Adjuvant Abemaciclib Provides Survival Benefit in Chinese Breast Cancer Population

Abemaciclib (Verzenio) plus endocrine therapy delivered sustained survival benefits with a tolerable safety profile when used as adjuvant treatment in Chinese patients with high-risk, hormone receptor (HR)–positive, HER2-negative early breast cancer, according to findings from a preplanned interim overall survival (OS) analysis of the phase 3 monarchE trial (NCT03155997), which were presented at the 2023 ESMO Breast Cancer Annual Congress.¹

At a data cutoff of July 1, 2022, in Chinese patients who received the oral CDK4/6 inhibitor abemaciclib plus endocrine therapy in the adjuvant setting, 26 invasive disease-free survival (IDFS) events (10.0%) occurred vs 40 IDFS events (16.5%) in those who received standard-of-care (SOC) endocrine therapy alone (HR, 0.563; 95% CI, 0.343-0.923; nominal P = .02091). The 4-year IDFS rates in the abemaciclib and SOC arms were 88.5% (95% CI, 82.9%-92.4%) and 79.6% (95% CI, 71.5%-85.7%), respectively, with a treatment difference of 8.9% (95% CI, 0.5%-17.3%).

“Consistent with reports from the intention-to-treat (ITT) population, abemaciclib in combination with endocrine therapy demonstrated clinically meaningful and sustained IDFS and distant relapse-free survival (DRFS) benefits among Chinese patients with HR-positive, HER2-negative, high-risk early breast cancer,” lead study author, Zhimin Shao, MD, of the Fudan University Shanghai Cancer Center in China, and colleagues, wrote in a poster of the data.

Between July 2017 and August 2019, the multicenter, randomized, open-label monarchE trial enrolled patients with node-positive, HR-positive, HER2-negative, high-risk, resected, early-stage breast cancer who had completed definitive locoregional therapy with or without prior neoadjuvant or adjuvant chemotherapy. Female, male, premenopausal, and postmenopausal patients without distant metastases were eligible.

Patients were separated into 2 cohorts. Cohort 1 consisted of patients with high-risk disease based on clinical pathological features, including those with at least 4 positive axillary lymph nodes (ALNs) or 1 to 3 ALNs and a tumor size of at least 5 cm and/or histologic grade 3. Cohort 2 consisted of patients with high-risk disease based on central Ki-67 status, including those with 1 to 3 ALNs, histologic grades 1 to 2, a tumor smaller than 5 cm, and a centrally tested Ki-67 status of at least 20%. Patients were stratified by prior chemotherapy status, menopausal status, and disease region.

A total of 501 Chinese patients, 12% (n = 61) of whom were from cohort 2 and 88% (n = 440) of whom were from cohort 1, were randomized 1:1 to receive abemaciclib at 150 mg twice daily plus SOC endocrine therapy of physician’s choice (n = 259) or endocrine therapy alone (n = 242) for a treatment period of 2 years, followed by a 3- to 8-year follow-up period where patients in both arms received endocrine therapy as clinically indicated.

The primary objective of monarchE was IDFS per Standard Definitions for Efficacy End Points criteria. Key secondary objectives included DRFS, OS, and safety.

At a data cutoff of July 8, 2020 for the primary analysis, 71.1% of Chinese patients enrolled in this trial were still receiving treatment, with a median follow-up of around 18.0 months in each arm. The IDFS hazard ratio was 0.657 (95% CI, 0.301-1.435) and the DRFS hazard ratio was 0.601 (95% CI, 0.245-1.477).

At a median follow-up of 42 months, all patients enrolled in the trial had discontinued abemaciclib treatment. The median IDFS was not reached in both arms, and the previously reported IDFS benefit was sustained, with a hazard ratio of 0.664 (95% CI, 0.578-0.762; nominal P < .0001). At 4 years, the IDFS rate was 85.5% (95% CI, 84.2%-87.3%) in the abemaciclib arm vs 79.4% (95% CI, 77.5%-81.1%) in the SOC arm.² Additionally, at the July 1, 2022, data cutoff date, the investigators had observed 330 OS events in the ITT population.¹

This prespecified exploratory analysis aimed to evaluate the preplanned interim OS monarchE results in patients from Mainland China, Hong Kong, and Taiwan in the ITT population.

At 24 months, 36 months, and 48 months, the IDFS rates were 94.9%, 90.5%, and 88.5%, respectively, in the abemaciclib arm, and 90.7%, 85.2%, and 79.6%, respectively, in the SOC arm. Patients who received abemaciclib experienced a 43.7% reduction in the risk of developing an IDFS event.

In the Chinese patients in the abemaciclib arm, 22 DRFS events (8.5%) occurred vs 33 DRFS events (13.6%) in those who received endocrine therapy alone (HR, 0.586; 95% CI, 0.341-1.006; nominal P = .05001). The 4-year DRFS rates in the abemaciclib and SOC arms were 90.0% (95% CI, 84.4%-93.7%) and 82.4% (95% CI, 74.4%-88.1%), respectively, with a treatment difference of 7.6% (95% CI, –0.5%-15.7%).

At 24 months, 36 months, and 48 months, the DRFS rates were 96.0%, 92.0%, and 90.0%, respectively, in the abemaciclib arm, and 92.4%, 87.9%, and 82.4%, respectively, in the SOC arm. Patients who received abemaciclib experienced a 41.4% reduction in the risk of developing a DRFS event.

The investigators reported 6 OS events (2.3%) in the abemaciclib arm and 5 events (2.1%) in the SOC arm. These OS data remain immature.

Of the Chinese patients in cohort 1, the 24-, 36-, and 48-month IDFS rates were 94.5%, 89.5%, and 87.4%, respectively, in the abemaciclib arm and 90.6%, 84.5%, and 78.9%, respectively, in the SOC arm (HR, 0.582; 95% CI, 0.351-0.965), translating to a 41.8% reduction in the risk of developing an IDFS event. Additionally, in cohort 1, the 24-, 26-, and 48-month DRFS rates were 95.9%, 91.2%, and 89.1%, respectively, in the abemaciclib arm and 92.6%, 87.5%, and 81.9%, respectively, in the SOC arm, translating to a 39.0% reduction in the risk of developing a DRFS event.

In cohort 2, the investigators observed 1 IDFS event (2.9%) in the abemaciclib arm and 2 IDFS events (7.7%) in the SOC arm. No deaths were reported in the Chinese patients in cohort 2.

In cohort 1, the IDFS and DRFS benefit with abemaciclib was consistent regardless of Ki-67 status. In patients with high Ki-67 proliferation, the investigators observed 17 IDFS events (17.3%) in the abemaciclib arm (n = 98) and 21 IDFS events (23.1%) in the SOC arm (n = 91; HR, 0.737; 95% CI, 0.388-1.399). In these patients, the 4-year IDFS rates were 82.0% (95% CI, 72.7%-88.4%) and 70.9% (95% CI, 54.2%-82.4%) in the abemaciclib and SOC arms, respectively, with a treatment difference of 11.1%. In patients with low Ki-67 proliferation, the investigators observed 6 IDFS events (6.9%) in the abemaciclib arm (n = 87) and 12 IDFS events (16.4%) in the SOC arm (n = 73; HR, 0.380; 95% CI, 0.143-1.014). In these patients, the 4-year IDFS rates were 92.7% (95% CI, 84.4%-96.7%) and 80.3% (95% CI, 66.4%-88.9%) in the abemaciclib and SOC arms, respectively, with a treatment difference of 12.4%.

Regarding DRFS, in patients with high Ki-67 proliferation, the investigators observed 14 DRFS events (14.3%) in the abemaciclib arm and 18 DRFS events (19.8%) in the SOC arm (HR, 0.699; 95% CI, 0.347-1.407). In these patients, the 4-year DRFS rates were 84.9% (95% CI, 75.8%-90.7%) and 72.9% (95% CI, 55.7%-84.3%) in the abemaciclib and SOC arms, respectively, with a treatment difference of 12.0%. In patients with low Ki-67 proliferation, the investigators observed 5 DRFS events (5.7%) in the abemaciclib arm and 9 DRFS events (12.3%) in the SOC arm (HR, 0.429; 95% CI, 0.144-1.283). In these patients, the 4-year DRFS rates were 93.8% (95% CI, 85.7%-97.4%) and 84.8% (95% CI, 71.2%-92.3%) in the abemaciclib and SOC arms, respectively, with a treatment difference of 9.1%.

Regarding OS, in patients with high Ki-67 proliferation, the investigators observed 4 OS events each in the abemaciclib arm (4.1%) and the SOC arm (4.4%). In patients with low Ki-67 proliferation, the investigators observed 2 OS events (2.3%) in the abemaciclib arm and 1 OS event (1.4%) in the SOC arm. These OS data remain immature.

The median duration of abemaciclib treatment was 103.14 weeks. In total, 495 Chinese patients in monarchE were evaluated for safety: 259 in the abemaciclib arm and 236 in the SOC arm. The investigators observed no new AEs at the time of the preplanned interim OS analysis.

All patients in the abemaciclib arm and 91.1% (n = 215) of patients in the SOC arm experienced at least 1 treatment-emergent adverse effect (TEAE), and 54.4% (n = 141) and 13.6% (n = 32) of patients in those arms, respectively, had TEAEs of grade 3 or higher. Additionally, 16.6% (n = 43) and 10.2% (n = 24) of patients in the abemaciclib and SOC arms, respectively, experienced at least 1 serious adverse effect (AE). Of the entire Chinese safety population, 10 patients discontinued the study treatment because of AEs; all were in the abemaciclib arm. No patients in either arm discontinued the study treatment because of a serious AE, and no patients died because of an AE while receiving the study treatment or within 30 days of treatment discontinuation.

The most common TEAEs included diarrhea (abemaciclib arm, 92.3%; SOC arm, 7.2%), neutropenia (77.2%; 13.1%), leukopenia (77.2%; 18.6%), anemia (36.7%; 5.1%), upper respiratory tract infection (34.7%; 28.0%), increased aspartate aminotransferase (34.4%; 12.7%), increased alanine aminotransferase (32.0%; 15.3%), thrombocytopenia (29.3%; 3.4%), abdominal pain (25.5%; 8.5%), and arthralgia (15.4%; 28.8%).

Other AEs of interest included venous thromboembolic events, which occurred in 1.2% (n = 3) patients in the abemaciclib arm, 2 of whom had deep vein thrombosis and 1 of whom had pulmonary embolism. Additionally, 8.5% (n = 22) and 4.2% (n = 10) of patients in the abemaciclib and SOC arms, respectively, experienced interstitial lung disease, and 6.2% (n = 16) and 2.5% (n = 6) experienced pneumonitis, specifically.

“The safety profile of abemaciclib is considered manageable and acceptable for this high-risk population,” the study authors concluded.

Disclosure: The study authors report that this study was sponsored by Eli Lilly and Company.

References

1. Shao Z, Zhang Q, Liao N, et al. Results in Chinese patients from preplanned overall survival interim analysis in monarchE: abemaciclib plus adjuvant endocrine therapy for high-risk HR+, HER2– early breast cancer. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 107P.
2. Johnston SRD, Toi M, O’Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial.Lancet Oncol. 2023;24(1):77-90. doi:10.1016/S1470-2045(22)00694-5