180P - Immunogenomic profiling of the randomized NeoPembrOv clinical trial reveals the VEGFR2 angiogenic axis as a promising actionable target to overcome immunoresistance of high-grade ovarian carcinomas

Background

Immune checkpoint inhibitors (ICI) have shown limited efficacy in high-grade serous carcinomas (HGSC). The NeoPembrOv randomized phase II trial investigated the combination of Pembrolizumab (P) with NeoAdjuvant ChemoTherapy (NACT), providing an opportunity to identify resistance mechanisms.

Methods

Patients (n=91) were randomized 2:1 to NACT+P or NACT. Paired samples were analyzed using RNA-seq (n=53) and multiplexed immunofluorescence staining (n=64) for CD8, PD-1, ActCasp3, panCK, CD31, and VEGFR2. Immune and endothelial signatures were assessed using MCP-counter and quanTIseq algorithms. Cell densities and nearest neighbors were determined based on InForm software output. We investigated the impact of NACT±P on the tumor microenvironment and identified parameters associated with survival. As no transcriptomic dataset of HGSC patients under ICI was available, we used an external validation cohort of 102 head and neck cancer patients.

Results

Analysis of DEG revealed a significant enrichment of T cell activation/differentiation pathways in the NACT+P arm only after treatment. We showed a significant increase in CD8⁺PD-1⁺ T cells density in tumor islets in the NACT+P arm compared to NACT (p=0.015). This increase observed in 15% of cases (n=6/41) was associated with improved overall survival (OS) (LR test, p=0.01).The median distance between apoptotic tumor and the nearest CD8⁺PD-1⁺ cell significantly decreased after NACT+P. Univariate cox models revealed a negative association between the MCP-counter endothelial cell signature and survival (HR=1.97, 95% CI [1.10-3.49], p=0.02) in the NACT+P arm, with a significant interaction with treatment arm (p=0.046). In situ analysis confirmed the negative predictive impact of high expression of VEGFR2 on CD31+ endothelial cells in patients receiving NACT+P, significantly affecting OS (p=0.005). KDR expression (VEGFR2) was validated as a predictive biomarker in an external cohort for OS (p=0.044).

Conclusions

Only a subset of HGSC patients can benefit from ICI. Targeting VEGFR2+ endothelial cells may overcome resistance. Clinical trials using VEGFR2 inhibitors are warranted.

Clinical trial identification

NCT03275506.

Legal entity responsible for the study

Arcagy-Gineco.

Funding

ARC Foundation.

Disclosure

O. Le Saux: Financial Interests, Personal, Advisory Board: Novartis, MSD, GSK; Financial Interests, Personal, Invited Speaker: Lilly, AstraZeneca, Clovis; Financial Interests, Institutional, Trial Chair: Novartis, Hospira-Pfizer foundation, Astellas. E. Coquan: Financial Interests, Personal, Advisory Board: Sanofi, MSD, BMS, Ipsen, AstraZeneca. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: Gineco. All other authors have declared no conflicts of interest.