Shaveta Vinayak1,2, Sara M Tolaney3, Lee Schwartzberg4, Monica Mita5, Georgia McCann6, Antoinette R Tan7, Andrea E Wahner-Hendrickson8, Andres Forero9, Carey Anders10,11, Gerburg M Wulf12, Patrick Dillon13, Filipa Lynce14, Corrine Zarwan15, John K Erban16, Yinghui Zhou17, Nathan Buerstatte17, Julie R Graham17, Sujata Arora17, Bruce J Dezube17, Melinda L Telli18. 1. Case Comprehensive Cancer Center, University Hospitals, Case Western Reserve University, Cleveland, Ohio. 2. currently affiliated with Fred Hutchinson Cancer Research Center, Division of Oncology, University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle. 3. Department of Medical Oncology, Center of Breast Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 4. Division of Hematology/Oncology, The West Clinic, Memphis, Tennessee. 5. Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, California. 6. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio. 7. Levine Cancer Institute, Atrium Health, Charlotte, North Carolina. 8. Department of Medical Oncology, Mayo Clinic Rochester, Rochester, Minnesota. 9. Department of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama. 10. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. 11. Department of Medicine, University of North Carolina at Chapel Hill. 12. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 13. Division of Hematology/Oncology, University of Virginia, Charlottesville. 14. Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC. 15. Department of Hematology and Oncology, Lahey Hospital and Medical Center, Burlington, Massachusetts. 16. Department of Medicine-Hematology/Oncology, Tufts Medical Center, Boston, Massachusetts. 17. TESARO: A GSK Company, Waltham, Massachusetts. 18. Department of Medical Oncology, Stanford University School of Medicine, Stanford, California.
Abstract
IMPORTANCE: Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC). OBJECTIVE: To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019. INTERVENTIONS: Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival. RESULTS: Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected. CONCLUSIONS AND RELEVANCE: Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02657889.
IMPORTANCE: Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC). OBJECTIVE: To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019. INTERVENTIONS: Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival. RESULTS: Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected. CONCLUSIONS AND RELEVANCE: Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02657889.
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