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
Por:
Mutch D, Voulgari A, Chen X, Bradley W, Oaknin A, Fidalgo J, Montosa F, Herraez A, Holloway R, Powell M, Nowicka M, Schaefer G, Merchant M, Yan Y
Publicada:
1 jun 2024
Ahead of Print:
1 ene 2024
Resumen:
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 <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. 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.
Filiaciones:
Mutch D:
Washington Univ, Sch Med, Div Gynecol Oncol, St Louis, MO 63110 USA
Washington Univ, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA
Voulgari A:
Roche Prod Ltd, Global Prod Dev Clin Sci, Welwyn Garden City, England
Chen X:
Genentech Inc, Translat Med, South San Francisco, CA USA
Bradley W:
Med Coll Wisconsin, Dept Obstet & Gynecol, Milwaukee, WI USA
Oaknin A:
Vall dHebron Barcelona Hosp Campus, Vall dHebron Inst Oncol, Med Oncol Serv, Barcelona, Spain
Fidalgo J:
Hosp Clin Univ Valencia, Biomed Res Inst INCLIVA, Ctr Invest Biomed Red Canc CIBERONC, Valencia, Spain
Montosa F:
Hosp Univ Jaen, Med Oncol Dept, Jaen, Spain
Herraez A:
Univ Complutense, Hosp Univ San Carlos, Dept Med Oncol, IdISSC, Madrid, Spain
Holloway R:
AdventHlth Canc Inst, Gynecol Oncol, Orlando, FL USA
Powell M:
Washington Univ, Sch Med, Div Gynecol Oncol, St Louis, MO 63110 USA
Nowicka M:
Genentech Inc, Translat Med, South San Francisco, CA USA
Schaefer G:
Genentech Inc, Mol Oncol, South San Francisco, CA USA
Merchant M:
Genentech Inc, Translat Ophthalmol, South San Francisco, CA USA
Yan Y:
Genentech Inc, Translat Med, South San Francisco, CA USA
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