Open-label Clinical Trial of Niraparib Combined with Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer

Shaveta Vinayak, Sara M. Tolaney, Lee Schwartzberg, Monica Mita, Georgia McCann, Antoinette R. Tan, Andrea E. Wahner-Hendrickson, Andres Forero, Carey Anders, Gerburg M. Wulf, Patrick Dillon, Filipa Lynce, Corrine Zarwan, John K. Erban, Yinghui Zhou, Nathan Buerstatte, Julie R. Graham, Sujata Arora, Bruce J. Dezube, Melinda L. Telli

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1132-1140
Number of pages9
JournalJAMA Oncology
Volume5
Issue number8
DOIs
StatePublished - Aug 1 2019

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Triple Negative Breast Neoplasms
Clinical Trials
Therapeutics
Disease-Free Survival
Safety
niraparib
pembrolizumab
Mutation
Poly Adenosine Diphosphate Ribose
Neoplasms
Death Domain Receptors

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Open-label Clinical Trial of Niraparib Combined with Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. / Vinayak, Shaveta; Tolaney, Sara M.; Schwartzberg, Lee; Mita, Monica; McCann, Georgia; Tan, Antoinette R.; Wahner-Hendrickson, Andrea E.; Forero, Andres; Anders, Carey; Wulf, Gerburg M.; Dillon, Patrick; Lynce, Filipa; Zarwan, Corrine; Erban, John K.; Zhou, Yinghui; Buerstatte, Nathan; Graham, Julie R.; Arora, Sujata; Dezube, Bruce J.; Telli, Melinda L.

In: JAMA Oncology, Vol. 5, No. 8, 01.08.2019, p. 1132-1140.

Research output: Contribution to journalArticle

Vinayak, S, Tolaney, SM, Schwartzberg, L, Mita, M, McCann, G, Tan, AR, Wahner-Hendrickson, AE, Forero, A, Anders, C, Wulf, GM, Dillon, P, Lynce, F, Zarwan, C, Erban, JK, Zhou, Y, Buerstatte, N, Graham, JR, Arora, S, Dezube, BJ & Telli, ML 2019, 'Open-label Clinical Trial of Niraparib Combined with Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer', JAMA Oncology, vol. 5, no. 8, pp. 1132-1140. https://doi.org/10.1001/jamaoncol.2019.1029
Vinayak, Shaveta ; Tolaney, Sara M. ; Schwartzberg, Lee ; Mita, Monica ; McCann, Georgia ; Tan, Antoinette R. ; Wahner-Hendrickson, Andrea E. ; Forero, Andres ; Anders, Carey ; Wulf, Gerburg M. ; Dillon, Patrick ; Lynce, Filipa ; Zarwan, Corrine ; Erban, John K. ; Zhou, Yinghui ; Buerstatte, Nathan ; Graham, Julie R. ; Arora, Sujata ; Dezube, Bruce J. ; Telli, Melinda L. / Open-label Clinical Trial of Niraparib Combined with Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. In: JAMA Oncology. 2019 ; Vol. 5, No. 8. pp. 1132-1140.
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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.",
author = "Shaveta Vinayak and Tolaney, {Sara M.} and Lee Schwartzberg and Monica Mita and Georgia McCann and Tan, {Antoinette R.} and Wahner-Hendrickson, {Andrea E.} and Andres Forero and Carey Anders and Wulf, {Gerburg M.} and Patrick Dillon and Filipa Lynce and Corrine Zarwan and Erban, {John K.} and Yinghui Zhou and Nathan Buerstatte and Graham, {Julie R.} and Sujata Arora and Dezube, {Bruce J.} and Telli, {Melinda L.}",
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TY - JOUR

T1 - Open-label Clinical Trial of Niraparib Combined with Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer

AU - Vinayak, Shaveta

AU - Tolaney, Sara M.

AU - Schwartzberg, Lee

AU - Mita, Monica

AU - McCann, Georgia

AU - Tan, Antoinette R.

AU - Wahner-Hendrickson, Andrea E.

AU - Forero, Andres

AU - Anders, Carey

AU - Wulf, Gerburg M.

AU - Dillon, Patrick

AU - Lynce, Filipa

AU - Zarwan, Corrine

AU - Erban, John K.

AU - Zhou, Yinghui

AU - Buerstatte, Nathan

AU - Graham, Julie R.

AU - Arora, Sujata

AU - Dezube, Bruce J.

AU - Telli, Melinda L.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

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