Kate Johnson

April 04, 2017

WASHINGTON, DC – The first biomarker analysis of the MONALEESA-2 trial failed to turn up any predictors of response in patients treated with first-line ribociclib (Kisqali, Novartis) and letrozole (Femara, Novartis) for HR-positive, HER2-negative metastatic breast cancer.

Results of the analysis, reported here at the American Association for Cancer Research (AACR) 2017 Annual Meeting, are a setback for those hoping to better define a patient population best suited to pricey inhibition of cyclin-dependent kinase 4/6 (CDK4/6).

Ribociclib received US Food and Drug Administration approval on the basis of interim results of the MONALEESA-2 trial, as previously reported by Medscape Medical News. Those results showed that adding ribociclib to letrozole improved progression-free survival (PFS) by 44% compared to letrozole plus placebo and significantly improved overall response to therapy.

Biomarkers of response were an exploratory endpoint of the trial. Using archival or fresh tumor samples obtained at screening, the researchers analyzed an initial six to see how they correlated with PFS, reported Fabrice André, MD, PhD, from the Institut Gustave Roussy, Université Paris-Sud, in Villejuif, France.

"We could not detect different hazard ratios according to each biomarker analysis," concluded Dr André. He notes that other biomarkers are still being analyzed.

The investigators examined total Rb expression in 479 patients in consideration of the hypothesis that loss of Rb could be associated with resistance. They examined p16 protein expression in 405 patients "to see whether loss of p16 expression could be predictive of drug sensitivity." They examined expression of CDKN2A, CCND1, and ESR1 in 386 patients, Ki67 protein expression in 463 patients, and PIK3CA status in 417 patients.

"The benefit of progression-free survival was seen in all subgroups regardless of the biomarker status," commented the discussant for the study, Filipa Lynce, MD, from the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.

Dr Lynce pointed out that other studies have also failed to find biomarkers to identify patients more likely to benefit from CDK4/6 inhibitors.

"While for sure we don't want to identify the wrong biomarker that would exclude patients who can potentially benefit from these promising drugs, we all can think of advantages of identifying a successful biomarker such as identification of nonresponders," she said.

Dr Lynce said that it was also desirable to identify patients who would do very well on endocrine therapy alone. Advantages of doing so would be better tolerability, minimization of additional monitoring associated with CDK4/6 inhibitors, the avoidance of some drug interactions, and lower costs.

She said perhaps rather than looking at all of the study subjects together, researchers should focus attention on "the extremes" ― those patients who do not benefit and have primary resistance to CDK4/6 inhibitors, or those who respond exceptionally well to endocrine therapy alone.

Dr Andre has disclosed no relevant financial relationships. Dr Lynce is a speaker for Pfizer and Genentech.

American Association for Cancer Research (AACR) 2017 Annual Meeting. Abstract CT045, presented April 3, 2017.

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