Background

Abemaciclib is an oral, selective cyclin-dependent kinase 4 & 6 inhibitor, approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) as monotherapy for endocrine refractory disease (US) and with endocrine therapy (ET) for initial treatment and after progression on ET. In the MONARCH 2 trial, abemaciclib + fulvestrant (F) significantly improved PFS compared to placebo (P) + F (median: 16.4 m vs 9.3 m; HR: 0.553) with a generally tolerable safety profile. Here we report the OS results of the prespecified interim.

Methods

MONARCH 2 (NCT02107703) was a global, randomized, double-blind phase III trial of abemaciclib + F or P + F in pre- or perimenopausal (with ovarian suppression) and postmenopausal women with advanced ET resistant HR+, HER2- ABC. 669 patients were randomized 2:1, stratified based on site of metastasis (visceral, bone-only, or other) and resistance to prior ET (primary vs secondary). Abemaciclib or P 150 mg was dosed Q12H, and F 500 mg was administered per label. The primary objective was investigator-assessed PFS. OS was a gated secondary endpoint. The boundary p-value for the interim analysis was 0.0208.

Results

At the prespecified interim analysis, 338 deaths (77% of the planned 441 events) were observed in the ITT population with a median OS of 46.7 m for abemaciclib + F and 37.3 m for P + F (HR: 0.757; 95% CI: 0.606, 0.945; P = 0.0137). These results met the predefined boundary for significance and are thus definitive. OS benefit was consistent in all stratification factors; among stratification factors, more pronounced effects were observed in subgroups of visceral disease (HR: 0.675) and primary resistance to prior ET (HR: 0.686). PFS2 (HR: 0.675; 95% CI: 0.558, 0.816) and time to chemotherapy (HR: 0.622; 95% CI: 0.499, 0.775) were also significantly improved. Safety data were consistent with known abemaciclib safety profile.

Conclusions

Treatment with abemaciclib plus fulvestrant provided a statistically significant and clinically meaningful median OS benefit of 9.4 months to pre- or perimenopausal and postmenopausal patients with HR+, HER2- ABC who progressed on ET with no new safety signals observed.

Clinical trial identification

NCT02107703.

Editorial acknowledgement

Scientific writing support was provided by Sarah C. Nabinger, employee of Eli Lilly and Company.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

G.W. Sledge: Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly and Company. M. Toi: Honoraria (self), Research grant / Funding (institution), lecture honoraria: Chugal; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Takeda; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Pfizer; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Kyowa-Hakko-Kirin; Honoraria (self), Research grant / Funding (institution), lecture honoraria: C & C Res Lab; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Talho; Research grant / Funding (institution), Officer / Board of Directors: JBCRG association; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Eisai; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Dallchl-Sankyo; Honoraria (self), Research grant / Funding (institution), lecture honoraria: AstraZeneca; Honoraria (self), lecture honoraria: Eli Lilly and Company; Honoraria (self): MSD; Honoraria (self), lecture honoraria: Novartis; Honoraria (self), Honoraria for a meeting: Konica Minorta; Honoraria (self), Honoraria for a meeting: Genomic Health; Officer / Board of Directors: Organisation for Oncology and Translational Research; Officer / Board of Directors: Kyoto Breast Cancer Research Network. P. Neven: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Roche; Research grant / Funding (self): Kom op Tegan Kanker; Honoraria (institution): Benelux. K. Inoue: Honoraria (self), Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self), Honoraria (institution): Esal; Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Chugal; Research grant / Funding (institution): Dailchl Sankyo; Research grant / Funding (institution): Parexel/Puma Biotechnology; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Bayer. X. Pivot: Research grant / Funding (institution): Eli Lilly and Company. N. Masuda: Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Chugai; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): AstraZeneca; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Pfizer; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Eli Lilly and Company; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Eisai; Honoraria (self), Lecture fees (Honoraria): Takeda; Research grant / Funding (institution): Kyowa-Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Officer / Board of Directors: Japan Breast Cancer Research Group Association. P.A. Kaufman: Honoraria (self), Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Novartis. H. Koh: Research grant / Funding (institution): Eli Lilly and Company. E. Grischke: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly and Company. P.F. Conte: Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, travel grant: Eli Lilly and Company; Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), travel grant: Celgene; Honoraria (self), travel grant: Tesaro. Y. Lu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. S. Barriga: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. K. Hurt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. M. Frenzel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. S.R.D. Johnston: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Puma Biotechnology; Speaker Bureau / Expert testimony: Elsal. A. Llombart-Cussac: Shareholder / Stockholder / Stock options: MedSIR; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self), Research grant / Funding (institution): Celgene; Honoraria (self), Research grant / Funding (institution): Plere Fabre; Research grant / Funding (institution): Genomic Health; Research grant / Funding (institution): Puma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Non-financial support: AstraZeneca; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): ELSAI; Honoraria (self): Ferrer Incode - Agendia. All other authors have declared no conflicts of interest.

Background

The phase III MONALEESA-3 trial (NCT02422615; N = 726) investigated RIB, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, + FUL as first-line (1L) or second-line (2L) treatment for postmenopausal pts with HR+/HER2− ABC. Here we report OS and 1L progression-free survival (PFS) results.

Methods

Postmenopausal pts with HR+/HER2− ABC were randomized 2:1 to receive RIB + FUL or PBO + FUL in 1L and 2L settings. This is the 2nd of 3 protocol-specified OS analyses.

Results

At the data cutoff (3 Jun 2019), 153 pts were still on treatment (RIB, n = 121 [25.0%]; PBO, n = 32 [13.2%]); OS was evaluated after 275 deaths (RIB, 167 [34.5%]; PBO, 108 [44.6%]). Median follow-up was 39.4 mo. RIB + FUL demonstrated a statistically significant OS prolongation over PBO + FUL (median, NR vs 40.0 mo; HR, 0.724, 95% CI, 0.568-0.924, P = 0.00455). The result crossed the prespecified Lan DeMets (O’Brien Fleming) stopping boundary (P = 0.01129) for superior efficacy. Per protocol, these OS results will be considered final. OS benefit with RIB vs PBO was consistent across all subgroups, including the 1L subgroup (median, NR vs 45.1 mo; HR, 0.700 [95% CI, 0.479-1.021]) and the early-relapse/2L subgroup (median, 40.2 vs 32.5 mo; HR, 0.730 [95% CI, 0.530-1.004]). In pts receiving 1L treatment, the median PFS (descriptive analysis) with RIB + FUL vs PBO + FUL was 33.6 vs 19.2 mo (HR, 0.546 [95% CI, 0.415-0.718]). Time to progression on next-line therapy or death (PFS2) was also longer with RIB vs PBO (median, 39.8 vs 29.4 mo; HR, 0.670 [95% CI, 0.542-0.830]). The safety profile was consistent with previously published analyses.

Conclusions

There was a statistically significant OS prolongation with RIB over PBO, which was consistent across all subgroups. The median PFS with RIB in the 1L setting is the longest reported in a phase III trial in HR+/HER2− ABC. These data, combined with results from MONALEESA-7, confirm RIB benefit with multiple combination partners in pre- and postmenopausal pts, and support RIB as a recommended CDK4/6 inhibitor as 1L and 2L treatment in pts with HR+/HER2- ABC.

Clinical trial identification

NCT02422615.

Editorial acknowledgement

Editorial assistance in the writing was provided by Tara Wabbersen, PhD, of MediTech Media, LLC, through funding by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

D.J. Slamon: Leadership role, Travel / Accommodation / Expenses: Biomarin; Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Eli Lilly. S. Chia: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Hoffman-La Roche; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly. P.A. Fasching: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Myelo Therapeutics GmbH; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Puma Biotechnology; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Teva; Research grant / Funding (institution): BioNTech AG. M. De Laurentiis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen. S. Im: Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai. K. Petrakova: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Travel / Accommodation / Expenses: BMS. F.J. Esteva: Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy: Celltrion Healthcare ; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (self): GlaxoSmithKline. M. Martin: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Roche-Genentech; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: Taiho Oncology ; Research grant / Funding (self): Roche. A. Nusch: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Amgen. G.S. Sonke: Honoraria (institution), Research grant / Funding (institution), institutional reimbursement for patient accrual; institutional reimbursement for education and steering committee activities: Novartis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche. J.T. Beck: Research grant / Funding (institution): Novartis . M. Sondhi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation. Y. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation. A. Chakravartty: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation. K. Rodriguez-Lorenc: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation. G. Jerusalem: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Puma Biotechnology. All other authors have declared no conflicts of interest.

Background

Neoadjuvant pembro + chemo had manageable safety and promising antitumor activity in participants (pts) with early TNBC in KEYNOTE-173 and I-SPY 2. KEYNOTE-522 (NCT03036488) is a pbo controlled phase III study of neoadjuvant pembro + chemo followed by adjuvant pembro in pts with early TNBC.

Methods

Pts with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to pembro 200 mg Q3W or pbo, both given with 4 cycles of paclitaxel + carboplatin, then with 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant phase). After definitive surgery, pts received pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase). Pts were stratified by nodal status (+ vs -), tumor size (T1/T2 vs T3/T4), and carboplatin schedule (Q3W vs QW). Dual primary endpoints were pCR defined as ypT0/Tis ypN0 and event-free survival (EFS). Secondary endpoints included pCR defined as ypT0 ypN0 and ypT0/Tis, OS, and efficacy in the PD-L1+ population.

Results

Median follow-up was 15.5 mo (range, 2.7-25.0). 784 pts were randomized to pembro, 390 to pbo. Among 602 pts evaluable for the definitive pCR analysis, pembro + chemo showed a statistically significant improvement in pCR (ypT0/Tis ypN0) vs pbo + chemo: 64.8% (95% CI, 59.9-69.5) vs 51.2% (95% CI, 44.1-58.3), P = 0.00055; results were consistent for the secondary pCR definitions, ypT0 ypN0 (59.9% vs 45.3%) and ypT0/Tis (68.6% vs 53.7%). For pembro vs pbo, pCR (ypT0/Tis ypN0) was 68.9% vs 54.9% in the PD-L1+ population and 45.3% vs 30.3% in the PD-L1- population. The addition of pembro to chemo followed by pembro showed a favorable trend in EFS (HR 0.63 [95% CI, 0.43-0.93]). Across phases, grade 3 or higher treatment-related AE rates were 78.0% in the pembro + chemo group and 73.0% in the pbo + chemo group (death incidence, 0.4% vs 0.3%, respectively).

Conclusions

Addition of pembro to neoadjuvant chemo significantly increased the pCR rate in pts with early TNBC. Neoadjuvant pembro + chemo followed by adjuvant pembro showed a favorable trend in EFS. AEs were consistent with the known safety profiles of each agent.

Clinical trial identification

NCT03036488.

Editorial acknowledgement

Writing assistance was provided by Christine McCrary Sisk and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

P. Schmid: Honoraria (self): Pfizer, AZ, Novartis, Roche, Merck, BI, Bayer, Eisai, Puma, Celgene; Advisory / Consultancy: Pfizer, AZ, Novartis, Roche, Merck, BI, Bayer, Eisai, Puma, Celgene; Research grant / Funding (institution): AZ, Genetech, Roche, Oncogenex, Novaris, Astellas; Spouse / Financial dependant: Spouse is a consultant for Genetech/Roche. J. Cortés: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharpe & Dohme; Advisory / Consultancy: Cellestia; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biothera Pharmaceuticals; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: Erytech; Advisory / Consultancy: Athenex; Advisory / Consultancy: Polyphor; Advisory / Consultancy: Servier; Research grant / Funding (institution): Ariad Pharmaceuticals; Research grant / Funding (institution): Baxalta GMBH/Servier Affaires; Research grant / Funding (institution): Bayer Healthcare; Research grant / Funding (institution): Guardian Health; Research grant / Funding (institution): Piqur Therapeutics ; Research grant / Funding (institution): Puma C; Research grant / Funding (institution): Queen Mary University of London; Research grant / Funding (institution): Seagen; Shareholder / Stockholder / Stock options: MedSIR. R. Dent: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. L. Pusztai: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pieris; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Immunomedics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Almac; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Syndax. H.L. McArthur: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Spectrum Pharm; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Immunomedics; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Puma Biotechnology. S. Kuemmel: Advisory / Consultancy: F. Hoffmann-La Roche Ltd; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Somatex; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma Biotechnology; Advisory / Consultancy: PFM Medical; Advisory / Consultancy: Lilly; Research grant / Funding (institution): WSG; Travel / Accommodation / Expenses: Roche Pharma. J. Bergh: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi Aventis. C. Denkert: Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen ; Advisory / Consultancy: MSD; Advisory / Consultancy: Daiichi Sankyo; Shareholder / Stockholder / Stock options: Sividon (Myriad); Licensing / Royalties: VmScope. Y.H. Park: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Research grant / Funding (self): AstraZeneca. R. Hui: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Eli Lilly. N. Harbeck: Honoraria (institution): only research grants; Advisory / Consultancy: Agendia; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Daiichi Sankyo; Advisory / Consultancy: Genomic Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Odonate; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Sandoz/Hexal; Advisory / Consultancy: Seattle Genetics; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Nanostring; Leadership role: German AGO Breast Committee; Research grant / Funding (institution): several phase II-III trials; Shareholder / Stockholder / Stock options: CO-Director West German Study Group; Full / Part-time employment: LMU Munich; Spouse / Financial dependant: West German Study Group. M. Takahashi: Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly ; Honoraria (self), Research grant / Funding (self): Eisai; Research grant / Funding (self): Taiho; Research grant / Funding (self): Kyowa-Hakko Kirin; Research grant / Funding (self): Nippon Kayaku . T. Foukakis: Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (institution), Research grant / Funding (institution): Pfizer; Licensing / Royalties: Wolters Kluwer Health (UpToDate). P.A. Fasching: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self), Advisory / Consultancy: TEVA; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp&Dohme; Honoraria (self), Advisory / Consultancy: Myelo Therapeutics; Honoraria (self), Advisory / Consultancy: Macrogenics; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Puma; Honoraria (institution), Research grant / Funding (institution): Biontech; Honoraria (institution), Research grant / Funding (institution): Cepheid. F. Cardoso: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: Astellas/Medivation; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Daiichi-Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: GE Oncology; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Macrogenics; Advisory / Consultancy: Medscape; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Merus BV; Advisory / Consultancy: Mylan; Advisory / Consultancy: Mundipharma; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Pierre-Fabre; Advisory / Consultancy: prIME Oncology; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Teva; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Fresenius GmbH; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Nerviano; Research grant / Funding (institution): Medigene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Millenium; Research grant / Funding (institution): Sonus; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Tigris; Research grant / Funding (institution): Wilex; Research grant / Funding (institution): Wyeth; Officer / Board of Directors: ESMO Board of Directors. L. Jia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. V. Karantza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J. Zhao: Full / Part-time employment: Merck & Co., Inc.. G. Aktan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J. O’Shaughnessy: Honoraria (self): AbbVie Inc; Honoraria (self): Agendia; Honoraria (self): Amgen Biotechnology; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene Corporation; Honoraria (self): Eisai; Honoraria (self): Genentech; Honoraria (self): Genomic Health; Honoraria (self): GRAIL; Honoraria (self): Immunomedics; Honoraria (self): Heron Therapeautics; Honoraria (self): Ipsen Biopharmaceuticals; Honoraria (self): Jounce Therapeutics; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Myriad; Honoraria (self): Novartis; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Puma Biotechnology; Honoraria (self): Prime Oncology; Honoraria (self): Roche; Honoraria (self): Seattle Genetics; Honoraria (self): Syndax Pharmaceuticals.

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

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.