AT ESMO 2016

COPENHAGEN (FRONTLINE MEDICAL NEWS) – Progression-free survival for postmenopausal women with hormone receptor–positive advanced breast cancer was significantly improved when the cyclin-dependent kinase inhibitor ribociclib was added to standard therapy with the aromatase inhibitor letrozole, interim analysis from a phase III randomized trial shows.

After 18 months of follow-up, the risk of progression-free survival (PFS) among patients assigned to receive letrozole (Femara) and ribociclib was 44% lower than for patients assigned to receive letrozole and placebo, reported Gabriel N. Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center, Houston, on behalf of coinvestigators in the MONALEESA-2 trial.

“We concluded that patients who received ribociclib with letrozole had a statistically significant and a clinically meaningful increase in progress-free survival compared to letrozole plus placebo, or letrozole alone,” he said at the European Society for Medical Oncology Congress.

“Is this a game changer? I think it probably is,” said invited discussant Stephen R.D. Johnston, MD, PhD, professor of breast cancer medicine and consultant oncologist at Royal Marsden Hospital in London.

The treatment benefit seen in MONALEESA-2 was present in all patient subsets regardless of age, performance status, extent or location of metastases. Other secondary endpoints, such as response rate and clinical benefit rate, also favored the combination, Dr. Hortobagyi noted.

Results of the first interim analysis of MONALEESA-2 (Mammary Oncology Assessment of LEE011’s Efficacy and Safety) were published simultaneously in the New England Journal of Medicine.

CDK 4 and 6 are frequently overexpressed in hormone receptor–positive breast cancer, and are key mediators of endocrine resistance, Dr. Hortobagyi explained.

Ribociclib is an oral small-molecule inhibitor of the pathway that includes CDK4/6 and the retinoblastoma protein, and has been shown to have efficacy in previously untreated HR-positive advanced breast cancer, and in patients with progressive disease on other therapies.

The MONALEESA-2 study is a phase III, double-blind, placebo-controlled trial of 668 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had not received prior therapy for advanced disease. Patients were stratified by the presence or absence of liver and/or lung metastases, and then assigned to receive letrozole 2.5 mg/day plus either ribociclib 600 mg/day for 3 weeks followed by 1 week off, or placebo on the same schedule.

At a preplanned interim analysis, after 243 events (disease progression or death) had occurred, the investigators found that the trial met its primary endpoint of locally assessed PFS, with a hazard ratio for ribociclib of 0.556 (P = .0000329 for superiority).

At the time of the analysis, median PFS had not been reached in the combination arm, compared with 14.7 months for the letrozole/placebo arm.

At 18 months’ follow-up (median 15.3 months), the PFS rate for ribociclib and letrozole was 63%, compared with 42.2% in the placebo group.

Respective response rates for patients with measurable disease at baseline were 52.7% vs. 37.1% (P less than .001).

Grade 3 or 4 adverse events occurring in more than 10% of patients included neutropenia in nearly two-thirds (59.3%) of the women who received ribociclib vs. 0.9% of those who received placebo, and leukopenia in 21% vs. 0.6%, respectively. In all, 7.5% of patients in the ribociclib group discontinued therapy because of adverse events, compared with 2.1% in the placebo group.

The challenge, Dr. Johnston said, will be to figure out how to integrate the findings from this trial and similar results with the CDK4/6 inhibitor palbociclib and letrozole seen in the PALOMA-2 trial into clinical practice.

Clinicians will be faced with deciding how to select various patient groups – endocrine sensitive, endocrine resistant, and treatment-naive – for targeted combinations or perhaps, for some patients, an aromatase inhibitor alone.

It also remains to be seen whether the CDK4/6 inhibitor/AI combination will be cost effective or affordable in many countries, and the pattern of resistance to CDK 4/6 inhibition is sill unknown, Dr. Johnston said.

The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma