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.

Objective Abemaciclib (A) is approved for pts with hormone receptor-positive (HR+), HER2− advanced breast cancer (ABC) who progressed on endocrine therapy (ET). MONARCH 2 showed statistical significant PFS and OS benefit and a manageable safety profile for A + fulvestrant (F) over F alone.

Two years (yrs) of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-yr treatment (tx) period in patients (pts) with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-yr efficacy results from a prespecified overall survival (OS) interim analysis. Pts were randomized (1:1) to receive ET for at least 5 yrs +/- abemaciclib for 2 yrs (tx period). High-risk EBC was defined as either ≥4 positive axillary lymph nodes (ALN) or 1-3 ALN with Grade 3 disease and/or tumor ≥5 cm (Cohort 1). A smaller group of pts were enrolled with 1-3+ ALN and central Ki67 ≥20% (Cohort 2). The intent-to-treat (ITT) population consisted of Cohort 1 (5120 pts) and Cohort 2 (517 pts). OS in the ITT population was tested for statistical significance in the gated strategy. Hazard ratios (HR) were estimated using Cox proportional hazard model. In the ITT population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with a HR of 0.680 (95% CI: 0.599, 0.772) for IDFS and 0.675 (95% CI: 0.588, 0.774) for DRFS. This persistence of abemaciclib benefit translated to continued separation of the KM curves resulting in a 5-yr absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with IDFS/DRFS rates of 6.0%/5.3% at 4 yrs and 4.8%/4.1% at 3 yrs. Tx benefit in Cohort 1 was consistent with ITT. No new safety signals were observed. There continued to be fewer deaths in the abemaciclib plus ET arm compared to the ET arm (208 vs 234; HR 0.903; p=0.284); significance was not met. At the pivotal 5-yr mark for adjuvant EBC trials, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence well beyond the completion of tx. The increasing absolute improvement at 5 yrs is consistent with a carryover effect and further supports the use of abemaciclib in pts with high-risk EBC. OS data are evolving in favor of abemaciclib arm, and follow-up continues.

Background: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. Patients and methods: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for >= 5 years +/- abemaciclib for 2 years. Cohort 1 enrolled patients with >= 4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor >= 5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (>= 20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. Results: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib thorn ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Conclusion: Abemaciclib thorn ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

Background: Abemaciclib is a CDK4 & 6 inhibitor dosed continuously with demonstrated efficacy and an acceptable safety profile in pts with HR+, HER2-negative advanced breast cancer as monotherapy (MONARCH 1) and in combination with endocrine therapy; with fulvestrant (MONARCH 2) or with non-steroidal aromatase inhibitors (MONARCH 3). The most frequent adverse event (AE) is low-grade diarrhea; neutropenia is the most frequent grade 3/4 AE. We describe the timing and management of common AEs in the MONARCH trials. Methods: Enrollment criteria, study designs and key eligibility criteria of MONARCH 1, 2 and 3 have been reported (Dickler et al. 2017; Sledge et al. 2017; Goetz et al. 2017). Pts were advised to initiate antidiarrheal therapy at first sign of diarrhea and notify the investigator, drink fluids. If not improved within 24 hours to < grade 1, treatment was suspended until diarrhea resolved. Dose reductions required for grade ≥3 or persistent grade 2 diarrhea. For grade 3 neutropenia, abemaciclib was held until < grade 2. The dose was reduced for recurrent grade 3 or grade 4 neutropenia. Results: Across MONARCH, the median time to onset of diarrhea was between day 6-8. First dose reductions for diarrhea occurred at a median of 28-41 days. Dose holds for diarrhea were brief, constituting 1.7-3.8% off total treatment time. The median time to onset of grade 3/4 neutropenia was 29-36.5 days, and resolved at a median of 11-15 days. AEs were managed by dose adjustments and/or supportive medication (Table).Table: 339PSummary of Dose Adjustments in Pts Experiencing Diarrhea or NeutropeniaCharacteristicsMONARCH 1 AbemaciclibMONARCH 2 Abemaciclib + FMONARCH 3 Abemaciclib + NSAIN = 132N = 441N = 327Diarrhea (any grade), n(%)119 (90.2)381 (86.4)269 (82.3)Grade 326 (19.7)59 (13.4)31 (9.5)Incidences per patient, n (%)160 (50.4)185 (48.6)124 (46.1)229 (24.4)90 (23.6)52 (19.3)≥330 (25.2)106 (27.8)93 (34.6)Outcome, number (%) of events263995802Not recovered/resolved15 (5.7)106 (10.7)70 (8.7)Treatment change, n (%)119381269Dose reduction of study drug27 (22.7)83 (21.8)45 (16.7)Dose omission32 (24.2)83 (21.8)51 (19.0)Treatment discontinuation1 (0.8)13 (3.4)6 (2.2)Antidiarrheal medication, n (%)80 (60.6)333 (75.5)226 (69.1)Neutropenia (any grade), N (%)49 (37.1)203 (46.0)143 (43.7)Grade ¾32 (24.2)117 (26.5)78 (23.9)Treatment change, n (%)Dose reduction of study drug14 (10.6)44 (10.0)42 (12.8)Dose omission21 (15.9)72 (16.3)57 (17.4)Treatment discontinuation07 (1.6)9 (2.8) Open table in a new tab Conclusions: The dose adjustment strategy used in the MONARCH studies was effective at managing AEs by dose adjustment and/or supportive medication. Understanding the safety profile of abemaciclib can inform AE management and can extend time on treatment. Clinical trial identification: NCT02102490 (MONARCH 1), NCT02107703 (MONARCH 2), NCT02246621 (MONARCH 3). Legal entity responsible for the study: Eli Lilly and Company. Funding: Eli Lilly and Company. Disclosure: H.S. Rugo: Grants/research support: GSK, Genentech/Roche, Novartis, Pfizer, Merck, Eisai, Plexxikon, Macrogenics, Lilly, OBI (all funding to UC Regents only). V. André, S. Barriga, T. Forrester: Employee and stakeholder: Eli Lilly and Company. M.P. Goetz: Consultant: Eli Lilly and Company, bioTheranostics, Novartis, Genomic Health, Eisai, Biovica, and Sermonix; Grant/Research support from Eli Lilly and Pfizer. All other authors have declared no conflicts of interest.