First 'basket' study showed treatment effects in mutation-specific nonmelanoma cancers

Researchers used a new “basket” study design to explore the therapeutic potential of vemurafenib in mutation-specific tumors. Preliminary results of the study found that vemurafenib was active in multiple nonmelanoma BRAF V600-mutated cancers, as reported in the August 20, 2015 issue of the New England Journal of Medicine.

Vemurafenib (marketed as Zelboraf®) has considerable therapeutic potential, the authors wrote, yet its efficacy in certain nonmelanoma cancers hasn’t been systematically explored. “The large number of tumor types involved, the low frequency of BRAF V600 mutations, and the rarity of some of the cancers make disease-specific studies difficult to conduct,” they wrote.

To address this unmet clinical need, researchers from 23 centers (including Memorial Sloan Kettering Cancer Center, in New York, NY; Vanderbilt University Medical Center, in Nashville, TN; University of Texas MD Anderson Cancer Center, in Houston, TX; Massachusetts General Hospital, in Boston, MA; as well as several centers in Europe) designed a histology-independent, flexible, early phase 2 “basket” study of vemurafenib in patients with nonmelanoma cancers harboring BRAF V600 mutations.

A basket study allows the detection of early signals of activity across multiple tumor types simultaneously, while permitting the possibility that tumor lineage might influence drug sensitivity. This new study—the first published one to follow this model—sought to explore treatment responses among tumors based on their mutation types (rather than their specific disease), and to identify promising signals of activity in individual tumor types that could be pursued in subsequent studies.

“This study is the first deliverable of precision medicine,” said the study’s senior author José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center. “We have proven that histology-independent, biomarker-selected basket studies are feasible and can serve as a tool for developing molecularly targeted cancer therapy. While we can—and should—be cautiously optimistic, this is what the future of precision medicine looks like.”

This study included 6 cohorts of patients with prespecified cancers (non-small-cell lung cancer, ovarian cancer, colorectal cancer, cholangiocarcinoma, breast cancer, and multiple myeloma), as well as a seventh (all-others) cohort, which permitted enrollment of patients with any other BRAF V600 mutation-positive cancer. The protocol allowed for additional tumor-specific cohorts to be analyzed if a sufficient number of patients were enrolled in the all-others cohort.

“This kind of study is a beneficial way to do rare tumor research because it allows us to open the study to patients with diseases that are completely underrepresented in clinical trials in general, such as anaplastic thyroid cancer and glioblastoma,” said the study’s first author David Hyman, MD, Acting Director of Developmental Therapeutics at Memorial Sloan Kettering Cancer Center. “By broadening eligibility, we are translating potential benefits to as large a patient population as possible.”

Of the 122 trial participants, clinical activity of vemurafenib was observed in non-small cell lung cancer, as well as Erdheim-Chester disease and Langherhans cell histiocytosis. In non-small cell lung cancer, the response rate was 42% and median progression-free survival was 7.3 months. In Erdheim-Chester disease and Langherhans cell histiocytosis, response rate was 43%; median treatment duration was 5.9 months and no patients progressed during therapy. In addition, anecdotal responses were reported in anaplastic pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary duct cancer, ovarian cancer, clear cell sarcoma, and colorectal cancer (but only when vemurafenib was combined with cetuximab).

“The basket study design is noteworthy because it allows for the possibility that different tumor types with the same molecular biomarker might differ in their sensitivity to therapy targeted at that biomarker,” the authors wrote. “The absence of responses in the cohort of patients with colorectal cancer who received vemurafenib monotherapy underscores this possibility.”

The results will ultimately guide researchers in looking for different drug targets or developing therapies that combine vemurafenib with complementary treatments.

“We now have the landscape of all the most frequent cancer-causing mutations in the majority of tumor types, and we know there are a number of genes that are frequently mutated in some tumors and less frequently in others,” Dr. Baselga said. “The next step is exploring appropriate drug combinations, knowing that these cells have a finite number of pathways.”

The study was funded by F. Hoffmann–La Roche/Genentech.