The European Medicine’s Agency Committee for Medicinal Products for Human Use has recommended expanding the approval of ribociclib (Kisqali) in women with HR+/HER2-negative breast cancer to include use in combination with fulvestrant (Faslodex).
The European Medicine’s Agency Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approval of ribociclib (Kisqali) in women with HR+/HER2-negative breast cancer to include use in combination with fulvestrant (Faslodex) as initial endocrine-based therapy, as well as for women who received prior endocrine therapy.1
Ribociclib was also recommended to be approved in combination with endocrine therapy and an LHRH agonist for pre- and perimenopausal patients. The agent is currently indicated in Europe for use in combination with an aromatase inhibitor (AI) as frontline treatment of postmenopausal patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer.
"Today's CHMP opinion brings us one step closer to providing more women with HR-positive/HER2-negative advanced breast cancer in Europe with a treatment option," said Liz Barrett, CEO of Novartis Oncology, the developer of the CDK4/6 inhibitor. "The MONALEESA phase III program enrolled more than 2000 women, giving Kisqali by far the most extensive first-line evidence in clinical trials among any of the CDK4/6 inhibitors. This is another testament to how we are reimagining cancer."
The positive CHMP opinion is based on data from the phase III MONALEESA-7 and MONALEESA-3 studies, which demonstrated an improvement in progression-free survival (PFS) for the ribociclib-based regimens versus endocrine therapy alone. The PFS benefits were observed as early as 8 weeks after start of ribociclib combination treatment.
In the phase III MONALEESA-7 trial, combining ribociclib with an AI resulted in a 14-month improvement in median PFS compared with an AI alone at 27.5 versus 13.8 months, respectively (HR, 0.569; 95% CI, 0.436-0.743).2
MONALEESA-7 randomized patients to either ribociclib plus tamoxifen or a nonsteroidal aromatase inhibitor plus goserelin (n = 335), or to endocrine treatment plus goserelin (n = 337). Across the overall study population, the median PFS was 23.8 months for the ribociclib arm compared with 13.0 months for the control arm (HR, 0.553; 95% CI, 0.441-0.694; P <.0001).
Among all patients, the overall response rate (ORR) was 40.9% for the ribociclib arm compared with 29.7% for the placebo arm (P = .00098). In patients with measurable disease, the ORRs were 50.9% versus 36.4%, respectively (P = .000317). Also among patients with measurable disease, the clinical benefit rate was 79.9% versus 67.3%, respectively (P = .000340).
The recommendation for ribociclib plus fulvestrant was based on the phase III MONALEESA-3 trial, in which the median PFS was 20.5 months in patients randomized to the ribociclib combination versus 12.8 months in those randomized to fulvestrant plus placebo (HR, 0.593; 95% CI, 0.480-0.732; P = .00000041).3
In this trial, 726 postmenopausal women with HR-positive, HER2-negative advanced breast cancer were randomized 2:1 to ribociclib combined with fulvestrant or placebo. The primary endpoint was investigator-assessed PFS.
The PFS benefit with ribociclib was equally apparent in all subgroups, including those defined by prior line of endocrine therapy, metastatic site and number of metastatic sites, prior tamoxifen therapy, prior AI therapy, age, race, and performance status. When ribociclib was given as first-line therapy, the median PFS was not reached in the ribociclib arm and was 18.3 months in the placebo group (HR, 0.577; 95% CI, 0.415-0802). When given as a second-line treatment, median PFS was 14.8 months and 9.1 months with ribociclib and placebo (HR, 0.565; 95% CI, 0.428-0.744).
Across the study population, the ORR was 32.4% with ribociclib versus 21.5% with placebo (P = .000912). In patients with measurable disease, ORR was 40.9% and 28.7%, (P = .003) with the CDK4/6 inhibitor and placebo, respectively. The clinical benefit rate was 70.2% for ribociclib versus 62.8% for placebo (P = .020) in the overall cohort, and 69.4% versus 59.7% (P = 0.015), respectively, in patients with measurable disease.
Across both studies, the most common adverse events reported were neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash, and cough.
The European Commission will review the CHMP opinion prior to its decision on both ribociclib regimens. If approved, the decision will be applicable to all 28 European Union countries, including Iceland, Norway, and Liechtenstein. Additional regulatory filings are underway with other global agencies.
In July 2018, the FDA approved frontline ribociclib for the same indications: 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, and 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.
Ribociclib was first approved by FDA in March 2017 for use in combination with an AI as initial endocrine-based therapy for postmenopausal women with HR-positive/HER2-negative locally advanced or metastatic breast cancer.