41P - BRCA2 pathogenic variant (PV): A novel agnostic biomarker for immune checkpoint blockers (ICB)?

Background

Immunotherapy has revolutionized cancer treatment improving survival rates for many cancer types. Unfortunately, resistances are common and predictive biomarkers are needed. Microsatellite Instability-high (MSI-H) usually predicts response to ICB in all tumour types, whereas we need more studies focusing on tumour mutational burden (TMB) to predict its role as a pan-cancer biomarker. Recent investigations in murine models and cohorts of patients (pts) have shown that BRCA2 PV improved response and overall survival to ICB compared to BRCA1 PV. The aim of this study was to evaluate the response to ICB in BRCA PV and its relation with TMB, MSI-H and prior treatments.

Methods

We conducted an unicohort retrospective study, between May 2020 and November 2022, in metastatic pts carrying BRCA1 or BRCA2 somatic PV and treated with ICB in phase I/II trials at Institute Gustave Roussy (France). Genomic analysis were performed by NGS (liquid biopsy and tumor samples). Data was extracted from electronic medical record and analysed with SPSS software.

Results

A total of 44 pts were enrolled. Median age was 54.6 years [range 29–74 years], 46.7% were female. Lung cancer was the most common tumour (20.5%) in an heterogenic histologic cohort of pts. Median previous lines of treatment was 2.7 [range 0-4]. Tissue analysis revealed 21.1% MSI-H, 36.8% TMB high, 23.8% BRCA1 PV, 38.1% BRCA2 PV. Blood analysis showed 7.3% MSI-H, 52.4% TMB high, 40,5% BRCA1 PV, 52.4% BRCA2 PV. All pts received immunotherapy, 69.8% ICB. The Objective Response Rate (ORR) was 34.1%. Pts with BRCA2 PV presented a better ORR to ICB compared to those with BRCA1 PV (28% vs. 4%, p = 0,030). Mean TMB was lower in BRCA2 PV than in BRCA1 PV pts and median previous lines of treatment was higher in BRCA2 PV than in BRCA1 PV (2.5 vs. 2.0). We didn´t find a significant association between BRCA1/2 PV and MSI status. Duration of response (DoR) to ICB by more than 6 months tended to be higher in pts with BRCA2 PV than those with BRCA1 PV (32% vs. 16%, p = 0,512).

Conclusions

Pts with somatic BRCA2 PV had better ORR to ICB regardless of TMB, MSI and prior lines of treatment than those with BRCA1 PV. Further research should be carried out to confirm BRCA2 as a predictive pan-cancer biomarker to ICB in a larger cohort with BRCA WT pts as comparison.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

K. Beshiri: Financial Interests, Personal, Invited Speaker: Gustave Roussy. All other authors have declared no conflicts of interest.