Ribociclib combined with letrozole reduces progression by 44% in advanced breast cancer

Quote: The MONALEESA2 trial is, “paradigm changing because there have not been studies in advanced breast cancer with this magnitude of benefit before.”
Dr Gabriel Hortobagyi, University of Texas, MD Anderson Cancer Center, Houston, US.

Patients on the combination showed a 44% reduction in disease progression compared to patients on letrozole alone. “The progression-free survival [in the combination arm] showed a statistically significant and clinically meaningful increase compared to letrozole alone, with a hazard ratio of 0.556 and a powerful p-value (p= 0.000),” reported Dr Gabriel Hortobagyi, from the University of Texas, MD Anderson Cancer Center, Houston, US, who led the study.

The MONALEESA2 trial is, “paradigm changing because there have not been studies in advanced breast cancer with this magnitude of benefit before.”
Dr. Gabriel Hortobagyi, University of Texas, MD Anderson Cancer Center, Houston, US.

“It’s a true finding and the magnitude of difference suggests conclusive evidence of the benefit of the combination,” he added.

MONALEESA2 followed patients for 16 months. “After this time, there was such a difference seen between the two arms that statistically and clinically the difference was very powerful,” remarked Dr Hortobagyi. He added that, “most phase III trials use a hazard ratio of around 0.75 but here we found a hazard ratio of 0.56.”

Hortobagyi explained the importance of finding a therapeutic option for these patients, given that two-thirds of breast cancers are hormone dependent and develop on the basis of abnormal hormone exposure. “Endocrine treatments are the treatment of choice in the primary and metastatic setting, but in the latter setting, after some months, the tumours can become resistant to this treatment, and preventing or reversing resistance to endocrine therapy has been a major unmet medical need.”

The randomised, double-blind trial represents one of the most promising lines of research in the quest to find agents that inhibit cyclin-dependent kinases. Ribociclib is a selective CDK4/6 inhibitor and has been shown to overcome or delay resistance to endocrine therapy.

In the trial, 668 postmenopausal women with hormone receptor-positive/ HER2-negative advanced breast cancer, with no prior therapy for advanced disease, were randomised (1:1) to ribociclib (or ribociclib at 600 mg per day for 3 weeks on followed by 1 week off) plus letrozole (2.5 mg per day), or letrozole (2.5 mg per day) plus placebo. Patients were stratified according to liver and/or lung metastases.

The primary endpoint was PFS, and secondary endpoints were overall survival, overall response rate, clinical benefit rate, health-related quality of life, safety and tolerability. Tumour assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter. The first analysis was planned when 70% of 302 PFS events had been reached.

The study met its primary endpoint at interim analysis, reported Dr Hortobagyi. “When 70% of the PFS events had occurred there was such a significant difference between the two curves in terms of PFS that it as declared that statistically the study had met its primary endpoint. There was a 44% reduction in progression with a median follow up of 15.3 months,” he reported, adding that the curves started to separate early and this continued and expanded.

The median PFS in the control group was 14.7 months, which is better than seen historically with endocrine therapy alone. In the investigation arm the median PFS had not been reached but “it is expected that this will far exceed the finding in the control arm.”

In terms of adverse events, adding ribociclib to letrozole led to an increase in side effects. Adverse events commonly seen in the combination arm were uncomplicated and were asymptomatic myelosuppression, neutropenia, anemia and thrombocytopenia. Less common events were nausea, vomiting, diarrhea, alopecia, rash, and transaminase elevations; these were reported more frequently with the combination arm than letrozole alone. “However, very few patients discontinued treatment based on adverse events,” said Dr Hortobagyi.

Treatment benefits were seen in all subgroups analyses regardless of age, performance status, extent or location of metastases, and for other secondary endpoints.

Need for biomarkers – who will benefit?

Dr Hortobagyi explained that the MONALEESA2 trial and the PALOMA2 trial [CDK 4/6 inhibitor palbociclib] are “paradigm changing because there have not been studies in advanced breast cancer with this magnitude of benefit before.”

But he pointed out that they needed biomarkers. “We do not know whether 100% of patients benefit, or 50% or 30% or 20%, so we cannot select a patient population to enrich.”

“I think there’s room today for patients with asymptomatic hormone receptor-positive metastatic breast cancer, perhaps especially those with comorbidities, to be treated with endocrine therapy alone, but if you want maximum benefit then you’re going to select the combination with CDK4/6 inhibitors as first choice,” he continued.
There are three leading CDK4/6 inhibitors and from available data they seem similar in therapeutic effect and toxicity profile. Ribaciclib is less advanced in development but until studies are completed we cannot choose one drug in preference to another.
Earlier this year, the US Food and Drug Administration (FDA) granted breakthrough therapy designation to ribociclib, in combination with letrozole, for the treatment of hormone receptor positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. On the basis of these results of this registration trial, the manufacturer will use the findings as a foundation for regulatory filings around the world.

Based on Hortobagyi G, Stemmer S et al. First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (ABC) (LBA1_PR). Presented on Saturday 8 October 2016.

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