1 mg/kg plus pembrolizumab (n = 32) experienced 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%. The rates of stable disease and progressive disease were 21.9% and 40.6%, respectively, and 12.5% of patients did not undergo a post-baseline assessment. In those treated with gotistobart at 2 mg/kg plus pembrolizumab (n = 29), the ORR was 27.6% (95% CI, 12.7%-47.2%) with 6.9% CR rate, a 20.7% PR rate, a 13.8% stable disease rate, and a 44.8% progressive disease rate; 13.8% of patients did not undergo a post-baseline assessment.

The safety profile was manageable at both dose levels, and no new safety signals were identified with the combination. All of patients in the 1-mg/kg cohort (n = 33) and 96.6% in the 2-mg/kg cohort (n = 29) experienced any-grade treatment-emergent adverse effects (TEAEs). Grade 3 or higher TEAEs occurred in 75.8% and 86.2% of patients in the 1-mg/kg and 2-mg/kg groups, respectively. Serious TEAEs were reported in 54.5% of patients in the 1-mg/kg cohort and 72.4% of those in the 2-mg/kg cohort. TEAEs led to the discontinuation of gotistobart in 21.2% and 27.6% of patients, respectively.

“Preliminary results for efficacy are encouraging,” lead study author Joyce N. Barlin, MD, of Women’s Cancer Care Associates in Albany, New York, said during a presentation of the data.

Study Design

PRESERVE-004 was a randomized, open-label, multicenter, phase 2 trial investigating the combination of gotistobart and pembrolizumab in patients at least 18 years of age with platinum-resistant high-grade serous ovarian cancer who underwent prior hysterectomy and salpingo-oophorectomy. At least 1 prior systemic platinum-based regimen was required, and patients needed to have platinum-resistant disease, have measurable lesions per RECIST 1.1 criteria, and have an ECOG performance status of 0 to 1.

Initially, 21 patients were randomly assigned 1:1 to receive either 3 mg/kg or 6 mg/kg of gotistobart combined with pembrolizumab at 200 mg once every 3 weeks. However, dose reductions were recommended after the launch of the study. The adjusted trial continued with 62 patients who were randomly assigned 1:1 to receive either 1 mg/kg or 2 mg/kg of gotistobart plus pembrolizumab at 200 mg administered once every 3 weeks. Patients continued treatment until confirmed CR, progressive disease, unacceptable toxicity, or a maximum of 35 cycles.

The primary end point of the study was the ORR per RECIST 1.1 criteria. Secondary end points included duration of response, disease control rate, best overall response, progression-free survival, and overall survival. Exploratory endpoints focused on pharmacokinetics, exposure-response, and treatment-related AE–related study discontinuation.

Baseline Characteristics

Patients enrolled in the 1-mg/kg cohort had a median age of 65.2 years (range, ±10.25), and those in the 2-mg/kg cohort had a median age of 63.5 years (range, ±8.46). The majority of participants in both groups were White (1-mg/kg cohort, 81.8%; 2-mg/kg cohort, 86.2%), had an ECOG performance status of 0 (57.6%; 51.7%), and had high-grade serous ovarian cancer (84.8%; 86.2%). 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.

The mean treatment duration for gotistobart was similar between the cohorts at 3.03 months (standard deviation [SD], 2.43) in the 1-mg/kg group and 3.18 months (SD, 2.45) in the 2-mg/kg group. Additionally, the median number of cycles of gotistobart received was 3.0 (range, 1-12) in both cohorts. The dose intensities were 98.4% (range, 56.6%-106.9%) and 98.4% (range, 56.7%-105.1%) for the 1-mg/kg and 2-mg/kg groups, respectively.

Additional Safety Data

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% of patients, with 37.9% experiencing grade 3 or higher effects.

The most common TEAEs related to either drug reported in 5% or more of patients among the total population of both groups included fatigue (grade 1/2, 30.6%; grade 3, 3.2%), increased aspartate aminotransferase (17.7%; 6.5%), increased alanine aminotransaminase (14.5%; 6.5%), diarrhea (12.9%; 6.5%), nausea (16.1%; 1.6%), pruritus (14.5%; 1.6%), colitis (8.1%; 6.5%), hypothyroidism (14.5%; 0%), maculopapular rash (12.9%; 1.6%), increased blood alkaline phosphatase (12.9%; 0%), headache (11.3%; 0%), vomiting (11.3%; 0%), adrenal insufficiency (3.2%; 6.5%), hyperthyroidism (9.7%); 0%), chills (8.1%; 0%), increased blood bilirubin (6.5%; 0%), increased blood creatinine (6.5%; 0%), dizziness (4.8%; 1.6%), dry mouth (6.5%; 0%), and pyrexia (6.5%; 0%).

Reference

Barlin NJ, Lim PC, Pepin JT, et al. A randomized, phase II, dose optimization of gotistobart, a pH-sensitive anti-CTLA-4, in combination with standard dose pembrolizumab in platinum-resistant recurrent ovarian cancer: Safety, efficacy and dose optimization (PRESERVE-004/GOG-3081). Ann Oncol; 2024;35(suppl 2):s1224-s1225. doi:10.1016/j.annonc.2024.08.2271