Antonio, Belén San

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.

Abstract Background Adjuvant abemaciclib (a CDK4 and 6 inhibitor) combined with ET resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high risk EBC in the monarchE trial, and is an approved adjuvant therapy for these patients. Here we present efficacy results from a pre-specified overall survival interim analysis (OS IA2) which was planned to occur 2 years (yrs) after the primary outcome analysis. Methods Pts were randomized (1:1) to receive ET for up to 10 yrs +/- abemaciclib for 2 yrs (study treatment period). High-risk EBC was defined as either ≥4 positive axillary lymph nodes (ALN), or 1-3 ALN with either Grade 3 disease and/or tumor ≥5 cm (Cohort 1). While the proliferation biomarker Ki-67 was centrally assessed in all pts with available tissue sample, an additional smaller group of pts with 1-3+ ALN and central Ki-67 ≥20% as the only high-risk feature were included (Cohort 2). The intent-to-treat (ITT) population consisted of both Cohort 1 (5120 pts) and Cohort 2 (517 pts). Hazard ratios (HR) were estimated using Cox proportional hazard model. Results At a median follow-up of 42 months, all pts were off abemaciclib. IDFS and DRFS data illustrate a sustained benefit beyond the treatment period. In the ITT population, the HR for IDFS was 0.664 (95% CI: 0.578, 0.762) and DRFS was 0.659 (95% CI: 0.567, 0.767). At 4 yrs, this reflected an improvement in IDFS rates from 79.4% to 85.8% (absolute difference 6.4%), and in DRFS rates from 82.5% to 88.4% (absolute difference 5.9%). The continued separation of the curves was associated with an increase in absolute benefit in IDFS 4-year rates compared to 2-and 3-year IDFS rates (absolute difference 2.8% and 4.8% respectively). While OS remained immature, there was a lower number of deaths observed in the abemaciclib plus ET arm compared to the ET alone arm (157 [5.6%] vs 173 [6.1%], HR 0.929 [95% CI: 0.748, 1.153], p = 0.503), suggesting that the robust benefit in IDFS and DRFS began to translate into a numerically favorable OS HR. As previously described, within Cohort 1, a Ki-67 index of ≥20% was associated with a worse prognosis, but similar abemaciclib treatment effects were observed regardless of Ki-67 index. No new safety signals were observed. Conclusion The clinically meaningful benefit of adjuvant abemaciclib added to ET in HR+, HER2-, node-positive, high-risk EBC persists beyond completion of abemaciclib therapy, yielding an increase in absolute IDFS and DRFS benefit at 4 yrs. While OS remains immature at this time, the lower number of deaths in the abemaciclib arm compared to the ET arm suggest that a survival signal favoring abemaciclib is emerging. Citation Format: Stephen Johnston, Masakazu Toi, Joyce O’Shaughnessy, Priya Rastogi, Mario Campone, Patrick Neven, Chiun Sheng Huang, Jens Huober, Georgina Garnica Jaliffe, Irfan Cicin, Sara Tolaney, Matthew P. Goetz, Hope Rugo, Elżbieta Senkus, Laura Testa, Lucia Del Mastro, Chikako Shimizu, Ran Wei, Ashwin Shahir, Maria Munoz, Belen San Antonio, Valerie Andre, Nadia Harbeck, Miguel Martín. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-09.

Abstract Background: Breast cancer incidence and mortality rates are increased in patients’ older than 65 years. However, there are limited reports on age-specific efficacy, safety, and drug tolerability, particularly in elderly patients older than 75 years old. Abemaciclib demonstrated clinically meaningful progression-free survival (PFS) improvement in combination with endocrine therapy (ET) in HR+, HER2- advanced breast cancer patients in the Phase 3 studies, MONARCH 2 and 3. Here we report exploratory subgroup analyses of MONARCH 2 and 3 to provide age-specific outcomes. Methods: In MONARCH 2 (NCT02107703), patients progressing while on prior ET received abemaciclib (or placebo) plus fulvestrant; in MONARCH 3 (NCT02246621), postmenopausal women with no prior systemic therapy for recurrent or metastatic breast cancer received abemaciclib (or placebo) plus letrozole or anastrozole. Exploratory outcome analyses of MONARCH 2 and 3 studies were performed for three age groups (women aged <65, 65-74, and ≥75 years). Using pooled safety data, we performed age-specific subgroup analyses of the most common treatment-emergent adverse events (TEAEs) associated with either ET or ET plus abemaciclib. To assess the impact of age on efficacy, a subgroup analysis of PFS was performed using a Cox model for each trial independently. Results: Pooled safety data were available for 1152 patients treated in MONARCH 2 and 3 trials, including 59.7% pts <65 years, 28.7% pts between 65 and 74 years, and 11.5% pts ≥ 75 years. Of those, 768 women received abemaciclib plus ET and 384 women received placebo plus ET. The most frequent TEAE was diarrhea and the most common Grade ≥3 TEAE was neutropenia. While diarrhea (any grade) occurred with similar incidence in abemaciclib-treated patients across age groups, clinically relevant diarrhea (Grade 2/3) was higher in the elderly (<65, 39.5%; 65-74, 45.2%; ≥75, 55.4%); however, in the ≥75 group, diarrhea (Grade 2/3) incidence was also higher for placebo plus ET (<65, 6.8%; 65-74, 4.5%; ≥75, 16.0%). Similarly, nausea and decreased appetite were moderately higher (by 10-20%) in the 2 abemaciclib-treated elderly subgroups. Fatigue (any grade) was higher in the 2 abemaciclib-treated elderly subgroups (<65, 34.8%; 65-74, 48.4%; ≥75, 51.8%), while no differences were found across the 3 placebo subgroups. In contrast, the rates of Grade 3/4 neutropenia did not differ as a function of age in either the abemaciclib plus ET arm (<65, 25.8%; 65-74, 27.4%; ≥75, 18.1%) or placebo plus ET arm. For efficacy, a consistent PFS benefit was observed with abemaciclib plus ET versus placebo plus ET across all three age-specified subgroups in both studies (Table). Conclusion: Abemaciclib in combination with ET demonstrates a tolerable safety profile and consistent efficacy benefit across all age subgroups examined, supporting the use of this combination in elderly patient populations. Despite the limited number of patients in the ≥75 group with potentially confounding comorbidities, the safety data suggest that patient education and appropriate management of toxicities, including dose adjustments and use of supportive medication for gastrointestinal toxicities, could maximize the benefit of abemaciclib. Table: Age-specified PFS outcomes from MONARCH 2 and 3MONARCH 2MONARCH 3Age GroupAbemaciclib + ETPlacebo + ETHR (95% CI)P-value *Abemaciclib + ETPlacebo + ETHR (95% CI)P-value *Events/NEvents/NEvents/NEvents/N<65140/29192/1330.52 (0.40, 0.68)0.69581/18065/910.48 (0.35, 0.67)0.63465-7461/11442/600.63 (0.43, 0.94)40/10631/540.64 (0.40, 1.02)≥7521/4123/300.62 (0.34, 1.11)17/4212/200.54 (0.26, 1.13)Abbreviations: CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; PFS, progression-free survival.*P-value corresponds to the interaction test between age and treatment. Citation Format: Matthew P. Goetz, Meena Okera, Hans Wildiers, Mario Campone, Eva-Maria Grischke, Luis Manso, Valerie Anne Marie Andre, Amy Lee Chong, Belen San Antonio, Masakazu Toi, George W Sledge Jr. Safety and efficacy of abemaciclib plus endocrine therapy (ET) in elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+, HER2-) advanced breast cancer: An age-specific subgroup analysis of MONARCH 2 and 3 trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-10.