The duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.— Gabriel N. Hortobagyi, MD, and colleagues
As reported by The ASCO Post from the recent European Society for Medical Oncology Conference, first-line treatment with ribociclib, a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), resulted in significantly longer progression-free survival vs placebo in women with hormone receptor–positive, HER2-negative breast cancer receiving letrozole. Full results of the phase III trial have been reported in The New England Journal of Medicine by Gabriel N. Hortobagyi, MD, of The University of Texas MD Anderson Cancer Center, and colleagues.1 Inhibition of CDK4/6 is hypothesized to overcome or delay resistance to endocrine therapy in this setting.
In this double-blind trial, 668 postmenopausal women from 223 sites in 29 countries with recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease were randomized between January 2014 and March 2015 to receive oral ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). Ribociclib was given at 600 mg/d on a 3 weeks on/1 week off schedule in 28-day cycles, and letrozole was given continuously at 2.5 mg/d. The primary endpoint was investigator-assessed progression-free survival.
Patients had a median age of 62 years, 80.5% to 83.8% of patients were white and 6.9% to 8.4% were Asian, more than 99% had stage IV disease, all but 1 in each group had HER2-negative disease, 34.0% had newly diagnosed advanced or metastatic disease, 59.4% had a disease-free interval of more than 24 months at baseline, and 58.8% had visceral disease and 22.0% had bone-only disease.
Prolonged Progression-Free Survival
A preplanned interim analysis was performed in January 2016, after 243 patients had disease progression or died. The prespecified criterion for superiority was a hazard ratio (HR) of ≤ 0.56 with a P value of < 1.29 × 10−5. Median follow-up was 15.6 months.
The trial met its primary endpoint; median progression-free survival was not reached in the ribociclib group (95% confidence interval [CI] = 19.3 months to not reached) vs 14.7 months (95% CI = 13.0–16.5) in the placebo group (HR = 0.56, P = 3.29 × 10-6 for superiority). Progression-free survival was 72.8% vs 60.9% at 12 months and 63.0% vs 42.2% at 18 months.
Hazard ratios favored ribociclib in all prespecified subgroups and were significant for nearly all, including subgroups according to age; estrogen receptor, progesterone receptor-positive, or other hormone receptor status; patients with or without liver or lung metastases; those with or without newly diagnosed disease; and those who had or had not received prior chemotherapy. The hazard ratio for progression-free survival on independent central review supported investigator assessment (HR = 0.59, P = .002).
Overall response rates were 40.7% in the ribociclib group vs 27.5% in the placebo group in the intention-to-treat population and 52.7% vs 37.1% among 501 patients with measurable disease at baseline (P < .001 for both). Clinical benefit rates were 79.6% vs 72.8% in the intention-to-treat population and 80.1% vs 71.8% among patients with measurable disease (P = .02 for both).
Overall survival results were not mature at the time of interim analysis; death had occurred in 23 patients in the ribociclib group and 20 patients in the placebo group. The trial remains blinded for follow-up of overall survival.
The most common adverse events of any grade in the ribociclib group were neutropenia (74.3% vs 5.2%), nausea (51.5% vs 28.5%), infections (50.3% vs 42.4%), fatigue (36.5% vs 30.0%), and diarrhea (35.0% vs 22.1%). The most common grade 3 or 4 adverse events were neutropenia (59.3% vs 0.9%), leukopenia (21.0% vs 0.6%), hypertension (9.9% vs 10.9%), increased alanine transaminase (9.3% vs 1.2%), lymphopenia (6.9% vs 0.9%), and increased aspartate transaminase (5.7% vs 1.2%). Febrile neutropenia occurred in 1.5% vs 0%. An increase of > 60 msec in QTcF interval occurred in 2.7% vs 0%.
Serious adverse events occurred in 21.3% vs 11.8% and were considered related to study treatment in 7.5% vs 1.5%. Treatment was discontinued due to adverse events in 7.5% vs 2.1%. Three patients in the ribociclib group and one patient in the placebo group died. One case of sudden death was considered related to ribociclib treatment; it occurred in a patient with hypokalemia and prolongation of QTcF interval who had taken a prohibited medication with a known risk for QT prolongation.
The investigators concluded: “Among patients receiving initial systemic treatment for hormone receptor–positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.” ■
Disclosure: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit www.nejm.org.