Durvalumab plus tremelimumab in combination with neoadjuvant chemotherapy did not yield any major adverse effects in patients with newly diagnosed advanced ovarian cancer in the phase 2 KGOG3046 trial.
Treatment with durvalumab (Imfinzi) plus tremelimumab (Imjudo) and neoadjuvant chemotherapy met the primary end point of progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer, according to findings from the final primary analysis of the phase 2 KGOG3046 study (NCT03899610) presented at The Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer.
The study met its primary end point of PFS at 12 months of 63.6% (P = .021) and showed durable responses at a follow-up of 30 months.
While other studies are exploring neoadjuvant chemotherapy in combination with immunotherapies for patients with advanced-stage ovarian cancer, this is the first of its kind to demonstrate survival outcomes with dual checkpoint blockades for this patient population.
“The primary end point was met and showed durable responses. Optimal regimens of neoadjuvant chemoimmunotherapy are actively being explored in ovarian cancer. We added an expansion cohort with a single high priming dose of [tremelimumab] and survival follow-up is ongoing,” said Jung-Yun Lee, MD, PhD, professor, department of obstetrics and gynecology at Yonsei University College of Medicine in a presentation of the findings.
Previously, several studies, including JAVELIN 100 (NCT02603432) and IMagyn 050 (NCT03038100) have studied the addition of immune checkpoint blockades to immunotherapies as a first-line treatment for ovarian cancer.
Currently, 3 ongoing studies with neoadjuvant chemotherapy plus immune checkpoint inhibitors for patients with ovarian cancer are ongoing, including TRU-D (NCT03899610), INeOV (NCT03249142), and iPRIME (NCT03360890).
KGOG3046 is a single-arm phase 2 study evaluating the use of neoadjuvant chemotherapy plus durvalumab and tremelimumab for the treatment of patients with advanced-stage ovarian cancer. The study, which is taking place in Korea, is assessing the progression-free survival and safety effects of the addition of durvalumab and tremelimumab to chemotherapy.
In the KGOG3046 trial, serial biopsies were performed on pre-treatment, at interval debulking surgery and progression to identify immune biomarkers and changes in the tumor microenvironment. Those enrolled in the trial had newly diagnosed, histologically confirmed, stage IIIC/IV epithelial ovarian cancer and an ECOG performance status of 0 or 1.
In the final analysis reported at SGO, patients had a median age of 60 years (range, 44-77), 20 patients had a high-grade serous tumor, 1 had a clear cell, 1 had carcinosarcoma, and 1 had another type. Three patients (13.0%) were clinical FIGO stage IIIC at presentation and 20 were stage IV (87.0%). A total of 15 patients (65.2%) had non-mutated disease, while 2 (30.4%) had BRCA1/2 mutations, and 1 (4.3%) patient’s disease was unknown.
Patients were administered 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. The expansion cohort consisted of 22 patients who were given 1500 mg of daratumumab plus 1 dose of tremelimumab at 300 mg then given the same amount of chemotherapy.
All patients underwent interval debulking surgery following neoadjuvant chemotherapy, after which, 3 cycles of durvalumab were administered at 1120 mg. Additional adjuvant chemotherapy was followed by durvalumab maintenance therapy of 1120 mg for a total of 12 cycles.
Investigators evaluated the primary end point of PFS for 12 months, and additional end points of overall survival, duration of response, pathologic complete response (pCR) rate, safety measures, exploratory analyses of predictive biomarkers, and immune dynamic changes.
Findings revealed that the objective response rate (ORR) was 95.7% with 3 patients having a complete response (13%), 19 having a partial response (PR; 82.6%), and 1 patient having stable disease (4.3%). A total of 17 patients (73.9%) had a tumor classified as R0, vs 5 (21.7%) that had R1, and 1 (4.3%) that was R2. Nine (39.1%) patients had a chemotherapy response score (CRS) of 3, vs 13 (56.5%) with a score of 2, and 1 (4.3%) with a score of 1. Among the 23 patients enrolled, 4 (17.4%) had pCR with up to 3 cycles of neoadjuvant chemotherapy vs 19 (82.6%) who did not.
In addition to the 12-month PFS rate of 63.6% (P = .021), the 24 months PFS rate was 45% and the PFS rate at 30 months was 40% (P = .093). Further, the most common TRAEs were rash (69.6%), 2 patients delayed IDS due to grade 4 skin rash and pneumonitis, respectively. However, all TRAEs were completely resolved after use of steroids.
“KGOG3046 is the first to study reporting survival outcomes with dual immune checkpoint blockades in newly diagnosed advanced-stage ovarian cancer,” added Lee.
Initial results from the single-arm study were previously announced at the 2022 American Association for Cancer Research Annual Meeting and showed that more than 80% of patients had a PR to treatment prior to the end of the trial. Five patients (11.11%) had a pCR, and 4 patients had their pCR in the first cohort of the trial, prior to the expansion phase of the study and changing the dose-level of tremelimumab in the second cohort of patients.
In the first cohort, 9 patients had a CRS of 3, complete, or near complete response, compared with 5 patients in the expansion arm. One patient had a CRS score of 1 in the first cohort and 4 had that score in the expansion cohort. In both arms, 13 patients were given a CRS score of 2.
While the overall immunologic characteristics of pre-treatment tumors was similar between both cohorts, a better response to neoadjuvant chemotherapy plus immunotherapy treatment was shown in the initial cohort with an ORR of 95.6% compared with 77.27% in the expansion cohort (P = .0477). Researchers noted that the difference between ORRs could be from the different dose levels and sequencing of tremelimumab in each cohort.
Looking at safety, grade 3-4 immune-related AEs were seen in both cohorts. While skin rash was the most common AE with 7 patients experiencing it (15.56%; 95% CI, 6.49%-29.46%), it was considered manageable during treatment. Three patients had an increase in aspartate aminotransferase levels (6.67%; 95% CI, 1.40%-18.27%) and 3 patients had grade 3-4 urticaria (6.67%; 95% CI, 1.40%-18.27%). A total of 39 patients had an adverse drug reaction, 28 AEs were non-drug related, and serious AEs were reported in 26 patients across both cohorts. In the original cohort, 23 patients had adverse drug reactions vs 16 patients in the expansion cohort.
“Randomized studies are needed to confirm the promising combination of neoadjuvant chemotherapy plus [durvalumab plus tremelimumab] in patients with newly diagnosed advanced ovarian cancer,” concluded Lee.
Lee JY, Kim JW, Lim MC, et al. Final primary analysis in the original cohort of KGOG3046/TRU-D: a phase 2 study of durvalumab and tremelimumab with frontline neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer. Annual Meeting on Women’s Cancer; March 25-28; Tampa, Florida.