Tryakin, A.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.

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Abstract Background monarchE is a phase 3, open-label study evaluating abemaciclib combined with endocrine therapy (ET) compared to ET alone in patients with node positive, HR+, HER2-, high risk early breast cancer (EBC) that resulted in a statistically significant improvement in invasive disease-free survival (IDFS) at a pre-planned interim analysis. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and overall survival. Methods After surgery and, as indicated, radiotherapy and/or chemotherapy, 5,637 patients with HR+, HER2-, high risk EBC were randomized (1:1) to standard of care adjuvant ET with or without abemaciclib (150 mg BD for 2 years). Patients with ≥4 positive nodes, or 1-3 nodes and either grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible. Here we present results of the primary outcome IDFS analysis which was planned after approximately 390 IDFS events. Results At the primary outcome analysis, median follow-up was approximately 19 months in both arms (an increase of 3.5 months from the interim analysis). A total of 1437 (25.5%) patients had completed the 2-year treatment period; 3281 (58.2%) were still in the 2-year treatment period. With 395 IDFS events observed in the intent-to-treat population, abemaciclib plus ET continued to demonstrate superior IDFS versus ET alone, with a 28.7% reduction in the risk of developing invasive disease (p=.0009; HR = 0.713; 95% CI = 0.583, 0.871). Two-year IDFS rates were 92.3% in the abemaciclib plus ET arm and 89.3% in the ET alone arm. There was a consistent benefit of abemaciclib in all prespecified subgroups. The addition of abemaciclib to ET also resulted in an improvement in distant relapse-free survival (DRFS). Overall survival was immature at the time of analysis. A key secondary endpoint was efficacy in patients with centrally assessed high Ki-67 (≥20%) (Ki-67H) (n=2498). Disease characteristics were well balanced between the arms of this population. Abemaciclib plus ET demonstrated superior IDFS vs ET alone, with a 30.9% reduction in risk of developing invasive disease (p=.0111; HR = 0.691; 95% CI = 0.519, 0.920) and 2-year IDFS rates of 91.6% and 87.1%, respectively. An improvement in DRFS treatment effect was also observed in the Ki-67H population. At the time of data cutoff, the median treatment duration of abemaciclib was 17.3 months and the median duration of ET was balanced between the arms (18.3 months in the abemaciclib arm and 18.7 months in the ET alone arm). Safety was consistent with the results at the interim IDFS analysis and with the known safety profile of abemaciclib. Conclusions At the primary outcome analysis, with a median follow-up of approximately 19 months, abemaciclib combined with ET continued to demonstrate a clinically meaningful improvement in IDFS in patients with HR+, HER2-, node-positive, high risk, EBC with a statistically significant improvement in IDFS in patients with central Ki-67 ≥20%. ClinicalTrials.gov: NCT03155997 Table 1: PrimaryOutcome EfficacyIntent-to-Treat PopulationIntent-to-Treat PopulationKi-67 ≥20% (Ki-67H) PopulationKi-67 ≥20% (Ki-67H) PopulationEndpointAbemaciclib + ET N=2808ET alone N=2829Abemaciclib + ET N=1262ET alone N=1236IDFS# events, n (%)163 (5.8)232 (8.2)82 (6.5)115 (9.3)log rank P value, HR (95% CI)p=.0009 0.713 (0.583, 0.871)p=.0111 0.691 (0.519, 0.920)Rate (%) at 2 years (95% CI)92.3 (90.9, 93.5)89.3 (87.7, 90.7)91.6 (89.4, 93.4)87.1 (84.3, 89.5)Difference (%) in 2-year rates (95% CI)3 (1.1, 5.0)4.5 (1.2, 7.7)DRFS# events, n (%)131 (4.7)193 (6.8)65 (5.2)102 (8.3)log rank P value, HR (95% CI)p=.0009 0.687 (0.551, 0.858)0.609 (0.445, 0.833)Rate (%) at 2 years (95% CI)93.8 (92.6, 94.9)90.8 (89.3, 92.1)93.6 (91.6, 95.1)88.5 (85.7, 90.7)Difference (%) in 2-year rates (95%CI)3 (1.2, 4.8)5.1 (2.1, 8.1) Citation Format: Joyce A. O'Shaughnessy, Stephen Johnston, Nadia Harbeck, Masakazu Toi, Young-Hyuck Im, Mattea Reinisch, Zhimin Shao, Pirkko Liisa Kellokumpu Lehtinen, Chiun-Sheng Huang, Alexey Tryakin, Matthew Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Michael Andersson, Kenji Tamura, Guenther G. Steger, Lucia Del Mastro, Joanne Cox, Tammy Forrester, Sarah Sherwood, Xuelin Li, Ran Wei, Miguel Martin, Priya Rastogi. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-01.