Lilly Announces Phase I Data of Abemaciclib in Chinese Patients with Advanced or Metastatic Cancer at AACR 2020

Text | Ye Fenghong

The second session of the 2020 American Association for Cancer Research (AACR) Annual Meeting was held virtually from June 22 to 24. The conference presented numerous new research findings on novel drugs and regimens, marking another surge in advances in oncology. Among these, the results of a Phase I study evaluating abemaciclib, a CDK4/6 inhibitor, as monotherapy in Chinese patients with advanced or metastatic tumors drew significant attention from domestic experts.

In recent years, a major research focus in HR+/HER2- advanced breast cancer has been the combination of novel molecular targeted therapies with endocrine therapy, among which CDK4/6 inhibitors represent a particularly important class of drugs. CDK4/6 are key regulators of the cell cycle; by forming complexes with cyclin D, they phosphorylate Rb, thereby releasing E2F and triggering the transition from the G1 phase (pre-DNA synthesis) to the S phase (DNA replication). In ER+ breast cancer, the CDK4/6–cyclin D–Rb pathway plays a critical role and serves as a key downstream target of ER signaling. Inhibiting CDK4/6 kinase activity restores cell cycle control, thereby blocking cancer cell proliferation and suppressing the growth of breast cancer cells.

Abemaciclib, a novel CDK4/6 inhibitor manufactured by Eli Lilly and Company, received approval from the US FDA in 2017 based on clinical trial data from Caucasian populations. To market the drug in China, studies on its safety and efficacy in the Chinese population were required. Therefore, this Phase I study of abemaciclib monotherapy in Chinese patients with advanced and/or metastatic tumors was conducted, yielding encouraging results.

Participants were randomized in a 1:1 ratio to receive either abemaciclib or standard adjuvant endocrine therapy. The primary endpoint was invasive disease-free survival, and the secondary endpoints included distant recurrence-free survival, overall survival, drug safety, pharmacokinetics, and health outcomes.

The results showed that the pharmacokinetic (PK) profiles of abemaciclib and its two major active metabolites were similar to those observed in previous studies in non-Chinese populations. A total of 2 patients achieved partial response (PR), with an overall response rate (ORR) of 8%, including 1 confirmed response. The disease control rate (DCR) in the overall population was 68%.

In terms of safety, patients overall tolerated the treatment well, with the vast majority of treatment-related adverse events (TRAEs) being Grade 1-2.

The safety profiles in the 150 mg and 200 mg dose cohorts were consistent with those reported in other studies, indicating that abemaciclib at doses of 150 mg or 200 mg (administered orally every 12 hours) was well tolerated. Preliminary antitumor activity was observed, supporting further investigation in Chinese patients.

There is a wide variety of CDK4/6 inhibitors under development or already marketed both domestically and internationally. In addition to abemaciclib, these include palbociclib and ribociclib.

Palbociclib

Palbociclib, developed by Pfizer, was approved in 2015 for the treatment of postmenopausal ER+/HER2- advanced breast cancer, becoming the first approved small-molecule CDK4/6 inhibitor. The FDA approval of palbociclib was primarily based on two clinical trials: CT00721409 (PALOMA-1) and NCT01942135 (PALOMA-3).

PALOMA-1: In a randomized, open-label, multicenter Phase II trial of palbociclib in combination with letrozole for patients with ER-positive and HER2-negative advanced breast cancer who had not previously received systemic therapy, the median progression-free survival (mPFS) was significantly prolonged with palbociclib plus letrozole (palbociclib: 125 mg QD; letrozole: 2.5 mg; n=84) compared to the control group (placebo plus letrozole, 2.5 mg QD; n=81) (20.2 months vs. 10.2 months; HR=0.488; 95% CI 0.319–0.748; p=0.0004).

PALOMA-3: An international, randomized, double-blind, parallel-group, multicenter Phase III trial of palbociclib in combination with fulvestrant in patients with ER-positive and HER2-negative advanced breast cancer who had received prior endocrine adjuvant therapy. The median progression-free survival (mPFS) was significantly prolonged with palbociclib plus fulvestrant (palbociclib: 125 mg QD; fulvestrant: 500 mg; n=347) compared to the control group (placebo plus fulvestrant, 500 mg; n=174) (9.5 months vs. 4.6 months; HR=0.461; 95% CI 0.360–0.591; p<0.0001)5.

Ribociclib

The approval of ribociclib was primarily based on the following three clinical trials. In the MONALEESA-2 trial (NCT01958021), 668 patients were divided into a treatment group receiving ribociclib and letrozole, and a control group receiving placebo and letrozole. Analysis of progression-free survival (PFS) in the ribociclib treatment group versus the placebo control group showed that the rates of tumor progression were 27.8% and 44.9%, respectively. The median PFS in the control group was 14.7 months, whereas the median PFS was not reached in the ribociclib treatment group (at the time of interim analysis, more than half of the patients in the ribociclib plus letrozole combination therapy group remained alive and progression-free). The overall response rates (ORR) for the ribociclib treatment group and the placebo control group were 52.7% and 37.1%, respectively.

In the second trial, MONALEESA-7 (NCT02278120), patients were divided into a group receiving ribociclib in combination with an NSAI or tamoxifen plus goserelin, and a group receiving placebo in combination with an NSAI or tamoxifen plus goserelin. The PFS analysis of both groups showed that the tumor progression rates for the ribociclib treatment group and the placebo control group were 37.1% and 53.4%, respectively, with median PFS values of 27.5 months and 13.8 months, respectively. The ORR for the ribociclib treatment group and the placebo control group was 50.5% and 36.2%, respectively.

In the MONALEESA-3 trial, the median PFS was 20.5 months in the ribociclib group and 12.8 months in the placebo group, with ORRs of 20.9% and 28.7%, respectively.

The Phase I study data presented at this conference confirmed that abemaciclib is the first and, to date, the only CDK4/6 inhibitor to demonstrate prolonged progression-free survival (PFS) primarily in Chinese patients. In addition to its efficacy in advanced or metastatic breast cancer, abemaciclib has recently achieved significant breakthroughs in the treatment of early-stage breast cancer. Relevant stakeholders have submitted an application to the Center for Drug Evaluation (CDE) of the National Medical Products Administration, with the expectation of swift approval and market launch in China to benefit more Chinese patients.

Reference:

1.Z. Jiang，X. Hu，Q.Zhang. et al. A Phase III Trial of Abemaciclib plus Nonsteroidal Aromatase Inhibitor (NSAI) or Fulvestrant (F) for Women with HR+/HER2- Advanced Breast Cancer (ABC).2019 ESMO LBA 25

2.Xichun Hu, Nong Yang, Jian Zhang, et al. A phase 1 study of abemaciclib in Chinese patients with advanced and/or metastatic cancers. 2020 AACR. Abstract CT164

3.https://www.nasdaq.com/articles/eli-lilly-reports-positive-results-from-interim-analysis-of-phase-3-monarche-study-2020-06

4.https://www.businesswire.com/news/home/20200529005610/en/Pfizer-Update-Phase-3-PALLAS-Trial-IBRANCE%C2%AE

5.World Health Organization. Breast cancer: prevention and control.