The combination of ribociclib and fulvestrant led to an approximate 28% reduction in the risk of death compared with placebo and fulvestrant in postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer.
Dennis J. Slamon, MD, PhD
The combination of ribociclib (Kisqali) and fulvestrant (Faslodex) led to an approximate 28% reduction in the risk of death compared with placebo and fulvestrant in postmenopausal patients with hormone receptor (HR)—positive, HER2-negative advanced breast cancer, according to findings of the phase III MONALEESA-3 trial that were presented at the 2019 ESMO Congress.1
The median OS was not reached in the ribociclib arm (42.5 to not reached [NR]) and was 40.0 months with placebo (37.0 to NR) at a median follow-up of 39.4 months (HR, 0.724; 95% CI, 0.568-0.924; P = .00455). The P value had crossed the prespecified boundary of .01129 to claim superior efficacy, noted lead study author Dennis J. Slamon, MD, PhD.
“[These data] show that there is a significant but also clinically meaningful benefit in terms of prolongation of progression-free survival (PFS) and now OS, regardless of whether the patient is premenopausal or postmenopausal, and regardless of whether they received their [treatment] in the frontline setting or subsequently,” Slamon, director of Clinical/Translational Research, Revlon/University of California, Los Angeles (UCLA) Women's Cancer Research Program, Jonsson Comprehensive Cancer Center, and a 2014 Giant of Cancer Care® in Breast Cancer, stated in a press conference during the meeting.
Ribociclib was initially approved in March 2017 for use in combination with an aromatase inhibitor (AI) for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer. In July 2018, the agency expanded its indication to include for use in combination with an AI for the treatment of pre/perimenopausal or postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer. It was simultaneously approved for use in combination with fulvestrant for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy.
The indication to include fulvestrant was based on PFS results from the MONALEESA-3 study, in which the median PFS was 20.5 months with ribociclib and fulvestrant compared with 12.8 months for placebo/fulvestrant (HR, 0.593; P <.0001).2 Moreover, in June 2019, results of the MONALEESA-7 trial showed that ribociclib plus endocrine therapy demonstrated a statistically significant improvement in OS compared with endocrine therapy alone in premenopausal patients with HR-positive advanced breast cancer (HR, 0.71; P = .00973).3
In MONALEESA-3, 726 postmenopausal men and women with HR-positive, HER2-negative advanced breast cancer were randomized 2:1 to ribociclib at 600 mg daily in a 3-weeks-on/1-week-off schedule plus fulvestrant at 500 mg daily or placebo. Patients were stratified by the presence or absence of liver or lung metastases and prior endocrine therapy.
“What was somewhat unique in this study was that essentially half of patients were getting their [study] therapy in the first-line setting,” said Slamon. “In other words, they had not received any therapy for metastatic breast cancer, and they were being compared with those who were getting fulvestrant [alone] in the same setting."
Baseline patient characteristics were generally balanced between arms. The median age was 63 years. Approximately 61% of patients had visceral disease and 21% had bone-only metastasis. About 60% of patients received prior endocrine therapy in the neoadjuvant setting and 16.5% (placebo arm) and 22.7% (ribociclib arm) in the adjuvant setting. Half of the patients received the study treatment in the first-line setting and half in the second-line setting.
The primary endpoint was locally assessed PFS per RECIST v1.1 criteria; secondary endpoints were OS, overall response rate, clinical benefit rate, time to response, duration of response, time to definitive deterioration of ECOG performance status, patient-reported outcomes, safety, and pharmacokinetics.
As of the data cutoff date of June 3, 2019, results also showed that 25% of patients on ribociclib treatment continued to be on therapy compared with 13% of those who received placebo. A landmark analysis of 3- and 4-year OS rates were 67.0% and 57.8% with ribociclib/fulvestrant compared with 58.2% and 45.9% for placebo/fulvestrant, respectively.
"What is interesting about the MONALEESA-3 data is that we have not yet reached the median [OS] in the experimental arm; they are continuing on and we don’t know how far up that curve will go,” Slamon added. “That is certainly good for the patients."
OS was also superior with ribociclib/fulvestrant in both the first-line or early relapse/second-line settings. In the frontline setting, the median OS with ribociclib/fulvestrant was not reached compared with 45.1 months for placebo/fulvestrant (HR, 0.700; 95% CI, 0.479-1.021). When given in the early relapse/second-line setting, ribociclib/fulvestrant was associated with a median OS of 40.2 months compared with 32.5 months for the fulvestrant/placebo arm (HR, 0.730; 95% CI, 0.530-1.004).
The CDK4/6 inhibitor also improved OS across several patient subgroups, including those with bone lesions (HR, 0.60; 95% CI, 0.33-1.07), no lung or liver metastases (HR, 0.65; 95% CI, 0.45-0.93), were white (HR, 0.68; 95% CI, 0.52-0.88), those with metastatic disease (HR, 0.69; 95% CI, 0.40-1.20), and those from North America (HR, 0.60; 95% CI, 0.33-1.12).
PFS, which was also updated with the available OS data, was consistent with the prior readout. With the longer follow-up, the median PFS with first-line ribociclib/fulvestrant and placebo was 33.6 months and 19.2 months, respectively (HR, 0.546; 95% CI, 0.415-0.718). Additionally, median PFS2 was also longer in the ribociclib arm versus the fulvestrant/placebo arm at 39.8 months versus 29.4 months, respectively (HR, 0.670; 95% CI, 0.542-0.830).
Moreover, no new safety signals were observed. Key grade 3/4 adverse events (AEs) of special interest in the ribociclib/fulvestrant and fulvestrant/placebo arms, respectively, included neutropenia (57.1% vs 0.8%, respectively), hepatobiliary toxicity (13.7% vs 5.8%), pulmonary disorders (0.2% vs 0%), and QTc prolongation (3.1% vs 1.2%). No grade 3/4 pneumonitis or interstitial lung disease were observed in either group, and no episodes of Torsades de Pointes were reported.
During the press conference, Nadia Harbeck, MD, PhD, head of Breast Center, Ludwig Maximilians University, discussed the clinical implications of the updated MONALEESA-3 data.
“MONALEESA-3, for the first time, gives us data in the first- and second-line setting. For patients who have not been receiving any endocrine therapy before that, that makes it highly clinically meaningful, because we were always struggling with whether to give these drugs in the first- or second-line setting,” Harbeck explained. “Now, we see there is a first-line survival benefit; that should be the new standard of care—a CDK4/6 inhibitor in the first-line setting. The data are highly clinically meaningful, and I think they’re going to make a huge impact in how we treat metastatic breast cancer.”