Dual immune checkpoint inhibition with the anti–PD-L1 antibody durvalumab (Imfinzi) and the investigational anti–CTLA-4 antibody tremelimumab combined with platinum-based chemotherapy showed promising clinical activity and a favorable safety profile in the neoadjuvant setting for patients with advanced ovarian cancer, according to results of a single-arm phase 2 study presented during the 2022 American Association for Cancer Research Annual Meeting.
In KGOG 3046, more than 80% of all 45 patients with stage IIIC/IV adenocarcinoma of the ovary, fallopian tube, or primary peritoneum had at least a partial response to treatment prior to the end of the trial. Moreover, 5 (11.11%) patients had a pathologic complete response, with 4 patients experiencing their pathologic complete response in the first cohort of the trial prior to expansion of the study and changing the dose level of tremelimumab in the second cohort of patients.
Nine patients in the first cohort of the trial also had a chemotherapy response score (CRS) of 3, with a complete or near-complete response in the first part of the trial compared with 5 patients in the expansion cohort. Moreover, only 1 patient had a CRS score of 1 in the initial cohort and 4 achieved that score in the expansion cohort. Thirteen patients had a CRS of 2 in both parts of the study.
“Neoadjuvant chemoimmunotherapy shows promising clinical response without major adverse events in advanced ovarian cancer,” said lead investigator Junsik Park, MD, PhD, Assistant Professor, Translational Research, Yonsei University, Seoul, South Korea, who presented the findings at the meeting.
The study had an original cohort (N = 20) and an expansion cohort (N = 24). Patients in the original cohort received durvalumab 1500 mg every 3 weeks plus tremelimumab 75 mg every 3 weeks plus carboplatin with an area under the curve of 5. The same dose of chemotherapy and durvalumab regimens were used in the expansion cohort, but the dosage of tremelimumab was increased to 300 mg.
After neoadjuvant chemotherapy, all patients underwent interval debulking surgery, followed by 3 cycles of durvalumab 1120 mg and adjuvant chemotherapy followed by durvalumab maintenance therapy of 1120 mg for a total of 12 cycles.
Among the patients enrolled in the study, 91.1% presented with high-grade serous carcinoma and 77.8% with stage IV disease. At baseline, the median patient age was 59 years (range, 34-77 years). Forty patients had an Eastern Cooperative Oncology Group performance score of 0 and 5 had a performance score of 2.
The primary end point of the trial was progression-free survival at 12 months. At the time of the presentation, data were immature. Dr Park stated he was hopeful that the end point would be reached. Key secondary end points included pathologic complete response, safety, and exploratory analyses of predictive biomarkers, and immune dynamic changes.
The initial cohort had a better response to neoadjuvant chemotherapy plus immunotherapy, with an overall response rate of 95.6% compared with 77.27% in the expansion cohort (P = .0477). Dr Park speculated that the difference in overall response rate between the 2 cohorts may have resulted from the different dose levels and sequencing of tremelimumab in each cohort.
Grade 3/4 immune-related adverse events were observed in both cohorts. The most common event was grade 3/4 skin rash (N = 7; 15.56%), but this was manageable with steroids. Other events included increased alanine aminotransferase (N = 3) and grade 3/4 urticaria (N = 3; 6.67%). Safety analysis is ongoing.
In total, 39 patients had an adverse drug reaction, and 28 patients had non–drug-related adverse events. Serious adverse events occurred in 26 patients.
During treatment, serial biopsies were performed to explore immunologic changes in the tumor microenvironment. According to this exploratory analysis, CCR8-positive regulatory T-cells appear to hold promise as a predictive marker of response, but Dr Park noted that further investigation is needed.