The US Food and Drug Administration (FDA) approved two ribociclib (Kisqali) combination treatments for subsets of advanced breast cancer in less than a month using a pilot process called the Real-Time Oncology Review.
The U.S. Food and Drug Administration (FDA) approved ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer as initial endocrine-based therapy for pre/perimenopausal or postmenopausal women. It also approved ribociclib in combination with fulvestrant (Faslodex) for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following 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). 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.
Using its new Real-Time Oncology Review process, the FDA processed this approval in less than a month, instead of the several months it would have ordinarily taken. This process is one of two new processes the FDA is piloting to increase efficiency and improve standards.
“[B]y analyzing data earlier in the process, before formal submission to the FDA, and evaluating submissions in a structured template, we can make it easier to identify earlier when applications are missing key analysis or information that can delay reviews,” said FDA Commissioner Scott Gottlieb, MD. “With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information. This enabled our approval less than one month after the June 28 submission date and several months ahead of the goal date.”
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.
Neutropenia was the most frequently reported adverse event (AE) for both the experimental arm (76%) and the placebo arm (8%) in updated safety results. Six in 10 patients in the ribociclib arm experienced grade 3/4 neutropenia compared with 4% in the placebo arm, but the condition was asymptomatic in most patients. Two percent of patients in the experimental arm and 1% in the placebo arm experienced neutropenia associated with fever and infection.
Other AEs included hot flashes, nausea, leukopenia, and joint pain/stiffness. The most common (≥5%) grade 3/4 AEs in patients receiving ribociclib combination therapy compared to endocrine therapy alone were neutropenia (60.6% vs 3.6%) and leukopenia (14.3% vs 1.2%)
Treatment was discontinued in 48.1% (n = 161) of the ribociclib arm and 64.1% (n = 216) of the placebo group. Disease progression and AEs were the cause of discontinuation for 36.4% (n = 22) versus 51.6% (n = 174) and 3.6% (n = 12) versus 3.0% (n = 10) of the ribociclib versus control arms, respectively.
In MONALEESA-3, a total of 726 postmenopausal women with HR-positive, HER2-negative advanced breast cancer were randomized 2:1 to ribociclib, 600 mg/day in a 3-weeks-on/1-week-off schedule plus fulvestrant, 500 mg/day, or placebo. The primary objective was investigator-assessed PFS.
Baseline patient characteristics were balanced between arms. The median patient age was 63 years. Approximately 60% of patients had visceral disease and 21% had bone-only metastasis. Half of the patients received treatment in the first-line setting and half in the second-line setting. 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.
The median duration from randomization to data cut-off was 20.4 months. At the time of the analysis, treatment was ongoing in 42.1% of those randomized to ribociclib and 31.4% of those in the placebo arm. Treatment was discontinued in 57.6% and 68.2% of patients, respectively. The primary reason for treatment discontinuation was disease progression in 39.9% of patients in the ribociclib arm and 58.7% of patients in the placebo arm.
In addition to investigator assessment, PFS by a blinded Independent Review Committee was assessed in 290 patients as a supportive analysis, which demonstrated that median PFS was not reached in the ribociclib arm and was 10.9 months in the placebo arm. Corresponding to a 51% reduction in the risk of progression with ribociclib (HR, 0.492; 95% CI, 0.345-0.703).
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 aromatase inhibitor 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 arm (HR, 0.577; 95% CI, 0.415-0802). When used in the second-line setting, median PFS was 14.8 months in the ribociclib arm and 9.1 months in the placebo arm (HR, 0.565; 95% CI, 0.428-0.744).
In all patients, the ORR was 32.4% in the ribociclib arm versus 21.5% in the placebo arm (P = 0.000912) and in those with measurable disease, ORR was 40.9% and 28.7%, (P = 0.003), respectively. The clinical benefit rate was 70.2% for ribociclib versus 62.8% for placebo (P = 0.020) in the overall cohort, and 69.4% versus 59.7% (P=0.015), respectively, in patients with measurable disease.
Overall survival data were not mature at data cut-off. At the time of data analysis, 14.5% of patients in the combination ribociclib/fulvestrant arm and 20.7% in the placebo/fulvestrant arm died.
Median relative dose intensity (ribociclib or placebo) was 92.1% in the ribociclib arm and 100% in the placebo arm. Dose interruption due to adverse events was required in 68.5% of the ribociclib arm and 18.7% of the placebo arm.
Grade 3 neutropenia occurred in 46.6% of the ribociclib recipients versus 0% of the placebo recipients, and the corresponding rates of grade 4 neutropenia were 6.8% and 0%, respectively. Febrile neutropenia was observed in 5 (1.0%) patients in the ribociclib arm and none in the placebo arm. Post-baseline QTcF >480 ms occurred in 5.6% of patients in the ribociclib arm and 2.5% in the placebo arm. Grade 3 and 4 elevation in alanine transaminase and aspartate transaminase occurred in 6.6% of patients and 1.9% of the ribociclib arm, respectively, and in 4.8% and 1.2% of the placebo arm.
New Processes Speed Approval
The FDA is beginning to implement two new pilot policies to improve efficiency in the approval processes while improving their efficacy and safety evaluation standards: the Real-Time Oncology Review, used for the first time for this ribociclib approval—and the Assessment Aid.
Under the Real-Time Oncology Review, the FDA is able to review pivotal clinical trial data as soon as it becomes available, prior to the formal submission of an application. Assessment Aid consists of a new template for submitting an application that is structured to facilitate a streamline process for the agency to review the application, keeping the focus on efficacy and safety of data over administrative information.
“With this approval, we’ve demonstrated some of the benefits of the new programs that we’re piloting for our review of cancer drugs, to improve regulatory efficiency while enhancing the process for evaluating the data submitted to us. This shows that, with smart policy approaches, we can gain efficiency while also improving the rigor of our process. These new programs were designed to reduce some of the administrative issues that can add to the time and cost of the review process, including the staffing burdens on the FDA,” Gottlieb said in the statement.
“With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information. This enabled our approval less than 1 month after the June 28 submission date and several months ahead of the goal date.”
Commenting on the approval, Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation, said “The approval adds a new treatment choice for patients with breast cancer. We are committed to continuing to bring more treatment options to patients.”