Dr. Gabriel Hortobagyi
The analyses were from the phase III MONALEESA-2 trial, in which 668 postmenopausal women with HR-positive/HER2-negative, previously untreated advanced breast cancer were randomly assigned in a 1-to-1 manner to ribociclib plus letrozole (600 mg/day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg/day) or placebo plus letrozole. The first interim analysis at a median follow-up time of 15.3 months, reported in The New England Journal of Medicine in October 2016, showed that the duration of PFS was significantly longer in the ribociclib group than in the placebo group (hazard ratio [HR] 0.56; 95% CI [0.43, 0.72]; p = 3.29 × 10−6 for superiority).1
The PFS rates after 12 months were 72.8% (95% CI [67.3%, 77.6%]) in the ribociclib group and 60.9% (95% CI [55.1%, 66.2%]) in the placebo group. The PFS rates after 18 months were 63.0% (95% CI [54.6%, 70.3%]) and 42.2% (95% CI [34.8%, 49.5%]), respectively. The overall response rates in patients with measurable disease at baseline were 52.7% and 37.1%, respectively (p < 0.001).
Updated Results From MONALEESA-2
Abstract 1038 reported the results of a second interim analysis of data at a median duration of 26.4 months. Results showed a PFS rate of 54.7% in the combination arm compared with 35.9% in the placebo arm at 24 months, consistent across patient subgroups. There were no additional safety signals.
Lead author Gabriel N. Hortobagyi, MD, FACP, of The University of Texas MD Anderson Cancer Center said that the updated analysis had two important objectives: “To provide more precise estimates of the time points and median PFS to help identify any slow responders and any change in the response rate; and to monitor and determine whether there are any adverse events related to long-term exposure.”
Some participants have been taking the study drug for 3 years now. “They continue to tolerate it very well without any sign of unexpected or new or more severe toxicities,” he said. “That has been very gratifying and reassuring.”
“These data are very important,” Hope S. Rugo, MD, of the University of California, San Francisco, said. Dr. Rugo is not associated with the MONALEESA-2 trial. “The benefit seen with the longer follow-up appears to be the same as what was initially reported, and that’s really good.” The lack of any safety signals, she added, “is also excellent.”
There were not enough events to report overall survival, Dr. Hortobagyi said, but data will be available in 2 to 3 years.
He noted the importance of identifying the most appropriate patients for this and other CDK4/6 inhibitors. “There has to be a way to predict who will benefit,” he said. “The search for biomarkers in these targeted therapies is critically important.”
Investigators continue to evaluate biomaterial from the trials to identify biomarkers, he said, “but it is a slow and plodding process.”
MONALEESA-2 Safety Results
Dr. Hope Rugo
The median time to first occurrence of grade 3/4 neutropenia was 29 days, said lead author Wolfgang Janni, MD, of Heinrich-Heine-University, in Germany. The events resolved to grade 1 or 2 after a median of 15 days.
Neutropenia also was the most common adverse event that led to dose interruptions in the treatment versus placebo groups (49.7% vs. 0.6%) or reductions (31.1% vs. 0%), the majority of which occurred within the first six cycles. Treatment discontinuation as a result of neutropenia occurred in 0.9% of patients.
However, neutropenia was transient and reversible with dose modifications. Logistic regression analysis of pooled data from 276 patients across four clinical trials demonstrated that an increased probability of grade 2 or higher neutropenia was associated with higher levels of ribociclib exposure.
“In general, the incidence and severity of neutropenia decreased over time,” Dr. Janni said. There were no new cases of grade 4 neutropenia reported after nine cycles of treatment and no new safety concerns identified in patients who received ribociclib therapy for more than 18 months.
Other grade 3/4 adverse hematologic events that occurred in the first year were leukopenia (7.6%), anemia (0.9%), and thrombocytopenia (0.5%). There were no instances of hematologic events after 18 months of treatment.
Grade 3/4 elevated ALT and AST levels were reported in, respectively, 9.3% and 5.7% of patients who received ribociclib plus letrozole, and in 1.2% and 1.2% of patients in the placebo arm. All liver enzyme levels returned to normal after ribociclib discontinuation. QT prolongation occurred in 3.3% of patients in the ribociclib arm compared with 0.3% in the placebo arm.
Overall, adverse events led to dose interruptions in 68.0% of patients in the ribociclib arm compared with 13.3% of patients in the placebo arm. Adverse events led to dose reductions in 50.6% of the intervention group compared with 4.2% of the placebo group, and to treatment discontinuation in 7.5% of patients in the intervention group compared with 2.1% in the placebo group.
“The data support the current impression of a drug with a high degree of tolerability, especially in the context of neutropenia,” Dr. Janni said.
Although rates of grade 3/4 nausea and vomiting, infections, and diarrhea in the intervention arm were low during the first year (3.3%, 4.3%, and 0.9%, respectively), all-grade rates of these adverse effects were significantly higher (55.5%, 57.3%, and 32.7%, respectively). Rates of all such events, however, decreased substantially after 18 months.
These low-grade events are important, Dr. Rugo said. Although the analysis reflects what is already known about safety in this class of drugs, “it is important for practitioners to understand that there are a fair bit of grade 1 and 2 adverse events that may be important to patients, but are generally manageable,” Dr. Rugo continued. Thus, she said, it is critical that clinicians convey this information to their patients and manage the potential effects proactively.
The U.S. Food and Drug Administration approved ribociclib in March as a first-line treatment for HR-positive/HER2-negative metastatic breast cancer in combination with an aromatase inhibitor.
–Debra Gordon, MS