KEY TAKEAWAYS
- The NEOPEMBROV, phase 2 trial, aimed to investigate the impact of sample site heterogeneity on biomarker evaluation for IT response in HGSC.
- Researchers noticed that CPS ≥ 1, not in primary tumors, was associated with pembrolizumab benefit in HGSC.
Biomarkers guiding immunotherapy (IT) response in high-grade serous ovarian cancer (HGSC) remain elusive, as PD-L1 expression failed to predict outcomes in the NeoPembrOv trial, a randomized study comparing peri-operative chemotherapy with or without pembrolizumab.
Recognizing this limitation, Laetitia Collet and her team aimed to address this gap in understanding. Their study, conducted within the NeoPembrOv trial framework, delved into the intricacies of tumor microenvironment heterogeneity between primary tumors and metastases in HGSC.
They performed an inclusive analysis, obtaining biopsies from intra-abdominal metastases (M) and primary tubo-ovaries (TO) before initiating any treatment. PD-L1 expression (Ventana SP263) (N = 85), multiplex immunofluorescence (mIF) (N = 64), and RNAseq data (N = 57) were assessed. Differentially expressed genes (DEG) and gene set enrichment analysis (GSEA) were derived through DESeq2. Survival analysis was conducted using Cox models.
No major differences in immune infiltration were observed between primary TO and intra-abdominal metastases (M) samples, as indicated by mIF data. Notably, TO samples exhibited enrichment in tumor cells and a higher prevalence of TPS ≥ 1 samples.
In metastatic samples (M), CPS ≥ 1 emerged as a predictor of improved progression-free survival (PFS) in the pembrolizumab arm compared to chemotherapy alone (HR interaction = 0.26, CI 95% 0.07-0.93, P = 0.034). Conversely, no significant benefits were observed with TPS and IC, and no discernible impact was noted in primary TO.
Intra-tumoral CD8 T cell (iCD8) density demonstrated an elevation in the IC, TPS, and CPS ≥ 1 subgroups, correlating with PD-L1 expression specifically in M samples but not in TO. Higher iCD8 T cell density (P = 0.03) and enrichment of immune hallmarks (Interferon alpha and gamma, allograft rejection, inflammatory response, P < 0.05) were evident in CPS ≥ 1 M vs CPS ≥ 1 TO. Conversely, CPS ≥ 1 TO samples were enriched in proliferative pathways (MYC and E2F target, G2M checkpoint, oxidative phosphorylation, P < 0.05) in contrast to CPS ≥ 1 M samples.
The study concluded that the presence of CPS ≥ 1 in M samples, contrasting with the absence of primitive tumors, correlates with the benefit of pembrolizumab. This association aligns with an observed augmentation of iCD8 T cells in PD-L1 positive M. These findings underscore the pivotal influence of the tumor sampling site on predicting the potential efficacy of PD-L1 inhibitors in HGSC.
The study is sponsored by ARCAGY/ GINECO GROUP
Source: https://cslide.ctimeetingtech.com/immuno23hybrid/attendee/confcal/show/session/34
Clinical Trial: https://clinicaltrials.gov/study/NCT03275506
Collet L, et al. (2023). “Deciphering tumor microenvironment heterogeneity between primary tumor and metastases in high grade serous ovarian cancer (HGSC) to predict response to immunotherapy (IT): analyses from the NeoPembrOv/GINECO phase II trial.” Presented at ESMO IO 2023 (Abstract 20P).
