In a phase II basket trial, vemurafenib, an enzyme inhibitor prescribed for certain BRAF V600–mutant melanomas, proved effective in some nonmelanoma cancers that also carried a BRAF V600 mutation.

Should cancer patients receive therapies based on their tumor's tissue of origin or its genetic profile? The answer is both, according to a first-of-its-kind “basket” study (N Engl J Med 2015;373:726–36).

This phase II trial of the melanoma drug vemurafenib (Zelboraf; Roche/Genentech) “tells us we're not moving to a purely molecularly defined nosology of cancers in the immediate future,” says first author David Hyman, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who led the study with senior investigator José Baselga, MD, PhD. “The histological context is also important.”

Cancer trials have traditionally tested treatments in a specific tissue type—a breast cancer therapy for breast cancer, or a lung cancer drug for lung cancer. Vemurafenib, a BRAF inhibitor, gained FDA approval in 2011 to treat BRAF V600E mutation–positive inoperable or metastatic melanoma. V600 mutations also appear at low rates in other cancers, some so rare that disease-specific studies would be impractical.

The basket study—a newer trial design that focuses on specific mutations across tumor types instead of just the tumor's tissue of origin—enrolled 122 patients with BRAF V600–mutant nonmelanoma cancers to determine if vemurafenib would prove effective in those cancers.

Patients at 23 centers worldwide were grouped into seven cohorts, one for each of six different cancers and one for all other BRAF V600–mutant cancers. Except for patients in one of two colorectal cancer cohorts, who also received cetuximab (Erbitux; Lilly), subjects took vemurafenib orally twice a day. Researchers used CT or MR imaging to assess tumor size at baseline and every 8 weeks until a patient worsened, died, or withdrew from the study.

Drug responses were seen in 10 tumor types, Hyman says. Patients with non–small cell lung cancer, Erdheim–Chester disease (ECD) and Langerhans'-cell histiocytosis (LCH) fared best, with response rates over 40%. Unlike patients with melanoma, people with ECD and LCH did not develop resistance to vemurafenib. “The response rate in those cases dramatically underrepresents the degree of benefit,” Hyman says. “The effect was very durable.”

In addition to suggesting that genetic mutations alone are not sufficient to predict responses to a therapy in all cancer types, the study shows that “signals in rare tumors, and tumors with few or no treatment options, may lead to novel trials to assess the strength of those signals,” says Barbara Conley, MD, associate director of the Cancer Diagnosis Program at the NCI's Division of Cancer Treatment and Diagnosis in Bethesda, MD.

In the future, Hyman says, basket studies could help fine-tune early drug development by identifying, within a certain gene, the mutant alleles that confer better responses.

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