Basket Study Yields Approval for Rare Cancer

In a regulatory first, the FDA expanded the indication for a targeted cancer therapy based only on the results of a basket study, a type of clinical trial design that tests drugs in a variety of cancer types with a specific mutation.

The new marketing authorization, announced on November 6, means that doctors can now prescribe vemurafenib (Zelboraf; Roche) for BRAF V600–mutant Erdheim–Chester disease (ECD), a rare blood disorder that has had no approved therapies.

“It's an indication that the FDA is willing to entertain nontraditional datasets for approval if we can unequivocally demonstrate efficacy,” says David Hyman, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who co-led the VE-BASKET study upon which the approval was based (N Engl J Med 2015;373:726–36).

In that phase II study, Hyman and his colleagues initially enrolled 122 patients with cancers of the lungs, colon, thyroid, blood, and other organ systems. All had tumors harboring the V600-mutant form of BRAF that's targeted by vemurafenib, a drug approved in 2011 for advanced melanoma. The researchers then expanded enrollment in tumor types that showed the most promising signals of activity. One of these was ECD, a cancer characterized by excessive production of histiocytes, a type of white blood cell. More than half of all ECD cases are thought to carry the BRAFV600 mutation.

Hyman's team ultimately recruited 22 patients with BRAFV600E–mutant ECD, one of whom had a complete response; 11 others experienced partial responses. However, “the response rate only tells part of the story here,” says Hyman. “Even in the so-called non-responders, we see what appears to be a dramatic departure from the natural history of the disease.”

Among 14 patients with ECD, including some defined by standard assessment criteria as having stable disease, PET scans showed that 11 had complete metabolic responses, whereas the other three had partial metabolic responses. Those results suggest the drug was working to some extent in practically everyone who received it, which helps explain why 2-year progression-free survival was 83%. It also indicates a durability of benefit that appears to surpass that seen in any other solid or hematologic malignancies.

The side effects documented in the trial were similar to those reported in patients with melanoma—joint pain, fatigue, rashes, hair loss, and skin tags among them.

Filip Janku, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, TX, points out that the new approval for vemurafenib would have been difficult had the FDA insisted on data from a traditional clinical trial, because it's challenging to run such trials for very rare cancers. “It's problematic for centers to open a study that actually enrolls so few patients or complete a study in a single center only,” he says. To date, Janku notes, there's been only one ECD trial ever published, and it included just 10 participants recruited over 5.5 years (Blood 2015;126:1163–71). An ongoing trial at the NIH Clinical Center managed to enroll only six patients over 3 years—and even that required a “herculean effort,” Janku says.

The basket design provides a more realistic pathway to registration for rare cancers, notes Hyman. “We were able to incorporate this pivotal program into a broader effort,” he says. “There's an economy of scale there that's probably not achievable in a disease-specific context for such an orphan disease.” –Elie Dolgin

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