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MONARCH 2 is a global, randomized, double-blind, phase 3 study of abemaciclib/placebo + fulvestrant in patients with hormone receptor positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat population in the MONARCH 2 trial. Consistent with the primary analysis, this subpopulation analysis of East Asian patients indicated progression-free survival benefit in the abemaciclib arm. The median overall survival was not reached in the abemaciclib arm and was 48.9 months in the placebo arm (hazard ratio 0.80; 95% confidence interval 0.52-1.24; p = 0.377). In addition, other efficacy endpoints, including time to chemotherapy, chemotherapy free survival, and time to second disease progression, indicated benefit in the abemaciclib arm. This analysis found no new safety concerns with longer follow-up. These findings support the positive benefit-risk balance of the MONARCH 2 regimen in East Asian patients with hormone receptor positive, human epidermal growth factor receptor 2-negative advanced breast cancer.

Background: Abemaciclib is an oral selective cyclin dependent kinases 4 & 6 inhibitor (CDK4 & 6i), administered on a continuous schedule. Abemaciclib demonstrated significant overall survival (OS) and progression-free survival (PFS) benefit in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in combination with fulvestrant in MONARCH 2 (M2). Similarly, abemaciclib demonstrated a PFS benefit in women with HR+, HER2- ABC in combination with nonsteroidal aromatase inhibitors (NSAI) in MONARCH 3 (M3). Here, we present the objective response rate (ORR) from the pooled cohort of endocrine-naïve (EN) participants with measurable disease enrolled in M2 and M3 that received abemaciclib. Methods: M2 (NCT02107703) and M3 (NCT02246621) were double-blind, Phase 3 studies in women with HR+, HER2- ABC. In M2, all patients received fulvestrant (500 mg, per label) and were randomized to receive either abemaciclib (150 mg or 200 mg BID) or placebo. 20 EN participants with measurable disease at baseline were enrolled to the abemaciclib arm. A M2 single arm addendum enrolled 90 additional EN participants with measurable disease to abemaciclib. EN M2 participants had received no previous endocrine therapy (ET) in any setting nor prior chemotherapy in the metastatic setting. In M3, all participants received NSAI (anastrozole 1 mg or letrozole 2.5 mg daily) and were randomized to receive abemaciclib (150 mg BID) or placebo based on stratification factors including prior neoadjuvant or adjuvant ET (NSAI, no ET or other) with 142 M3 EN participants with measurable disease randomized to abemaciclib. The population for analysis consisted of a pooled EN cohort from M2 and M3 with measurable disease that received abemaciclib (N=252). The primary endpoint was investigator-assessed ORR (percentage of participants with best response of complete [CR] or partial response [PR]). The secondary endpoints included PFS, clinical benefit rate (CBR = CR + PR + stable disease persistent for ≥6 months), disease control rate (DCR = CR + PR + SD), duration of response (DoR), and safety. Results: 252 EN participants with measurable disease (43.7% M2, 56.3% M3) from 21 countries were included in the analysis population. Median participant age was 59.0 years. Most patients (n=167 [66.3%]) had ≥3 metastatic organ sites involved. In the pooled EN cohort, confirmed ORR was 57.5% (95% CI 51.4-63.6). CBR was 78.6% (95% CI 73.5-83.6) and DCR was 92.9% (95% CI 89.7-96.0). PFS and DoR data for the M2 EN addendum are not yet mature. No new safety signals were observed. The safety profile was consistent with the previously reported M2 and M3 populations. Conclusion: Primary analysis of confirmed ORR in M2 and M3 EN participants with measurable disease compares favorably with previously reported ORR for fulvestrant monotherapy (FALCON study: 46% unconfirmed; FIRST study: 36% unconfirmed) or NSAI (PALOMA-2 study: 44.8% confirmed; MONALEESA-2: 34% unconfirmed) in participants with a similar disease state. The safety profile is similar to that reported in the primary M2 and M3 main studies. Citation Format: Matthew P. Goetz, Jose Luis Gonzalez Trujillo, Masakazu Toi, Jens Huober, Antonio Llombart-Cussac, Wei Zhang, Holly Knoderer, Nadine Haddad, Gertjan Van Hal, George W. Sledge, Jr. Abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitor in participants with HR+, HER2- breast cancer - A pooled analysis of the endocrine therapy-naïve participants with measurable disease in MONARCH 2 and MONARCH 3 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-21.

Background: Abemaciclib is an orally administered inhibitor of cyclin-dependent kinase (CDK) 4/6, dosed twice daily (BID) on a continuous schedule. Diarrhea is a frequently associated adverse event. It is predictable and manageable with antidiarrheal medication, typically occurs within the first month of therapy, and decreases over the duration of treatment. In the MONARCH 1, 2, and 3 studies, Grade 3 diarrhea was experienced by 9% to 20% of patients (pts) receiving abemaciclib. Study design/Objectives: Study I3Y-MC-JPCP (ClinicalTrials.gov, NCT03703466) was a multicenter, randomized, open-label phase 2 study designed to evaluate the impact of food on the incidence of Grade 3 or prolonged Grade 2 diarrhea in HR+, HER2− metastatic breast cancer (mBC) pts receiving abemaciclib monotherapy 200 mg orally BID during the first 3 cycles of study treatment. Methods: Pts with HR+, HER2− mBC and ECOG performance status ≤1 who had progressed after prior anti-estrogen therapy for mBC and received prior treatment with ≥1 chemotherapy regimen for mBC, but were CDK4/6i naive, were randomly assigned 1:1:1 to receive abemaciclib with a meal, in a modified fasted condition (defined as ≥1 h before or ≥2 h after a meal), or without regard to food. Primary study endpoints were the incidence of ≥Grade 3 diarrhea; incidence of Grade 2 diarrhea lasting >7 days; dose reductions, dose interruptions, and treatment discontinuations due to diarrhea; and use of antidiarrheal agents. Secondary endpoints included overall safety and pharmacokinetic analysis. A pt-held electronic diary was used to record daily information on number of stools, diarrhea, loperamide use, and timing of abemaciclib intake relative to meals. Compliance with diary completion was centrally monitored. Multicenter training and implementation of e-diaries used a variety of paper and electronic resources tailored to end user (research staff, site staff, patient). Physicians had real-time access to data enabling accurate assessment of diarrhea. Results: This study randomized 72 pts in five countries from December 2018 to April 2019; 71 pts (median age 56.0 y) were treated with abemaciclib in one of three study arms: with a meal (Arm 1, n=24), modified fasted condition (Arm 2, n=23) and without regard to food (Arm 3, n=24). Mean compliance for e-diary completion was 95.7% for the overall population. Mean compliance with meal conditions was 99.5% in Arm 1 and 95.2% in Arm 2 (not applicable for Arm 3). In Arms 1, 2 and 3, 83.3%, 78.3% and 91.7% of pts received ≥3 cycles, respectively. Primary endpoints during the first three treatment cycles are summarized (Table). Table 1Arm 1 (n=24)Arm 2 (n=23)Arm 3 (n=24)Overall (n=71)≥1 Grade 2 diarrhea lasting >7 days, %8.317.420.815.5≥1 Grade 3 diarrhea, %4.2*001.4≥1 Grade 4 diarrhea, %0000≥1 Dose reduction due to diarrhea, %16.78.712.512.7≥1 Dose interruption due to diarrhea, %16.74.38.39.9Treatment discontinued due to diarrhea, %0000Loperamide use, %95.891.395.894.4* Duration of Grade 3 diarrhea was 1 day. This study was descriptive and not powered to analyze differences between study arms. Overall, the most frequently reported Grade 3/4 treatment-emergent adverse events related to treatment were neutropenia (28.2%), leukopenia (11.3%), thrombocytopenia (7.0%), fatigue (5.6%), nausea (5.6%) and lymphopenia (5.6%). Details on patient-reported diarrhea incidence and management, and PK analyses will be presented at conference. Conclusions: Global compliance with e-diary completion and meal condition was >95%. Diarrhea at high grade occurred at much lower incidence than previously reported (1.4% overall) and was of short duration (1 day). Diarrhea was predominantly low grade and managed with loperamide and dose modifications in all meal cohorts. Citation Format: Elgene Lim, Frances Boyle, Meena Okera, Sherene Loi, Sema Sezgin Goksu, Gertjan van Hal, Daisy G Hartman, Jonathon Colby Gable, Gregory L Price, Anwar Hossain, M C Gainford, Meritxell Bellet Ezquerra. The impact of food on tolerability of abemaciclib in patients with previously treated hormone receptor-positive, HER2-negative, metastatic breast cancer: An open-label, randomized phase 2 study [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 P5-14-05.

Breast cancer; CDK4/6 inhibitor; Tolerability Cáncer de mama; Inhibidor de CDK4/6; Tolerabilidad Càncer de mama; Inhibidor de CDK4/6; Tolerabilitat Purpose Abemaciclib, a CDK4 & 6 inhibitor, is indicated for advanced breast cancer treatment. Diarrhea is a frequently associated adverse event of abemaciclib. The study objective was to investigate if food intake impacts local gastrointestinal toxicity. Methods This Phase 2 study (I3Y-MC-JPCP, NCT03703466) randomized 72 patients 1:1:1 to receive abemaciclib 200 mg monotherapy twice daily (1) with a meal, (2) in a modified fasting state or (3) without regard to food. Primary endpoints included: incidence of investigator assessed severe (≥ Grade 3), prolonged (> 7 days) Grade 2 diarrhea, treatment discontinuation, dose modifications, and loperamide utilization during the first 3 cycles of treatment. Patient outcomes were captured via a daily electronic diary. Pharmacokinetics (PK) are reported. Results Incidence of investigator assessed severe diarrhea (Grade ≥ 3) was 1.4% (1 patient in Arm 1). Median duration of Grade 3 diarrhea was 1 day by both investigator assessment (1 patient in Arm 1) and patient-reported assessment (1 patient each in Arms 1 and 3). Median duration of investigator-assessed Grade 2 diarrhea was 2 days overall. No patient discontinued treatment due to diarrhea. Nine patients (12.7%) had a dose reduction, and 7 patients (9.9%) had a dose omission due to diarrhea. Ninety-four percent of patients used loperamide at least once. Abemaciclib PK was comparable across the 3 arms. Conclusion The results suggest that diarrhea incidence associated with abemaciclib was unrelated to timing of food intake, was predominantly low grade, of short duration and well managed with loperamide and dose modifications. Open Access funding enabled and organized by CAUL and its Member Institutions. The authors are grateful to the patients, their families, and caregivers for participating in study JPCP, and to the study investigator and site staff for their collaboration. Writing and editing provided by Nicholas Pulliam, Sandra Deady and John Hurley of Eli Lilly and Company. Funding provided by Eli Lilly and Company.

Background Abemaciclib is approved for patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) with progression on prior endocrine therapy (ET). The MONARCH 2 trial showed a statistically significantly benefit in progression-free survival (PFS) (hazard ratio [HR]: 0.553; 95% CI: 0.449-0.681; p < 0.001), overall survival (OS) (HR: 0.757; 95% CI: 0.606-0.945; p = 0.01) and a manageable safety profile for abemaciclib plus fulvestrant compared with fulvestrant alone. Here we report the pre-specified final overall survival (OS) analysis from the MONARCH 2 trial (NCT02107703). Methods MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib or placebo, plus fulvestrant for treatment of pre-, peri- or postmenopausal women with CDK 4 & 6 inhibitor naïve HR+, HER2- ABC that progressed during ET. Pts were randomized 2:1 to receive abemaciclib or placebo, 150 mg twice daily, plus fulvestrant. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary versus secondary). OS and safety were key secondary endpoints, and chemotherapy-free survival was an exploratory endpoint defined as the time from randomization to initiation of chemotherapy or death, whichever occurs the earliest. Kaplan-Meier (KM) method was used to analyze time-to-event variables. A stratified Cox proportional hazards model was used to estimate treatment effect hazard ratio (HR). The prespecified final analysis was planned to occur based on approximately 441 OS events. Data cutoff was March 18, 2022. Results 669 women were randomized 2:1 to receive abemaciclib (n = 446) or placebo (n = 223), plus fulvestrant. Baseline characteristics have been previously reported (Sledge et. al., Jama Oncol 2020). The median follow-up time was approximately 80 months and at the time of the data cutoff, 11% of pts were still receiving study drug in the abemaciclib arm versus 2% in the placebo arm. 440 OS events were observed in the ITT population (abemaciclib arm: 283 events; placebo arm: 157 events). The median OS was 45.8 months in the abemaciclib arm and 37.2 months in the placebo arm (HR: 0.784; 95% CI: 0.644-0.955). The maintained separation of the KM curves beyond the medians is illustrated by the differences in the estimated 5- and 6-year OS rates between arms (5-year: 41.2% versus 29.2%; 6-year: 34.7% versus 23.7%; abemaciclib versus placebo respectively). While OS benefit was generally consistent across subgroups, a more pronounced benefit is noted in subgroups associated with a poorer prognosis such as visceral disease (HR: 0.643; 95% CI: 0.499-0.829), primary resistance to ET (HR: 0.634; 95% CI: 0.436-0.922) or negative progesterone receptor status (HR: 0.623; 95% CI: 0.405-0.959). Moreover, the addition of abemaciclib to fulvestrant deferred the initiation of chemotherapy (HR: 0.674; 95% CI: 0.562-0.809), with substantial difference in yearly chemotherapy-free survival rates (3 year: 42% vs 29.3%; 4 year: 37% vs 18.6%; 5 year: 32.4% vs 14.7%). Notably with longer exposure to abemaciclib, no new additional safety risks or cumulative toxicities were identified. Conclusions At the prespecified final OS analysis of the MONARCH 2 trial, with a median follow-up of 6.5 years, the statistically significant benefit previously demonstrated was confirmed and maintained. OS benefit was generally consistent across subgroups, with numerically greater effect size observed among patients with poorer prognosis. Importantly, the survival benefit came with a substantial extension of the chemotherapy-free survival time, which is an important consideration for pts with ABC. The results also provide assurance of the safety of abemaciclib with longer-term use. Citation Format: Antonio Llombart-Cussac, George Sledge, Masakazu Toi, Patrick Neven, Joo Hyuk Sohn, Kenichi Inoue, Xavier Pivot, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Valerie Andre, Yuanyuan Bian, Ashwin Shahir, Gertjan van Hal. PD13-11 Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer [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 PD13-11.

Purpose: Enzastaurin targets the protein kinase C and phosphatidylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin. Experimental Design: Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m2 and cisplatin doses were either 60 or 75 mg/m2. Circulating endothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers. Results: Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily (≥250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1%) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation. Conclusions: Recommended phase II dose is 500 mg enzastaurin once daily, 1,250 mg/m2 gemcitabine, and 75 mg/m2 cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.