168P - Tumor microenvironment (TME) and PD-L1 expression heterogeneity in high grade serous ovarian cancer (HGSC) samples analysis from the randomized NeoPembrOV/GINECO phase II trial

Background

In the NeoPembrOV phase II trial (NCT03275506) investigating peri-operative Pembrolizumab (P) in treatment naïve ovarian cancer (OC) patients, an exploratory analysis found that PD-L1 expression was not associated with benefit from P. Here, we aim to describe PD-L1 expression pattern and the associated TME between tubo-ovary primary localization (PL) and metastases (M) and assess how that impacts PD-L1 predictive value for response to P.

Methods

PD-L1 expression was assessed for 85 patients (56 on M, 29 on PL) using the tumor proportion score (TPS) and immune cell (IC) score, considering positivity if ≥ 1% (Ventana SP263). RNA sequencing and multiplex immunofluorescence were conducted. The Australian Ovarian Cancer Study (AOCS) served as an external validation cohort.

Results

In M, PD-L1 was primarily expressed on ICs with PD-L1 expression restricted to ICs in 48% of PD-L1 positive M samples compared to 17% of PD-L1 positive PL (P = 0.05). In PL, PD-L1 was primarily expressed by tumor cells (TCs). Only IC score assessed on M was associated with PFS benefit with P compared to chemotherapy alone (HR_interaction = 0.46 CI95% 0.22-0.96 P = 0.04). Compared to PL, M displayed increased density of B cells and an enrichment of gene signature expression for B and T cells including GZMB CD8 cytotoxic T cells (P < 0.05) in the NeoPembrOv and AOCS cohorts. M with IC score ≥ 1 showed greater immune infiltrate and overexpressed additional immune checkpoints such as IDO1, LAG3, ICOS compared to IC score negative samples (P < 0.05). In M, the TPS was associated with immune infiltration and interferon-gamma pathway (P < 0.05). In contrast, PL with TPS ≥ 1% were depleted in activated immune pathways compared to PD-L1 negative samples. In PL, CD274 correlated with mTORC1 signaling in the NeoPembrOV and AOCS cohorts (spearman ρ = 0.435 and ρ = 0.450, respectively).

Conclusions

PD-L1 expression differs across tissue type and is associated with different biological pathways and TME impacting PD-L1 predictive value in OC. PD-L1 expression by TCs in PL might promote tumor proliferation and immune escape. Our results provide novel insights into HGSC biology for tailoring immunotherapy in OC patients.

Editorial acknowledgement

Clinical trial identification

NCT03275506.

Legal entity responsible for the study

The authors.

Funding

ESMO Fellowship Programme.

Disclosure

L. Collet: Financial Interests, Personal, Other, travel support: AstraZeneca, PharmaMar, GSK; Financial Interests, Personal, Invited Speaker: GSK. A. Martinez: Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Other, travel support: GSK, Eisai, MSD. N. Cloarec: Non-Financial Interests, Personal, Principal Investigator, clinical studies: MSD; Non-Financial Interests, Personal, Principal Investigator: AZD, Novartis, Roche, Takeda, BMS; Other, Personal, Other, Medical Meeting: Takeda. F. Selle: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK Tesaro, MSD, AbbVie; Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK Tesaro, MSD, Eisai, Seagen. P. Just: Financial Interests, Personal, Other, Honoraria: GSK. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, Amgen, INC, Merck & Co.; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime Oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Personal, Advisory Board, Stock options: Signatur Biosciences. 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, Immunogen, Seagen, PMV Pharma; 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. O. le Saux: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, honoraria: GSK, MDS, Clovis Oncology. All other authors have declared no conflicts of interest.