Data from the phase 2 KGOG 3046 trial revealed evidence of antitumor activity with the neoadjuvant chemoimmunotherapy regimen containing durvalumab and tremelimumab for patients with advanced-stage ovarian cancer.
Initial data from the phase 2 KGOG 3046 trial (NCT03899610) that were presented at the American Association for Cancer Research (AACR) 2022 Annual Meeting demonstrated early promise of dual immune checkpoint inhibitors durvalumab (Imfinzi) and tremelimumab in combination with chemotherapy as neoadjuvant therapy for patients with advanced-stage ovarian cancer.
Results from the single-arm study presented at the AACR meeting showed that more than 80% of all patients (n = 45) at least had a partial response (PR) to treatment prior to the end of the trial. Moreover, a total of 5 patients (11.11%) had a pathologic complete response (pCR) with 4 patients experiencing their pCR 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 cohort of the trial compared with 5 patients in the expansion arm. Moreover, just 1 patient had a CRS score of 1 in the first cohort and 4 were given that score in the expansion cohort, however, 13 patients were given a CRS score of 2 in both arms of the study.
Patients included in the trial were a median of 59-years-old (34-77) with 20 patients in the original cohort, and 21 in the expansion cohort, having a high-grade serous tumor. Forty patients in total had an ECOG performance score of 0 with 5 patients having a score of 5.
Twenty-three patients with stage IIIC/IV adenocarcinoma of the ovary, fallopian tube, or primary peritoneum were assigned to the original cohort of 1500 mg of durvalumab given every 3 weeks plus 75 mg of tremelimumab and 3 cycles of paclitaxel at 175 mg/m2 plus carboplatin with an area under the curve of 5. In the expansion cohort, 22 patients were given 1500 mg of daratumumab plus 1 dose of tremelimumab at 300 mg then given the same amount of chemotherapy.
After neoadjuvant chemotherapy, all patients underwent interval debulking surgery, after which, 3 cycles of durvalumab were administered at 1120 mg. Further adjuvant chemotherapy was followed by durvalumab maintenance therapy of 1120 mg for a total of 12 cycles.
The primary end point of the trial is to see how many patients are progression free for 12 months. Data are still immature but researchers are confident they will reach the primary end point in June of this year, according to Junsik Park, MD, PhD. Additional objective of the study are the pCR rate, safety, and exploratory analyses of predictive biomarkers and immune dynamic changes.
Currently, Park highlighted that although the overall immunologic characteristics of pre-treatment tumors was similar between the 2 cohorts, it was the initial cohort that showed a better response to neoadjuvant chemotherapy plus immunotherapy treatment with an overall response rate (ORR) of 95.6% compared with 77.27% in the expansion cohort (P = .0477). Park, translational research assistant professor at the Yonsei University in Korea, explained that the difference seen in ORR between the 2 cohorts may have resulted from the different dose levels and sequencing of tremelimumab in each cohort.
“After neoadjuvant chemoimmunotherapy, the T-cell inflamed (gene expression profile) score was increased in both cohorts,” he said, when discussing further evidence for the clinical response to the combination treatment. A significant amount of CD39-positive CD8 tumor-infiltrating lymphocytes (TILs) decreased after neoadjuvant chemotherapy, in both cohorts. “Ovarian TILs were decreased after neoadjuvant chemotherapy; however, PD-1 or (CCR8-positive regulatory T cells [Tregs]) only decreased in the original cohort. These data show those kinds of channeling may affect the tumor microenvironment.”
Grade 3-4 immune-related AEs were observed in both cohorts with skin rash being the most common with 7 patients experiencing it (15.56%; 95% CI, 6.49%-29.46%); however, this was considered manageable during treatment. An increase in aspartate aminotransferase levels was observed in 3 patients (6.67%; 95% CI, 1.40%-18.27%) and 3 patients experienced grade 3-4 utricaria (6.67%; 95% CI, 1.40%-18.27%). Safety analysis is still ongoing in the trial. In total, 39 patients experienced an adverse drug reaction, and 28 patients AEs were non-drug related, moreover, serious AEs occurred in 26 patients across both cohorts. Adverse drug reactions were occurred frequently in the original cohort with 23 patients compared to 16 patients in the expansion cohort.
According to Park, further validation is needed for the use of CCR8-positive Tregs as predictive biomarker of response to neoadjuvant chemoimmunotherapy, but current results show promise for the continued use of this therapy. CRS results were inversely correlated to the percentage of exhausted CD39+CD8 TILs, but researchers found no significant difference between TILs and PD-L1 status. The number of suppressive Treg cells was also lower in patients with CRS 3, Park said, indicating an inverse correlation.
“Neoadjuvant chemoimmunotherapy shows promising clinical response without major AEs in advanced ovarian cancer,” he concluded. “Immunologic status or pretreatment tumor effected response to neoadjuvant chemotherapy, and those in sequence of tremelimumab effect on the tumor cells and patient's response.”
Park J, Park E, Joung Je-Gun, et al. A phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer (KGOG 3046/ TRU-D). Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; Virtual. Accessed April 12, 2022. https://bit.ly/3KExhvZ