2021 SGO | Are genomically unstable tumors more sensitive to immune checkpoint inhibitors?

The 2021 American Society of Gynecological Oncology (SGO) Annual Meeting will be held in the form of an online meeting on March 19-25.

As a global event in the field of gynecological oncology, the SGO conference brought together top experts and scholars in the field of gynecological oncology to discuss the latest research progress and best clinical practice in the field of gynecological oncology.

During the conference, a study exploring the sensitivity of genomically unstable tumors to immunotherapy announced the results.

Research background Researchers hypothesized that genomically unstable tumors characterized by BRCA1/2 mutations and homologous recombination defects (HRD) are more susceptible to mutations and more sensitive to immune checkpoint inhibitors.

The IMagyn050 study was stratified according to the expression status of BRCA1/2, HRD and PD-L1, and explored the efficacy of immune checkpoint inhibitors in patients with genomically unstable tumors.

Research method IMagyn050 (NCT03038100) is a randomized, double-blind phase III clinical trial designed to evaluate carboplatin + paclitaxel + bevacizumab (CPB) + atilizumab/placebo, sequential bevacizumab Monoclonal antibody + atelizumab/placebo maintains the effectiveness and safety of the treatment.

Use VENTANA SP142 analysis to detect PD-L1 status (PD-L1+ is defined as: tumor infiltrating immune cells express PD-L1 ≥ 1%).

Use FoundationOne genetic testing technology to assess BRCA1/2 harmful germline/somatic mutations, genomic loss of heterozygosity (gLOH), tumor mutational burden (TMB) and microsatellite instability (MSI).

Regardless of BRCA1/2 status, HRD and homologous recombination capability (HRP) are defined as gLOH≥16% and <16%, respectively.

Standard correlation analysis and Kaplan-Meier curve were used to assess the potential correlation of clinical outcomes (progression-free survival as defined by RECIST [PFS]) with BRCA1/2, HRD, and PD-L1 status.

Results of the study: Among 1301 randomized patients, 1050 patients can be assessed for BRCA1/2 status (22% are BRCA1/2 mutations, and patients without BRCA1/2 mutations account for 78%), and 980 patients can be assessed for gLOH (46% are HRD, 54 % Is HRP).

The median TMB was lower in patients with BRCA1/2 mutations and without BRCA1/2 mutations (3.
78 vs.
2.
52 Mut/Mb, respectively), as well as in patients with HRD and HRP (3.
78 vs.
2.
52 Mut/Mb, respectively).

Only 3% (29/1024) of patients had TMB ≥ 10 Mut/Mb, and 0.
3% (3/1022) had high degree of microsatellite instability (MSI-H) (1 mixed, 1 undifferentiated, 1 other).

All high-grade serous ovarian cancer cases are microsatellite stable (MSS).

The PFS (placebo+CPB group) of patients with BRCA1/2 mutation (HR 0.
62; 95% CI: 0.
46-0.
84) and HRD (HR 0.
63; 95% CI: 0.
49-0.
80) improved.

This suggests that there is a correlation between PD-L1+ and HRD (the incidence of HRD in PD-L1+ and PD-L1- subgroups is 40% vs.
25%, respectively; P=0.
0001), but there is no correlation with BRCA1/2 mutations (The incidence of BRCA1/2 mutations was 21% vs.
14%, respectively; P=0.
064).

Regardless of BRCA1/2 mutation or HRD status, CPB+atelizumab cannot improve PFS.

In the PD-L1+ population, the HR of the subgroups with and without BRCA1/2 mutations, as well as the HRD and HRP subgroups, was similar.

In the PD-L1- population, the addition of atelizumab did not improve PFS.

Study conclusions The study found that regardless of BRCA1/2 or HRD status, most patients with ovarian cancer have low TMB scores.

BRCA1/2 mutations and HRD status have nothing to do with the greater clinical benefit of CPB+atelizumab.

When using atelizumab+CPB combination regimen, PD-L1 status is correlated with an increase in PFS value.

This is the first randomized double-blind trial conducted in ovarian cancer.
The study proved that genomically unstable tumors characterized by BRCA1/2 mutations and HRD are not more sensitive to immune checkpoint inhibitors.

References: Association of BRCA1/2, homologous recombination deficiency, and PD-L1 with clinical outcomes in patients receiving atezolizumab versus placebo combined with carboplatin, paclitaxel, and bevacizumab for newly diagnosed ovarian cancer: Exploratory analyses.
abstract 10938