Neoadjuvant Chemoimmunotherapy Combination Is Active and Tolerable in Ovarian Cancer

The addition of durvalumab (Imfinzi) and tremelimumab (Imjudo) to chemotherapy in the neoadjuvant setting produced responses with a manageable safety profile in patients with advanced-stage ovarian cancer, according to Jung-Yun Lee, MD, PhD.

The phase 2 KGOG3046/TRU-D trial (NCT03899610) evaluated the combination of durvalumab and tremelimumab added to neoadjuvant carboplatin and paclitaxel in patients with advanced-stage ovarian cancer. Findings from the final primary analysis of this trial, which were presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, showed that at a median follow-up of 29.2 months, the 12-month progression-free survival (PFS) rate was 63.6% (P = .093), and the median PFS was 17.5 months.¹

“The TRU-D study is the first study reporting survival outcomes with dual immune checkpoint blockade in patients with newly diagnosed advanced ovarian cancer,” Lee said in an interview with OncLive^®.

Previously, the phase 3 JAVELIN Ovarian 100 trial (NCT02718417) missed its primary end point of PFS with avelumab (Bavencio) plus chemotherapy in patients with previously untreated epithelial ovarian cancer. Findings from this trial showed a median PFS of 11.1 months (95% CI, 7.0-15.3) in patients who received chemotherapy followed by avelumab maintenance therapy, 11.0 months (95% CI, 7.4-14.5) in those who received avelumab plus chemotherapy followed by avelumab maintenance therapy, and 10.2 months (95% CI, 6.7-14.0) in those who received chemotherapy followed by observation.²

The phase 3 IMagyn050 trial (NCT03038100) also failed to meet its co-primary end points of PFS and overall survival (OS). In this trial, the median PFS was 19.5 months (95% CI, 18.1-20.8) in patients with newly diagnosed, untreated stage III or IV ovarian cancer who received atezolizumab (Tecentriq) plus chemotherapy and bevacizumab (Avastin), and 18.4 months (95% CI, 17.2-19.8) in those who received placebo plus chemotherapy and bevacizumab (HR, 0.92; 95% CI, 0.79-1.07; stratified log-rank P = .28). The 2-year OS rates were 81% (95% CI, 77%-84%) in the atezolizumab arm and 79% (95% CI, 75%-83%) in the placebo arm.³

In the interview, Lee discussed the TRU-D trial within the context of these prior negative trials to emphasize the need for more effective therapies in the advanced-stage ovarian cancer population, highlighted key findings from TRU-D, and elaborated on future steps for this research.

Lee is from the Department of Obstetrics and Gynecology at Yonsei University College of Medicine in Seoul, South Korea.

OncLive: Please describe the rationale and design of the TRU-D study.

Lee: TRU-D is a Korean single-arm study investigating the addition of durvalumab and tremelimumab to paclitaxel and carboplatin as frontline neoadjuvant treatment in advanced-stage ovarian cancer. So far, immune checkpoint inhibitor blockade [added] to chemotherapy has been tried in several trials. However, the JAVELIN Ovarian 100 and IMagyn050 trials did not meet their primary end points. For this study, we hypothesized that the addition of durvalumab and tremelimumab to neoadjuvant chemotherapy could increase the efficacy [of the chemotherapy] with minimal effects on safety in [patients with] advanced-stage ovarian cancer.

What patient population was enrolled in TRU-D?

The study population [included patients with] stages IIIC to IV epithelial ovarian cancer of all histologic subtypes except mucinous disease. [These patients were deemed ineligible] for primary debulking surgery by their gynecologic oncologists. This population has a huge unmet need because [although these patients] have initially responded to platinum-based chemotherapy, most of them, more than 80%, ultimately have disease recurrence.

What key efficacy data with durvalumab, tremelimumab, and chemotherapy were reported in this trial?

The primary end point was the 12-month PFS rate, which was 63.6%. In addition, the 24-month PFS rate was 45%, and the 30-month PFS rate was 40%. These were remarkable outcomes without bevacizumab or PARP inhibitors. The PFS curve [had a] long tail, [indicating that] some patients had durable responses with this study regimen.

Interestingly, 4 patients, or 17.4% of the 23 patients [enrolled in the study], had a pathologic complete response [pCR] after 3 cycles of neoadjuvant chemoimmunotherapy. This is an interesting finding because usually pCR is [achieved in] less than 5% [of patients who receive] conventional neoadjuvant chemotherapy.

What is the safety profile of this combination?

The most common treatment-related adverse effect [AE] was rash, and 3 patients had grade 3/4 rash. There was also a delay in interval debulking surgery in 2 patients because of grade 4 pneumonitis and [grade 4] skin rash, respectively. However, most of the AEs were resolved with systemic steroids.

What next steps are needed to further expand on the findings from TRU-D?

We need randomized studies to confirm the promising [activity of the] combination of neoadjuvant chemotherapy plus durvalumab plus tremelimumab in patients with newly diagnosed advanced ovarian cancer.

Optimal regimens of neoadjuvant chemotherapy plus immunotherapy are [being] actively explored in ovarian cancer. In expansion cohorts from TRU-D, [we evaluated the efficacy of] a single, high priming dose of tremelimumab. Survival follow-up [in this cohort] is ongoing.

What else were you excited to see at the 2023 SGO Annual Meeting on Women’s Cancer?

I was looking forward to seeing the results with immunotherapy in endometrial cancer from the [phase 3] RUBY [NCT03981796] and NRG GY018 trials [NCT03914612]. [However, there have not been] many immunotherapy studies in ovarian cancer, so we are waiting for other ovarian cancer immunotherapy studies.

Disclosure: Dr Lee reports advisory board positions, lecture positions, and/or reimbursements from AstraZeneca, Janssen, Eisai, Merck, MSD, Roche, and TAKEDA; and institutional financial interests with Ascendis Pharma, AstraZeneca, Beigene, BerGenBio, Cellid, Clovis Oncology, Eisai, GII, Immunogen, Janssen, Merck, Mersana, MSD, Novartis, OncoQuest, ONO, Roche, Seagen, Synthon, and TAKEDA.

References

1. Lee JY, Park J, Lim MC, et al. Final primary analysis in the original cohort of KGOG3046/TRU-D: a phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28; Tampa, Florida.
2. Monk BJ, Colombo N, Oza AM, et al. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(9):1275-1289. doi:10.1016/S1470-2045(21)00342-9
3. Moore KN, Bookman M, Sehouli J, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol. 2021;39(17):1842-1855. doi:10.1200/JCO.21.00306