A groundbreaking clinical trial is demonstrating the promise of BRAF inhibition in multiple types of cancer and helping change the way researchers test treatments for cancers with actionable genetic aberrations.
About 15% of cancers have BRAF mutations, and approximately 70%–90% of these are BRAF V600 point mutations. BRAF V600 mutations, which were first discovered and successfully targeted therapeutically in melanoma, have also been reported in non–small cell lung cancer (NSCLC), colorectal cancer, cholangiocarcinoma, papillary thyroid cancer, multiple myeloma, and hairy cell leukemia. Now, in one of the first multicenter trials enrolling patients on the basis of their genetic aberration status rather than tumor type, investigators are finding that BRAF V600 mutations in many cancers can be targeted with the BRAF inhibitor vemurafenib, which is already approved for the treatment of advanced melanoma.
“We wanted to know how to go after this gene mutation in other cancers like we did in melanoma,” said Vivek Subbiah, M.D., an assistant professor in the Department of Investigational Cancer Therapeutics and The University of Texas MD Anderson Cancer Center’s principal investigator for the trial. “If we see promising signals of activity in these tumor types, they could be definitively explored in another study.”
A “basket” study design
Traditional clinical trials enroll cancer patients on the basis of their tumors’ site of origin and histologic subtype. This approach presents a bit of a problem when investigating BRAF inhibitors. BRAF aberrations occur in about half of melanomas and virtually all hairy cell leukemias, but they are otherwise rare, even among common cancers, making it exceedingly difficult to recruit sufficient numbers of patients for clinical trials.
The answer, Dr. Subbiah and his colleagues found, is to use a “basket” study design, which allows investigators to assess, in a single study, groups of patients with many different tumor types for therapy response. Study arms with high response rates can be expanded to include more patients, and arms with low response rates can be eliminated, enabling investigators to zero in on the populations that would most benefit from the drug.
“In a basket study, you can include multiple cancer types as opposed to designing 15 different trials,” Dr. Subbiah said. “One important thing our study showed was that the basket design can be used across multiple institutions. Before this trial, we didn’t know if we would be able to accrue enough patients in this manner.”
Since Dr. Subbiah and his colleagues began their phase II trial, the basket study design has become increasingly common in early trials of targeted cancer therapies. Dr. Subbiah expects this trend to continue. “This type of study can broaden our understanding of the complex biology of tumor development and evolution,” Dr. Subbiah said. “And this may open doors in several cancers. It’s a really good opportunity to help patients whose disease has not responded to conventional treatment.”
Early results show promise
The phase II trial, whose preliminary results for 122 patients were published last August in the New England Journal of Medicine, enrolled patients with BRAF V600–positive cancer in cohorts according to cancer type: NSCLC, ovarian cancer, colorectal cancer, cholangiocarcinoma, breast cancer, multiple myeloma, and all others. Vemurafenib was found to be especially effective in two of these groups. Among 19 NSCLC patients, eight (42%) had a complete or partial response to vemurafenib, and the median progression-free survival duration was 7.3 months. And among 14 patients with either Erdheim-Chester disease or Langerhans cell histiocytosis (two rare dendritic cell disorders), six (43%) had a complete or partial response. Furthermore, none of these 14 patients had disease progression during therapy, the median duration of which was 5.9 months.
“What we’ve seen in the trial has been interesting,” Dr. Subbiah said. “We’ve learned that common diseases like lung cancer and even rare diseases like Langerhans cell histiocytosis can be treated with vemurafenib if they have BRAF aberrations.”
The researchers also found that colorectal cancer was not treatable with vemurafenib alone (citing no responses in 10 patients) but was treatable with vemurafenib plus cetuximab, an epidermal growth factor receptor (EGFR) inhibitor. With the MAPK and EGFR signaling pathways blocked by vemurafenib and cetuximab, respectively, about half of the 27 patients with aggressive BRAF V600–positive colorectal cancer had some tumor regression (though not a complete or partial response), and one patient had sufficient regression to meet the criteria for a partial response. These findings underscore the biological aggressiveness and treatment- resistant nature of BRAF V600–positive colorectal cancer.
“It’s important that we learn not only which cancers respond to BRAF inhibitor therapy but also which cancers don’t respond; and if they don’t respond, we need to learn why they don’t respond,” Dr. Subbiah said.
In addition, two of seven patients with anaplastic thyroid cancer had a complete or partial response. “Anaplastic thyroid cancer is one of the toughest diseases known to humankind,” Dr. Subbiah said. “These patients typically don’t live beyond 6 months. But a subset of patients with anaplastic thyroid cancer have the BRAF V600 mutation, and some of these patients responded to BRAF inhibitor therapy in our study. And this gives us the motivation to go after this target in other patients with this disease.”
For more information, contact Dr. Vivek Subbiah at 713-563-0393.
Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373:726–736.
OncoLog, June 2016, Volume 61, Issue 6