Ribociclib, a CDK 4/6 inhibitor, plus endocrine therapy in Asian women with advanced breast cancer

Abstract

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2-phase study consisting of a dose-escalation phase to determine the maximum-tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose-expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose-escalation phase, the maximum-tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non-Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non-Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non-Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370.

Keywords: Asian; CDK4/6i; biomarker; breast cancer; ribociclib.

Conflict of interest statement

Yoon‐Sim Yap has received honoraria, consulting fees, and travel grants from Pfizer, AstraZeneca, Eisai, Novartis, Eli Lilly, and Roche outside the submitted work; Yoshinori Ito has received lecture fees, honoraria, or other fees from Pfizer and received research funds from Daiichi Sankyo, Chugai Pharmaceutical Co., Novartis, Parexel, EPS, MSD, AstraZeneca, Eli Lilly, Kyowa Kirin, Covance, Taiho, A2 Healthcare, Esai, and VIA service Japan; Takashi Ishikawa has received lecture fees, honoraria, or other fees from Pfizer, Eli Lilly, and Eisai; Tomoyuki Aruga has received lecture fees, honoraria, or other fees from Chugai Pharmaceutical Co., LTD and Pfizer Japan Inc; Tatsuya Toyama has received lecture fees, honoraria, or other fees from AstraZeneca and research funds from Chugai Pharmaceutical Co. and Eisai; Toshiaki Saeki has received research funds from Eisai and Taiho Pharmaceutical Co. Ltd; Ioannis Gounaris was an employee of Novartis Pharmaceuticals Corporation when the reported analyses were conducted and is now an employee of Merck Serono Ltd UK; Fei Su is an employee of Novartis and holds stocks in Novartis; Yan Ji is an employee of Novartis and hold stocks in Novartis; Yu Han is an employee of Novartis and holds stocks in Novartis; Mihaela Gazdoiu is an employee of Novartis and holds stocks in Novartis; Norikazu Masuda has received honoraria from Chugai Pharmaceutical Co., AstraZeneca, Pfizer, Eli Lilly, Eisai, and Takeda Pharmaceutical Company, and research funds through his institution from Chugai Pharmaceutical Co., AstraZeneca, Kyowa Kirin, MSD, Novartis, Pfizer, Eli Lilly, Eisai, and Daiichi Sankyo. The study was designed under the responsibility of Novartis Pharmaceuticals Corporation, and it was funded by Novartis Pharmaceuticals Corporation; ribociclib was provided by Novartis Pharmaceuticals Corporation and letrozole, fulvestrant, tamoxifen, and goserelin were provided locally; Novartis Pharmaceuticals Corporation collected and analyzed the data and contributed to the interpretation of the study. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication; medical editorial assistance was provided by Sara Henriques of Healthcare Consultancy Group, LLC, and funded by Novartis Pharmaceuticals Corporation; Joanne Chiu has no conflicts of interest; Seung Jin Kim has no conflicts of interest; Mitsue Saito has no conflicts of interest.

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

FIGURE 1

Treatment groups for Japanese and Asian non‐Japanese patients. ET, endocrine therapy; FUL, fulvestrant; GOS, goserelin; HER2−, human epidermal growth factor receptor 2‐negative; HR+, hormone receptor‐positive; LET, letrozole; MTD, maximum‐tolerated dose; PK, pharmacokinetics; QD, once daily; RIB, ribociclib; RP2D, recommended Phase II dose; TAM, tamoxifen

FIGURE 2

Preliminary efficacy in Japanese patients. CBR, clinical benefit rate; FUL, fulvestrant; LET, letrozole; ORR, overall response rate; RIB, ribociclib; TAM, tamoxifen

FIGURE 3

Preliminary efficacy in Asian non‐Japanese patients. CBR, clinical benefit rate; LET, letrozole; ORR, overall response rate; RIB, ribociclib

FIGURE 4

Pharmacodynamic changes of gene expression. The gene expression dynamics were assessed in patients for (A) E2F‐responsive genes, (B) cell cycle‐related genes, (C) MYC, and (D) TYMS. BL, baseline; CC, cell cycle; CDK, cyclin‐dependent kinase; C1D15, cycle 1 day 15; FUL, fulvestrant; LET, letrozole; PD, progressive disease; PR, partial response; RIB, ribociclib; SD, stable disease; TAM, tamoxifen

FIGURE 5

Differential mRNA expression at baseline between good and poor responders* for genes involved in cell cycle, proliferation, and breast cancer. Gene expression was assessed between good and poor responders for (A) E2F‐responsive genes, (B) MAP3K8, (C) cell cycle‐related genes, (D) FGFR1, and (E) TYMS. *At the cut‐off date (March 2, 2018), patients who had not progressed after 24 mo post‐randomization (n = 5) were considered good responders; patients who had progressed within 8 wk (n = 6) were considered poor responders. FUL, fulvestrant; LET, letrozole; RIB, ribociclib