Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti–PD‐L1, for BRCA wild‐type, platinum‐sensitive, recurrent ovarian cancer

Author:

Mutch David1ORCID,Voulgari Athina2,Chen Xian (Marissa)3,Bradley William H.4,Oaknin Ana5,Perez Fidalgo José Alejandro6,Montosa Fernando Galvez7,Herraez Antonio Casado8,Holloway Robert W.9,Powell Matthew A.1,Nowicka Malgorzata3ORCID,Schaefer Gabriele10,Merchant Mark11,Yan Yibing3

Affiliation:

1. Division of Gynecology Oncology Washington University School of Medicine St Louis Missouri USA

2. Global Product Development Clinical Science Roche Products Ltd. Welwyn Garden City UK

3. Translational Medicine Genentech, Inc. South San Francisco California USA

4. Department of Obstetrics and Gynecology Medical College of Wisconsin Milwaukee Wisconsin USA

5. Medical Oncology Service Vall d’Hebron Institute of Oncology Vall d’Hebron Barcelona Hospital Campus Barcelona Spain

6. Hospital Clínico Universitario Valencia Biomedical Research Institute INCLIVA Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Valencia Spain

7. Medical Oncology Department Hospital Universitario de Jaén Jaén Spain

8. Department of Medical Oncology Hospital Universitario San Carlos Universidad Complutense IdISSC Madrid Spain

9. Gynecologic Oncology AdventHealth Cancer Institute Orlando Florida USA

10. Molecular Oncology Genentech, Inc. South San Francisco California USA

11. Translational Oncology Genentech, Inc. South San Francisco California USA

Abstract

AbstractBackgroundThis 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).MethodsPatients 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 <12 vs. ≥12 months). Coprimary end points were safety and the investigator‐determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super‐responders (complete response or those with progression‐free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized.ResultsThe 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.ConclusionsChemotherapy‐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.

Publisher

Wiley

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