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FDA Expands Ribociclib Breast Cancer Approval Under New Pilot Programs

Jason M. Broderick @jasoncology
Published: Wednesday, Jul 18, 2018

The FDA has approved upfront ribociclib (Kisqali) for use in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer. The agency also approved the CDK4/6 inhibitor 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 approval for the ribociclib/AI regimen was based on the phase III MONALEESA-7 trial, in which combining ribociclib with an AI resulted in a 14-month improvement in median progression-free survival (PFS) compared with an AI alone (27.5 vs 13.8 months; HR, 0.569; 95% CI, 0.436-0.743).1 The approval 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, compared with 12.8 months in those randomized to fulvestrant plus placebo (HR, 0.593; 95% CI, 0.480-0.732; P =.00000041).2

According to a statement from the FDA, “This is the first approval that the FDA has granted as a part of two new pilot programs announced earlier this year that collectively aim to make the development and review of cancer drugs more efficient, while improving FDA’s rigorous standard for evaluating efficacy and safety. With this real-time review, the FDA was able to start evaluating the clinical data as soon as the trial results become available, enabling the FDA to be ready to approve the new indication upon filing of a formal application with the agency.”


MONALEESA-7 randomized patients to either ribociclib in combination with tamoxifen or a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole) 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).

Patient characteristics were balanced between the 2 arms. The median patient age in the ribociclib arm was 43 (range, 25-58); 55.8% of patients were white; 29.6% were Asian; 8.7% were black, Native American, and other; and the race of 6.0% of patients was unknown.

The ECOG performance status was 0 for 73.1% of patients, 1 for 26.0%, and unknown for the remaining 0.9%. Visceral metastases was detected in 57.6% of patients, with 24.2% having bone-only metastases.

Prior neoadjuvant or adjuvant endocrine therapy was reported for 37.9% of patients. Fourteen percent of patients had prior chemotherapy for advanced disease, 41.2% had prior neoadjuvant or adjuvant chemotherapy, and 44.8% of patients had no prior chemotherapy. At baseline, the disease-free interval was ≤12 months for 6.9% of patients and >12 months for 52.5% of patients.

The experimental regimen consisted of daily oral administration of ribociclib at 600 mg; tamoxifen at 20 mg, or letrozole at 2.5 mg, or anastrozole at 1 mg; and a subcutaneous injection of goserelin at 3.6 mg once every 28 days. Ribociclib treatment was administered for 3 weeks followed by 1 week off.

The PFS benefit with ribociclib was similar when the CDK4/6 inhibitor was combined with either tamoxifen or an NSAI. For the 87 patients receiving ribociclib/tamoxifen, the median PFS was 22.1 months (95% CI, 16.6-24.7) compared with 11.0 months (95% CI, 9.1-16.4) for the 90 patients treated with tamoxifen plus placebo (HR, 0.585; 95% CI, 0.387-0.884). Among the 248 patients treated with ribociclib plus an NSAI, the median PFS was 27.5 months (95% CI, 19.1 to not reached) compared with 13.8 months (95% CI, 12.6-17.4) for patients receiving an NSAI plus placebo (HR, 0.569; 95% CI, 0.436-0.743).

The ribociclib PFS benefit was also consistent across other prespecified subgroups, including age (<40 years: HR, 0.443; ≥40 years: HR, 0.590), race (Asian: HR, 0.401; non-Asian: HR, 0.657), ECOG performance status (0: HR, 0.549; 1: HR, 0.495), ER/PgR status (ER+/PgR+: HR, 0.574; other: 0.444), liver and/or lung involvement (no: HR, 0.642; yes: HR, 0.503), bone-only disease (no: HR, 0.533; yes: HR, 0.703), prior chemotherapy for advanced disease (no: HR, 0.566; yes: HR, 0.547) and disease-free interval (≤12 months: HR, 0.560; >12 months: HR, 0.615; de novo: HR, 0.428).

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 median duration of exposure was 15.1 months for the ribociclib arm compared with 11.4 months for the control arm. Patient-reported outcomes showed that ribociclib was associated with a statistically significant improvement in time to deterioration, as well as a durable, clinically meaningful reduction in pain score as early as 8 weeks after initiation.

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