Ribociclib’s benefit extends across intrinsic subtypes and over time

BY SUSAN LONDON


Ribociclib has benefit across diverse intrinsic subtypes of hormone receptor (HR)–positive, HER2-negative advanced breast cancer and improves overall survival long term in younger women, according to two new analyses from the MONALEESA trials.

Ribociclib, an oral CDK4/6 inhibitor, was approved by the Food and Drug Administration for use along with endocrine therapy in this patient population about 4 years ago, but specifics of its efficacy are still being clarified.

The new analyses, reported at the 2020 San Antonio Breast Cancer Symposium, help provide a clearer picture.

Intrinsic subtypes

In the first analysis (Abstract GS1-04), investigators pooled data from the MONALEESA-2, -3, and -7 trials. All trials had a phase 3, randomized, controlled design and were conducted among women with HR-positive, HER2-negative advanced breast cancer. Each trial showed a significant benefit of ribociclib over placebo when added to endocrine therapy.

In the new analysis, investigators analyzed data from 1,160 women with known intrinsic subtypes: 47% had luminal A disease, 24% had luminal B disease, 14% had normal-like disease, 13% had HER2-enriched disease, and 3% had basal-like disease.

Intrinsic subtype was prognostic, with median progression-free survival that differed across subtypes in both the placebo group (P < .001) and the ribociclib group (P < .001). Longest values were seen in the luminal A subtype, and shortest values were seen in the basal-like subtype. Findings were similar in analyses adjusted for clinical factors.

When patients were stratified by subtype, the progression-free survival benefit of ribociclib over placebo was seen in luminal A disease (hazard ratio, 0.63; P < .001), luminal B disease (HR, 0.52; P < .001), and especially HER2-enriched disease (HR, 0.39; P < .001), but not basal-like disease.


Dr. Aleix Prat
“These results confirm previous studies looking at the independent prognostic value of intrinsic subtypes,” said investigator Aleix Prat, MD, PhD, of Hospital Clinic of Barcelona.

“This study clearly shows that the HER2-enriched, luminal A, and luminal B subtypes all exhibited a consistent progression-free survival benefit with ribociclib treatment, while patients with basal-like subtype did not. Importantly, the group of patients with HER2-enriched subtype, which had a very poor prognosis in the placebo arm, is shown for the first time to have the greatest relative reduction in risk of progression or death with ribociclib plus endocrine therapy,” Dr. Prat noted.

Durable benefit

In the second analysis (Abstract PD2-04), investigators performed an exploratory update of overall survival for MONALEESA-7. This trial enrolled only pre- and perimenopausal women, a population of special interest given their differences in disease biology and degree of ovarian suppression.

“HR-positive, HER2-negative breast cancer has a long natural history, and the outcomes of patients may change over time. So, for this group of patients, it’s important to have long-term follow-up,” said investigator Debasish (Debu) Tripathy, MD, of the University of Texas MD Anderson Cancer Center, Houston.

“We’re still early in the phases of CDK inhibitor use in patients. One of the important outcomes is what happens to patients afterward,” he added.



Dr. Debasish (Debu) Tripathy

The trial’s final protocol-specified analysis of overall survival included 672 women with a median follow-up of 34.6 months (N Engl J Med. 2019;381:307-16). The median overall survival was not reached in the ribociclib arm and was 40.9 months in the placebo arm (HR, 0.71; P = .00973). This corresponds to a 29% reduction in risk of death with ribociclib. After unblinding, 15 women in the placebo arm opted to cross over to ribociclib.

The median follow-up at the time of the update was 53.5 months. Overall, 12.9% of patients in the ribociclib arm and 26.1% in the placebo arm received a subsequent CDK4/6 inhibitor.

The median overall survival was 58.7 months in the ribociclib arm and 48.0 months in the placebo arm (HR, 0.76; 95% CI, 0.61-0.96), corresponding to a 24% reduction in the risk of death with ribociclib.

In subgroup analyses, findings were similar whether the partner endocrine therapy was a nonsteroidal aromatase inhibitor (HR, 0.80) or tamoxifen (HR, 0.71).

The ribociclib group also had a longer median time to first subsequent chemotherapy (50.9 vs. 36.8 months; HR, 0.69), chemotherapy-free survival (42.4 vs. 26.4 months; HR, 0.67), and second progression-free survival (44.2 vs. 31.0 months; HR, 0.68).

The safety profile was generally consistent with that in previously reported analyses.

“This analysis demonstrated a consistent significant overall survival benefit with ribociclib after a median follow-up of 53.5 months, despite crossover and use of subsequent CDK4/6 inhibitors in the placebo arm,” Dr. Tripathy summarized. “The median overall survival of 58.7 months in the ribociclib arm is the longest reported among the phase 3 trials for HR-positive, HER2-negative breast cancer.”

“Progression-free survival 2 was prolonged overall, so it’s not as though the effect went away when you factored in control of disease with the next line of therapy,” he added. “It’s reassuring to know that, over the course of the patient’s overall treatment sojourn, a first choice of using CDK inhibitor does, in fact, produce a long-lasting benefit.”

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‘Here to stay’


“The median overall survival was not reached in the ribociclib group in the previous analysis, so I do think it was important to continue to follow these results,” noted invited discussant Amy S. Clark, MD, of University of Pennsylvania, Philadelphia.

The findings of the update demonstrate durable benefit of ribociclib in this patient population, she said, as well as a prolongation of the time to chemotherapy.

“This is an incredibly important outcome for these patients who live for many years and who would like to delay the time to chemotherapy as much as possible,” she noted.

“These data are continued evidence that ribociclib should be considered for use in pre- and perimenopausal women with newly diagnosed, ER-positive metastatic breast cancer. We all know that CDK4/6 inhibitors are here to stay, and this analysis of MONALEESA-7 really underscores the fact that all patients with ER-positive metastatic disease should be receiving CDK4/6 inhibitors,” Dr. Clark concluded.

The analyses were sponsored by Novartis Pharmaceuticals. Dr. Prat and Dr. Tripathy disclosed relationships with Novartis and many other companies. Dr. Clark disclosed no conflicts of interest.

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