Chemotherapy Response Score as a surrogate endpoint for clinical efficacy of neoadjuvant durvalumab and tremelimumab in combination with chemotherapy in newly diagnosed advanced high grade serous ovarian cancer (iPRIME): A randomized, non-comparative phase 2 clinical trial

Technical Summary of the iPRIME Clinical Trial

Problem Statement
Advanced high-grade serous ovarian cancer (HGSOC) remains a leading cause of gynecological cancer mortality, with a 5-year survival rate of only 48% for stage III/IV disease. While standard treatment involves neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), there is a significant unmet need for patients with chemotherapy-resistant disease, particularly those with homologous recombination-proficient tumors. Although immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have shown efficacy in other malignancies, single-agent ICIs combined with frontline chemotherapy failed to improve progression-free survival (PFS) in ovarian cancer. The hypothesis driving this study was that dual checkpoint blockade (targeting both PD-L1 and CTLA-4) combined with chemotherapy could overcome the immunosuppressive tumor microenvironment more effectively than single-agent blockade. However, traditional Phase II trials are often underpowered to detect PFS differences, necessitating the identification of a robust surrogate endpoint for clinical efficacy in the neoadjuvant setting.

Methodology
The iPRIME study was an open-label, randomized, non-comparative, multicenter Phase II clinical trial conducted across 10 Australian sites between June 2018 and July 2021.

• Population: 75 patients with newly diagnosed FIGO stage IIIC or IV HGSOC, fallopian tube, or peritoneal carcinoma were enrolled. Patients were required to have omental disease confirmed by imaging or laparoscopy and be candidates for IDS.
• Intervention: Patients were randomized in a 2:1 ratio to two arms:
  • Arm 1 (Du-T-NACT): Received durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) combined with carboplatin (AUC 5) and paclitaxel (175 mg/m²) every 21 days for three cycles, followed by IDS, then three additional cycles of the same regimen, followed by maintenance durvalumab and tremelimumab.
  • Arm 2 (NACT): Received standard neoadjuvant carboplatin and paclitaxel alone for three cycles, followed by IDS and three post-operative cycles.
• Primary Endpoint: The rate of Chemotherapy Response Score (CRS) 3 (indicating complete or near-complete pathological response with scattered microscopic foci <2mm) in the Du-T-NACT arm among patients evaluable for CRS. A rate exceeding 50% was pre-specified as the threshold for a positive result.
• Secondary Endpoints: Included CRS 3 rates in both arms, radiological response (RECIST 1.1), CA-125 response (GCIG criteria), PFS, residual disease status, and safety/toxicity profiles.
• Statistical Design: The study aimed to recruit 50 patients (43 in the experimental arm) to achieve 80% power to detect a CRS 3 rate >50% against a null hypothesis of 30%.

Key Contributions

• Novel Endpoint Application: This study represents the first Phase II trial in frontline ovarian cancer to utilize CRS 3 as a primary efficacy endpoint. It aimed to validate CRS 3 as a surrogate for long-term clinical outcomes (PFS/OS) in the context of chemo-immunotherapy, similar to the use of pathological complete response in breast cancer trials.
• Dual Blockade in Neoadjuvant Setting: It provided clinical data on the safety and activity of combining dual immune checkpoint inhibition (durvalumab/tremelimumab) with standard neoadjuvant chemotherapy in a randomized setting, addressing the limitations of single-agent trials.
• Safety Profile: The trial characterized the toxicity profile of this specific combination, noting that while immune-related adverse events were increased, they were manageable and did not significantly compromise surgical outcomes or quality of life (QoL).

Results

• Primary Endpoint: The trial did not meet its primary efficacy endpoint. In the Du-T-NACT arm, 40 of 49 patients were evaluable for CRS. The observed CRS 3 rate was 32% (13/40; 90% CI 20–47%), falling short of the pre-specified 50% threshold. Sensitivity analyses (best/worst case) yielded rates between 27% and 44%, none of which met the success criteria.
• Comparative Analysis: In an exploratory comparison, the CRS 3 rate was numerically higher in the Du-T-NACT arm (27% [13/49]) compared to the NACT arm (3.8% [1/26]), with a statistically significant difference (p=0.03). However, the study was not powered for this comparative analysis.
• Secondary Endpoints:
  • Radiological Response: RECIST 1.1 response rates were similar between arms (45% Du-T-NACT vs. 50% NACT; p=0.82).
  • CA-125 Response: Rates were comparable (80% vs. 81%).
  • Progression-Free Survival: Median PFS was identical at 14.7 months for both arms. There was no significant difference in PFS at 12 or 24 months (p=0.64).
  • Surgical Outcomes: Complete cytoreduction (R0) was higher in the Du-T-NACT arm (51% vs. 32%), though this difference was not statistically significant (p=0.26).
• Safety: All patients experienced treatment-related adverse events. Grade 3–4 events occurred in over 50% of patients in both arms. The most common Grade 3–4 events included febrile neutropenia and maculopapular rash. Immune-mediated adverse events (e.g., colitis, hepatitis, hypothyroidism) were observed in the experimental arm but were managed without significant impact on QoL or surgical completion rates.

Significance and Claims
The authors conclude that the combination of durvalumab and tremelimumab with neoadjuvant chemotherapy did not achieve the primary efficacy endpoint of a >50% CRS 3 rate. Consequently, the study does not support the routine adoption of this specific dual-blockade regimen in the frontline setting based on the current data.

However, the paper highlights several significant methodological and clinical insights:

1. Validation of CRS 3: The study successfully demonstrated the feasibility of using CRS 3 as a primary endpoint in a Phase II neoadjuvant ovarian cancer trial, establishing a framework for future studies to use pathological response as a surrogate for clinical efficacy.
2. Signal of Activity: While the primary endpoint was not met, the numerically higher CRS 3 rate in the experimental arm compared to chemotherapy alone suggests a potential pathological response signal that warrants further investigation, particularly given the lack of PFS benefit in single-agent ICI trials.
3. Future Directions: The authors assert that further research is required to assess the role of neoadjuvant dual blockade, specifically to identify biomarkers of response and to determine if longer follow-up or different patient selection (e.g., specific molecular subtypes) might yield different outcomes. They note that the CRS 3 rate observed (32%) was consistent with other recent dual-blockade studies (KGOG 3046, INEOV), suggesting this level of pathological response may be the ceiling for this specific combination in the unselected population.

The study emphasizes that while the specific regimen failed to meet its aggressive primary target, the trial design itself provides a valuable template for evaluating novel chemo-immunotherapy combinations in ovarian cancer.