Staff reviewers at the FDA have questioned whether the lung cancer treatment rociletinib (Clovis Oncology) is more effective than available treatments. The reviewers also recommended including a boxed warning in the drug’s label, if it is approved.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) has scheduled a meeting on April 12 to discuss approval of the drug. The Prescription Drug User Fee Act (PDUFA) date for a final decision is June 28, 2016.
Rociletinib is an investigational therapy for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non–small-cell lung cancer (NSCLC) who have been previously treated with an EGFR-targeted therapy and have the T790M mutation. Rociletinib was granted a breakthrough therapy designation by the FDA in May 2014.
Data from two single-arm, nonrandomized trials (TIGER-X and TIGER-2) served as the basis for the U.S. regulatory submission. The studies were conducted in patients with EGFR T790M mutation-positive metastatic NSCLC who experienced progressive disease while receiving at least one EGFR tyrosine kinase inhibitor (TKI). In both trials, the patients received rociletinib at doses ranging from 500 mg twice daily (BID) to 1,000 mg BID. In the new drug application for rociletinib, the proposed recommended dosage was 500 mg BID. In patients who received this dosage (n = 79), the objective response rate (ORR) was 23%, with a median duration of response (DoR) of 9.1 months. In December 2015, Clovis Oncology notified the FDA of plans to amend the proposed recommended dosage to 625 mg BID; draft labeling reflecting this change was submitted to the FDA in January 2016. In the 170 patients who received rociletinib 625 mg BID, the ORR was 32%, with a median DoR of 8.8 months.
According to Clovis, the ongoing TIGER-3 trial will confirm the clinical benefit of rociletinib, should it be approved. TIGER-3 is an open-label, randomized, multinational study of rociletinib compared with single-agent chemotherapy (pemetrexed, docetaxel, or gemcitabine) in patients with EGFR-mutation positive NSCLC with disease progression following both an EGFR TKI and platinum doublet chemotherapy.
In November 2015, the FDA approved a similar drug, osimertinib (Tagrisso, AstraZeneca), for patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy. The approval was based on an ORR of 59% in a pooled analysis of 411 patients in two single-arm trials. The median DoR in a cohort of 63 patients with EGFR T790M mutation-positive NSCLC who received osimertinib in phase 1 was 12.4 months.
In a pooled safety analysis of rociletinib in 400 patients receiving dosages of 500 mg, 625 mg, 750 mg, or 1,000 mg BID, the most common grade 3 or 4 adverse events (AEs) were hyperglycemia and QTc prolongation. Dose reductions occurred in 51% of the patients. The most common AEs leading to these reductions were hyperglycemia (22%) and QTc prolongation (11%). Discontinuation due to an AE occurred in 11% of patients, most commonly due to QTc prolongation (2%) and pneumonia/pneumonitis (2%). Seventeen percent of patients had post-baseline QTc intervals of greater than 500 msec on at least one occasion. There were two sudden deaths, and one patient experienced Torsades de pointes.
During its April 12 meeting, ODAC will consider the following key issues: 1) whether Clovis’ proposed recommended dosage of 625 mg BID is supported by the clinical and pharmacology data; 2) whether the antitumor activity of rociletinib, as reflected by its ORR and DoR, are reasonably likely to predict clinical benefit and are superior to that of available therapy; 3) whether the risks (particularly with respect to QTc prolongation leading to Torsades de pointes) are acceptable in the intended population; and 4) whether a risk evaluation and mitigation strategy (REMS) or other strategies may be necessary to lessen the risks of treatment with rociletinib and to ensure safe use.