FDA Approves Vemurafenib for Rare Blood Cancer

Richard Pazdur, MD

The FDA has approved vemurafenib (Zelboraf) as a treatment for patients with BRAF V600-mutated Erdheim-Chester disease (ECD), representing the first approved therapy for this rare blood disorder.

The approval was based on findings from the phase II VE-BASKET study, which included 22 patients with the rare, non-Langerhans histiocytic neoplasm. In the trial, patients with ECD treated with vemurafenib had an objective response rate (ORR) of 54.5% (95% CI, 32.2%-75.6%), which consisted of a partial response for 11 patients and 1 complete response. After 26.6 months of follow-up, the median progression-free survival, duration of response, and overall survival were not yet reached.

“Today’s approval of Zelboraf for patients with ECD demonstrates how we can apply knowledge of the underlying genetic characteristics of certain malignancies to other cancers,” 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 and Research, said in a statement. “This product was first approved in 2011 to treat certain patients with melanoma that harbor the BRAF V600E mutation, and we are now bringing the therapy to patients with a rare cancer with no approved therapies.”

In the multi-cohort, single-arm study, 22 patients with BRAF-mutant ECD were treated with a starting dose of vemurafenib at 960 mg twice daily (BID). Eight patients subsequently received a reduced 720 mg BID dose and the remaining 14 patients were reduced to 480 mg BID. The median age of patients was 58.5 years (range, 34-77), and most were male (55%). Two-thirds (68.2%) had received prior therapy before entering the trial.

The median duration of treatment following the initial dose reduction to 720 mg BID was 77 days. Those receiving the 480 mg BID reduced dose received a median of 236 days of treatment. The median time to response was 11 months (95% CI, 3.7-14.6), and response rates remained consistent across groups, regardless of dose reductions.

The most frequently reported all-grade adverse events (AEs) were creatinine elevation (86%), arthralgia (82%), maculopapular rash (59%), alopecia (55%), fatigue (55%), QT interval prolongation on electrocardiogram (55%), and skin papilloma (55%). The most common grade ≥3 AEs were cutaneous squamous cell carcinoma (cuSCC; 36%), hypertension (23%), maculopapular rash (18%), and arthralgia (14%).

The median time to appearance of first cuSCC was 12.1 weeks following treatment with vemurafenib. The rate of grade 3 creatinine elevation was 9.1%. Additionally, cases of myeloid neoplasms were observed in the study, warranting the monitoring of blood counts for this patient population, the FDA advised.

“This FDA decision means people living with Erdheim-Chester disease will now, for the first time, have an FDA-approved treatment option,” Sandra Horning, MD, chief medical officer and head of Global Product Development, said in a statement. “We are committed to finding new ways to bring medicines to patients with high unmet need, and we are pleased that this innovative clinical trial helped identify Zelboraf for treatment of this rare disease.”

The approval for vemurafenib arrived approximately 1 month ahead of a deadline set by the Prescription Drug User Fee Act. Initial results from the basket study were published in 2015 in the New England Journal of Medicine, and the agent was granted a breakthrough therapy designation and orphan drug designation.

The FDA initially approved vemurafenib as a single-agent for patients with BRAF-mutant metastatic melanoma in 2011. In November 2015, the FDA also approved the combination of vemurafenib and the MEK inhibitor cobimetinib (Cotellic) for BRAF-mutant melanoma. When used together, BRAF and MEK inhibition has shown lower rates of secondary skin cancers, suggesting a similar approach could be utilized for ECD.