FDA Uses New Process to Approve Ribociclib Extensions

Zosia Chustecka


July 18, 2018

The US Food and Drug Administration (FDA) has used a new process to approve extensions to the use of a drug for treatment of breast cancer, ribociclib (Kisqali, Novartis).

The drug is a selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, and this strategy of CDK4/6 inhibition has been shown to overcome or delay resistance to endocrine therapy.

Ribociclib was first approved by the FDA in March 2017 for use in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in postmenopausal women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer.

Approximately 72% of patients with breast cancer have tumors that are HR positive and HER2 negative, the agency notes.

This approval was based on the interim results from the pivotal phase 3 MONALEESA-2 trial involving 668 postmenopausal women who received no prior systemic therapy for their advanced breast cancer. The results showed that that ribociclib plus the AI letrozole reduced the risk for progression or death by 44% over letrozole alone (N Engl J Med. 2016;375:1738-1748).

Now, the FDA has added pre- and perimenopausal women to this indication.

The new approval is for ribociclib use in combination with an AI as initial endocrine-based therapy for the treatment of pre-/perimenopausal or postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

This additional indication for use in pre-/perimenopausal women was demonstrated in a clinical trial of 495 participants, all of whom received ovarian suppression with goserelin. This trial showed that progression-free survival (PFS) was longer for patients taking ribociclib plus an AI (median PFS, 27.5 months) than patients who received placebo plus an AI (median PFS, 13.8 months).

The FDA also approved another use of the drug: ribociclib in combination with fulvestrant 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 efficacy of ribociclib in combination with fulvestrant in treating advanced or metastatic breast cancer was demonstrated in a clinical trial that included 726 participants. It showed that PFS was longer for patients taking ribociclib plus fulvestrant (median PFS, 20.5 months) than patients who received placebo plus fulvestrant (median PFS, 12.8 months).

The FDA notes that common side effects of ribociclib are infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss, and rash.

Warnings include the risk for a cardiac QT prolongation that can cause an abnormal heartbeat and may lead to death, as well as the risk for serious liver problems, low white blood cell counts that may result in possibly severe infections, and fetal harm.

Two New Pilot Programs

In approving these additional two indications for ribociclib, the FDA used for the first time two new pilot programs announced earlier this year.

Together, these two new programs "collectively aim to make the development and review of cancer drugs more efficient, while improving FDA's rigorous standard for evaluating efficacy and safety," the agency commented.

The first of these new programs, known as Real-Time Oncology Review, allows for the FDA to review much of the data earlier, after the clinical trial results become available and the database is locked, before the information is formally submitted to the FDA.

"This allows the FDA to begin its analysis of the data earlier, and provide feedback to the sponsor on how they can most effectively analyze the data to answer key regulatory questions," the agency explained.

The second of the two new programs is a new templated Assessment Aid that the applicant uses to organize its submission into a structured format to facilitate FDA's review of the application, the agency notes.

"By using a structured template, the FDA is able to layer its assessment into the same file submitted by the sponsor, allowing this annotated application to serve as the document that contains the FDA review. This voluntary submission form provides for a more streamlined approach to reviewing data and illustrating FDA's analysis. It allows for drug reviewers to focus on the key benefit-risk and labeling issues rather than administrative issues," the agency explains.

FDA Commissioner Scott Gottlieb, MD, commented: "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."

In this case, using the new process "enabled our approval less than one month after the June 28 submission date and several months ahead of the goal date," he noted.

"These new processes are good for patients, good for health care providers, good for product developers, and good for the FDA, by allowing our staff to have more time to engage with product developers and focus on the key aspects of drug reviews," he said.

The two pilot programs are being used for supplemental applications for already-approved cancer drugs, but they could later be expanded to original drugs and biologics, the agency commented.

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