AI Summary
This study focused on combining PARP and MEK inhibition, with or without anti-PD-L1 treatment, for patients with BRCA wild-type, platinum-sensitive, recurrent ovarian cancer. Results showed that the doublet and triplet therapy regimens demonstrated promising activity, particularly in patients with HRDsig-positive tumors. Additionally, NF1 and MKNK1 mutations were associated with sustained benefit in specific treatment regimens. The study highlights the potential efficacy of targeted therapies for patients with recurrent ovarian cancer, emphasizing the importance of genetic biomarkers in treatment response.
Abstract
Background
This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC).
Methods
Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1–21) plus niraparib 200 mg daily (days 1–28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to 15 months) and progressors (disease progression as the best response) were characterized.
Results
The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%–53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%–44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively.
Conclusions
Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.