Phase 3 study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer

Date 29 September 2019
Event ESMO 2019 Congress
Session Presidential Symposium II
Topics Breast Cancer
Presenter Veronique Dieras
Citation Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394
Authors V.C. Dieras1, H.S. Han2, B. Kaufman3, H. Wildiers4, M. Friedlander5, J. Ayoub6, S.L. Puhalla7, I. Bondarenko8, M. Campone9, E.H. Jakobsen10, M. Jalving11, C. Oprean12, M. Palácová13, Y.H. Park14, Y. Shparyk15, E. Yañez16, M. Dudley17, C.K. Ratajczak17, D. Maag17, B.K. Arun18
  • 1Praticien Specialiste En Oncologie Medicale, Institut Curie, Paris, and Centre Eugene - Marquis, 35042 - Rennes/FR
  • 2Breast Oncology, Moffitt Cancer Center, 33612 - Tampa/US
  • 3Cancer Center, Sheba Medical Center, Tel Hashomer/IL
  • 4Department Of General Medical Oncology, University Hospitals Leuven, 3000 - Leuven/BE
  • 5Medicine, Prince of Wales Clinical School UNSW and Prince of Wales Hospital, Sydney/AU
  • 6Département De Médecine, Centre hospitalier de l’Université de Montréal, Montreal/CA
  • 7Hillman Cancer Center, UPMC Cancer Centers, Pittsburgh/US
  • 8Oncology And Medical Radiology Department, Dnipropetrovsk Medical Academy, City Hospital №4, 49000 - Dnipro/UA
  • 9Medical Oncology, Institut de Cancérologie de l'Ouest -Pays de la Loire, Pays de la Loire/FR
  • 10Department Of Oncology, Vejle Hospital/Lillebaelt Hospital, Vejle/DK
  • 11Medicine, University Medical Center Groningen, University of Groningen, Groningen/NL
  • 12Medicine, University of Medicine and Pharmacy Timisoara; Oncomed SRL, Timisoara/RO
  • 13Medicine, Masaryk Memorial Cancer Institute, Brno/CZ
  • 14Medicine, Samsung Medical Center, Seoul/KR
  • 15Oncology, Lviv State Regional Treatment and Diagnostic Oncology Center, Lviv/UA
  • 16Medicine, Universidad de la Frontera, Temuco/CL
  • 17Oncology, AbbVie Inc., North Chicago/US
  • 18Department Of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston/US

LBA9: Phase 3 study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer by Véronique Dieras

Abstract

Background

BRCA-mutated tumors are susceptible to both platinum and PARP inhibitors due to deficiency in homologous recombination repair. Veliparib (Vel) is a PARP1/2 inhibitor with antitumor activity and acceptable toxicity as a single-agent or combined with carboplatin and paclitaxel (C/P) in pts with BRCA mutated breast cancer.

Methods

This double blind, placebo (Pbo)-controlled, phase III trial (NCT02163694) randomized pts 2:1 to C/P with Vel or Pbo. Pts had gBRCA1/2 mutations and ≤2 prior lines of cytotoxic therapy for metastatic breast cancer. Vel (120 mg p.o. BID) or Pbo was given on Days −2 to 5 with C (AUC 6, d1) and weekly P (80 mg/m2, d1, 8, 15) in 21-d cycles. Pts who discontinued both C and P but had not progressed received blinded single-agent Vel or Pbo (300-400 mg BID). Treatment was to progression. Primary endpoint was PFS (per investigator); secondary endpoints included OS, clinical benefit rate, objective response rate, and PFS2.

Results

Median age was 47 years (range 24–82), 48% were ER/PgR–, 8% had prior platinum therapy, 4% had history of CNS metastases, and 19% had prior chemotherapy for metastatic disease. Efficacy data are summarized in the Table. Among AEs of special interest (all-grades), neutropenia occurred in 91%/91%, thrombocytopenia in 82%/72%, anaemia in 81%/70%, and nausea and vomiting in 75%/68% of pts in Vel vs Pbo arms, respectively. Most common (≥20%) study drug-related G3+ AEs in Vel and Pbo arms were anaemia (27%/17%), neutropenia (52%/50%), and thrombocytopenia (25%/15%). In Vel vs Pbo arms, 88%/86% had C dose reduction and 74%/70% had P dose reduction.Table:

LBA9

Efficacy summaryVeliparib + C/P, n = 337Placebo + C/P, n = 172
mPFS per INV (months, 95% CI)14.5 (12.5, 17.7)12.6 (10.6, 14.4)
PFS per INV HR (95% CI); P value0.71 (0.57, 0.88); 0.002
3-year PFS rate (%, 95% CI)26 (20, 31)11 (5.8, 17)
mPFS per IRC (months, 95% CI)19.3 (16.5, 23.3)13.5 (12.5, 16.3)
PFS per IRC HR (95% CI)0.70 (0.54, 0.90)
mOS [interim] (months, 95% CI)33.5 (27.6, 37.9)28.2 (24.7, 35.2)
OS HR (95% CI); P value0.95 (0.73, 1.2); 0.67
CBR at 24 weeks (%)90.7%93.2%
ORR (%)75.8%74.1%
mPFS2 per INV (months, 95% CI)21.3 (19.8, 25.1)17.4 (16.0, 20.0)
PFS2 per INV HR (95% CI)0.76 (0.60, 0.96)
mDoR per INV (months, 95% CI)14.7 (12.1, 18.7)11.0 (10.2, 12.3)

C/P, carboplatin and paclitaxel; CBR, clinical benefit rate; HR, hazard ratio; INV, investigator; IRC, independent review committee; m, median; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PFS2, time from randomization to progression on first subsequent therapy; DoR, duration of response.

Conclusions

Vel + C/P demonstrated significant improvement in PFS over C/P alone. Median PFS for both arms was over 12 months. Pts on the Vel arm had durable benefit compared to control, with 26% of pts on Vel arm alive and progression-free at 3 years vs. 11% of pts on Pbo arm. Vel did not substantially alter the toxicity profile of C/P.

Clinical trial identification

NCT02163694.

Editorial acknowledgement

Medical writing support was provided by Ana Mrejeru, Ph.D., of AbbVie.

Legal entity responsible for the study

AbbVie.

Funding

AbbVie.

Disclosure

V.C. Diéras: Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Nektar; Advisory / Consultancy: Astellas; Advisory / Consultancy: AbbVie; Advisory / Consultancy: MSD; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Odonate; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: AstraZeneca. H.S. Han: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Prescient; Research grant / Funding (institution): Horizon; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): TapImmune; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (self): Department of Defense; Speaker Bureau / Expert testimony: Lilly. B. Kaufman: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Steering committee member : AbbVie; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. H. Wildiers: Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche ; Honoraria (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (institution): AstraZeneca; Honoraria (institution): Amgen; Honoraria (institution): Lilly; Honoraria (institution): Novartis; Honoraria (institution): AbbVie; Honoraria (institution): Vifor Pharma; Honoraria (institution): Celldex Therapeutics; Honoraria (institution): Janssen-CILAG; Honoraria (institution): TRM Oncology; Honoraria (institution): PUMA Biotechnology; Honoraria (institution): ORION corporation. M. Friedlander: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Takeda; Research grant / Funding (self): BeiGene. J. Ayoub: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma; Advisory / Consultancy: Roche. S.L. Puhalla: Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy: MedImmune; Advisory / Consultancy: Celldex; Advisory / Consultancy: Puma; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: Nanostring; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Covance-Bayer; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Lilly. M. Campone: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Advisory / Consultancy: Accord; Speaker Bureau / Expert testimony: Novartis. M. Jalving: Advisory / Consultancy, Non-remunerated activity/ies, Clinical studies: Merck; Advisory / Consultancy, Non-remunerated activity/ies, Clinical studies: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Tesaro; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Sanofi; Non-remunerated activity/ies, Clinical studies: Cristal Therapeutics; Non-remunerated activity/ies, Clinical studies: AbbVie. C. Oprean: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sandoz; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: Roche; Speaker Bureau / Expert testimony: Teva; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: BMS; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Janssen; Non-remunerated activity/ies, Research /Clinical studies: AbbVie; Non-remunerated activity/ies, Research /Clinical studies: Genentech; Non-remunerated activity/ies, Research /Clinical studies: BeiGene; Non-remunerated activity/ies, Research /Clinical studies: Trio Oncology. M. Palácová: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Eisai. Y.H. Park: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Novartis; Research grant / Funding (self): Merck; Research grant / Funding (self): Roche. Y. Shparyk: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony, Non-remunerated activity/ies, Research /Clinical studies: Roche; Speaker Bureau / Expert testimony: AstraZeneca; Non-remunerated activity/ies, Research /Clinical studies: MSD; Non-remunerated activity/ies, Research /Clinical studies: Boehringer Ingelheim; Non-remunerated activity/ies, Research /Clinical studies: AbbVie. M. Dudley: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. C.K. Ratajczak: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. D. Maag: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. B.K. Arun: Research grant / Funding (self), Non-remunerated activity/ies, Steering Committee: AbbVie; Research grant / Funding (self): PharmaMar; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Invite. All other authors have declared no conflicts of interest.