Ribociclib-fulvestrant combination extends OS among postmenopausal women with advanced breast cancer
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BARCELONA, Spain — The addition of ribociclib to fulvestrant significantly extended OS among postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, according to results of the randomized phase 3 MONALEESA-3 trial presented at European Society for Medical Oncology Congress.
The combination of ribociclib (Kisqali, Novartis) — a cyclin-dependent kinase (CDK) 4/6 inhibitor — and fulvestrant conferred benefit to women who had not previously received hormonal therapy, as well as those who had developed resistance to endocrine therapy.
The findings are practice changing, Dennis J. Slamon, MD, PhD, director of clinical/translational research at UCLA Jonsson Comprehensive Cancer Center and chief of the division of hematology/oncology for UCLA’s department of medicine, told HemOnc Today.
“These results put to rest the debate about whether this drug should be used in the first-line setting,” Slamon said in an interview. “Many people argued we should hold it in reserve, give hormonal therapy only and wait until recurrence before adding a CDK 4/6 inhibitor. These data clearly show patients have a survival advantage if you give it upfront.”
Prior studies showed combinations of CDK 4/6 inhibitors and fulvestrant were effective for patients with hormone receptor-positive breast cancer whose disease progressed during prior endocrine therapy. However, no study had evaluated the ribociclib-fulvestrant combination for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and no study had evaluated the combination of a CDK 4/6 inhibitor and fulvestrant for patients with hormone receptor-positive, HER2-negative de novo advanced breast cancer or patients who developed relapse more than 1 year after prior endocrine therapy.
Results of the MONALEESA-7 study, presented at this year’s ASCO Annual Meeting, showed premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer derived a significant survival benefit from the addition of ribociclib to endocrine therapy.
The international, double-blind MONALEESA-3 trial evaluated the combination among postmenopausal women.
Researchers randomly assigned 726 women 2:1 to fulvestrant plus ribociclib or fulvestrant plus placebo as first-line or second-line treatment. About half of patients had received no prior therapy for metastatic disease.
Results published last year in Journal of Clinical Oncology showed the ribociclib-fulvestrant combination significantly improved median PFS (20.5 months vs. 12.8 months; HR = 0.59; 95% CI, 0.48-0.73).
At ESMO, Slamon presented results from the second of three protocol-specified OS analyses, as well as additional PFS data.
At data cutoff, 275 patients (167 assigned ribociclib and 108 assigned placebo) had died, and 153 patients (121 assigned ribociclib and 32 assigned placebo) remained on treatment.
Median follow-up was 39.4 months.
Results showed a statistically significant improvement in OS among ribociclib-treated patients (median, not reached vs. 40 months; HR = 0.72; 95% CI, 0.56-0.92).
“One very exciting thing about these data is we have not yet reached the median in the experimental arm,” Slamon said. “They are continuing on, and we don’t know how far up that curve will go to tell you what the difference is going to be. That’s certainly good for the patients.”
Landmark analyses estimated higher OS rates among ribociclib-treated patients at 36 months (67% vs. 54.2%)
Researchers observed the OS benefit with ribociclib-fulvestrant across all patient subgroups, including patients who received the combination as first-line treatment (median, not reached vs. 45.1 months; HR = 0.7; 95% CI, 0.47-1.02) and those in the early relapse/second-line setting (median, 40.2 months vs. 32.5 months; HR = 0.73; 95% CI, 0.53-1).
Among patients who received first-line treatment, median PFS was significantly longer with ribociclib-fulvestrant (33.6 months vs. 19.2 months; HR = 0.54; 95% CI, 0.41-0.71).
In addition, PFS2 — defined as time to progression on next-line therapy or death — also was significantly longer in that group (median, 39.8 months vs. 29.4 months; HR = 0.67; 95% CI, 0.54-0.83).
The safety profile of the ribociclib-fulvestrant combination appeared consistent with that observed in previously published analyses.
The most common grade 3/grade 4 adverse events of special interest were neutropenia (57.1% for ribociclib0fulvestrant vs. 0.8% for fulvestrant alone), hepatobiliary toxicity (13.7% vs 5.8%), QTc prolongation (3.1% vs 1.2%), respiratory disorders (2.3% vs 3.3%) and interstitial lung disease (0.2% vs 0%).
Three decades ago, Slamon discovered the link between the HER2-positive gene alteration and aggressive breast cancer. He was one of three cancer researchers who received this year’s Lasker-DeBakey Clinical Medical Research Award for their role in the development of trastuzumab (Herceptin, Genentech), an anti-HER2 monoclonal antibody.
“I was very fortunate to be involved in bringing the HER2 story forward, and it’s wonderful to now see this other class of agents provide the same sort of magnitude of effect for this subtype as we saw with trastuzumab in HER2-positive disease,” Slamon told HemOnc Today. “I think it’s clear these drugs will make a big impact.”
The “remarkable results” confirm the benefit patients with hormone receptor-positive, HER2-negative advanced breast cancer derive from the combination of CDK 4/6 inhibition and endocrine therapy, according to Matteo Lambertini, MD, medical oncologist at IRCCS Policlinico San Martino Hospital and adjunct professor at University of Genoa in Italy.
“This treatment should be made widely available to all our patients in this setting,” Lambertini, who was not involved with the study, said in an ESMO-issued press release. “Uniquely, MONALEESA-3 is the only trial with a CDK4/6 inhibitor to include patients with endocrine-sensitive as well as those with endocrine-resistant disease. This is the first time we have seen improved overall survival with a combination of a CDK4/6 inhibitor plus fulvestrant in [the] first line.” – by Mark Leiser
Reference s :
Slamon DJ, et al. Abstract LBA7_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Slamon DJ, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.78.9909.
Slamon DJ, et al. Ribociclib plus fulvestrant in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from MONALEESA-3. Presented at: Chemotherapy Foundation Symposium; Nov. 7-9, 2018; New York.
Disclosures: Novartis funded this study. Slamon reports a board of directors role with Biomarin; stock or other ownership in Pfizer and Vertex; honoraria from Novartis; consultant/advisory roles with Eli Lilly and Novartis; research funding form Novartis and Pfizer; and travel accommodations or expenses from Biomarin, Novartis and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures. HemOnc Today could not confirm Lambertini’s relevant financial disclosures at the time of reporting.
Perspective
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Nadia Harbeck, MD, PhD
We have struggled with whether to give these drugs in the first- or second-line setting. This study gives us for the first time data from the first- and second-line settings, and we see there is a first-line survival benefit.
These new data strengthen the argument that we should start treatment in the metastatic setting with a CDK 4/6 inhibitor plus endocrine therapy because these drugs substantially improve patient outcomes compared [with] antihormonal treatment alone.
These data are highly clinically meaningful and I think they are going to make a huge impact on how we treat metastatic breast cancer. We didn’t even see a median OS because patients are doing so well.
These drugs should be a first-line standard in the metastatic setting, as we should always give our best drugs first. It will be important to explore the potential of these drugs in the early breast cancer setting, where we can go beyond trying to prolong survival and actually reach for a cure.
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