BRAF May Be a Good 'Target' in Nonmelanoma Cancers

Roxanne Nelson, RN, BSN

August 19, 2015

Preliminary findings from a "basket study" show that BRAF V600 may be a targetable oncogene for some cancers other than melanoma.

The study used vemurafenib (Zelboraf, Roche/Genentech), a selective oral inhibitor of BRAF V600 kinase that was approved in 2011 for use in melanoma.

But in this study, the researchers evaluated the clinical efficacy of vemurafenib in 122 patients with cancers other than melanoma, all of which were found to harbor BRAF V600 mutations.

Patients with non-small-cell lung cancer had a response rate of 42% and a median progression-free survival of 7.3 months.

A similar response rate (43%) was observed in those with Erdheim–Chester disease or Langerhans cell histiocytosis, with a median treatment duration of 5.9 months.

None of the patients experienced disease progression while undergoing treatment.

In addition, there were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma, as well as those with colorectal cancer who received vemurafenib and cetuximab (Erbitux, Eli Lilly).

The study was published in the August 20 issue of the New England Journal of Medicine.

"This study identified certain tumor types where the targeted BRAF V600 biomarker with vemurafenib was particularly promising — for example, lung cancer — and others where vemurafenib was ineffective, such as colon cancer," said David Hyman, MD, the study's first author and acting director of developmental therapeutics at Memorial Sloan Kettering Cancer Center in New York City.

"In tumor types that did respond, we believe there is an opportunity to improve the degree of patient benefit through the use of a combination of targeted therapy," he told Medscape Medical News.

In particular, Dr Hyman pointed to the combination of vemurafenib with MEK inhibitors, which may be particularly promising (based on melanoma data), although this combination was not tested in this study.

"Similarly, for tumor types where vemurafenib alone was not effective, combining with other targeted therapy may overcome resistance to vemurafenib alone," Dr Hyman said. "As a proof of this concept, the likelihood of tumor regressions for colorectal cancer patients in this study was increased with the combination of vemurafenib and cetuximab, compared with vemurafenib alone."

Basket Design

The basket design is a relatively new concept, in which cancers are placed together in a "basket" based on genetic mutations rather than the primary tumor site. This type of study design allows for patients to be enrolled with various types of cancer, and to evaluate treatment based on genetic make up rather than tumor site.

"I expect that basket studies will become an increasingly important complement to more traditional disease-specific clinical studies rather than a replacement," said Dr Hyman. "One of the most important findings of this first basket study was that both specific mutations and tumor types matter and both must be taken into account in order to improve the care of our patients."

"Basket studies are an extremely valuable tool for identifying the potential benefit of targeting a specific mutation across many tumor types simultaneously," he added. "In this way, I think these studies will help us accelerate the process of bringing effective new treatments to patients desperately awaiting these breakthroughs."

Responses Noted in Some Cancers

In this study, Dr Hyman and colleagues enrolled 122 patients with BRAF  V600–mutated cancers from 23 centers worldwide, from April 11, 2012 through June 10, 2014. The entire cohort was divided into six groups 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) group, that allowed patients with any type of BRAF V600–mutation-positive cancer to participate.

The most common disease types were colorectal cancer (37 patients) and non-small-cell lung cancer (20 patients).

The majority of participants (89%) had received at least one previous line of therapy, and most (n = 95) received vemurafenib monotherapy during the trial, while 27 patients with colorectal carcinoma received vemurafenib and cetuximab combination therapy.

The primary end point was the response rate, and secondary end points included progression-free and overall survival.

Overall, preliminary findings showed that vemurafenib had efficacy in BRAF V600–mutation-positive non-small-cell lung cancer, Erdheim–Chester disease, and Langerhans cell histiocytosis.

In non-small-cell lung cancer, 14 patients experienced tumor regression, and the 12-month rate of progression-free survival was 23% (95% confidence interval [CI], 6 - 46). The median overall survival has not yet been reached, while the preliminary 12-month overall survival rate was 66% (95% CI, 36 - 85). At the time of the cutoff date, five patients were still on treatment.

Among patients with Erdheim–Chester disease or Langerhans cell histiocytosis, 14 patients could be evaluated for a response at the time of analysis. Six of this group had a response (one complete and five partial responses), for a response rate of 43% (95% CI, 18 - 71).

Disease regression was observed in the majority of patients (12 of 14), and improvement in disease-related symptoms was observed across all degrees of tumor regression, the authors note. Median progression-free and overall survival had not been reached at the time of the analysis, but the preliminary 12-month progression-free survival rate was 91% (95% CI, 51 - 99), and the 12-month overall survival rate was 100%.

No responses were observed in patients with colorectal cancer who received vemurafenib monotherapy. One response was observed among those receiving combination therapy (combined with cetuximab), and while about half experienced tumor regression, it did not meet the standard criteria for a partial response.

The median progression-free survival and overall survival for patients who received monotherapy was 4.5 months (95% CI, 1.0 - 5.5) and 9.3 months (95% CI, 5.6 to not reached), respectively. For those on combination therapy, it was 3.7 months (95% CI, 1.8 - 5.1) and 7.1 months (95% CI, 4.4 to not reached), respectively.

Safety data for vemurafenib monotherapy, overall, were similar to data observed in previous melanoma studies. The authors note that the sample sizes within the individual cohorts in this trial were too small to allow a definitive comparison.

The most common adverse effects seen in this study, among all patients, were rash (68% of patients), fatigue (56%), and arthralgia (40%).

"This study is the first deliverable of precision medicine," said senior author José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center, in a statement. "We have proven that histology-independent, biomarker-selected basket studies are feasible and can serve as a tool for developing molecularly targeted cancer therapy."

This is what the future of precision medicine looks like.

"While we can — and should — be cautiously optimistic, this is what the future of precision medicine looks like," he noted.

This study is ongoing and the authors plan to publish additional information as it becomes available. The primary focus now is to confirm the preliminary activity identified in this initial report.

The study was supported by F. Hoffmann–La Roche/Genentech. Dr Hyman reports personal fees from Chugai and Santa Maria Biotherapeutics, nonfinancial support from PUMA Biotherapeutics outside the submitted work, and a pending patent related to detecting and monitoring mutations in histiocytosis (PCT/US2014/061281). Several other coauthors report relationships with industry.

N Engl J Med. 2015; 373:726-736. Abstract

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