1605 - MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer

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.