Rapid Way to Identify Responders to Melanoma Targeted Drugs?

'Functional' Biomarker Is Needed

October 23, 2013

A new biomarker could quickly identify which patients with BRAF-mutant melanomas respond to targeted therapies, eliminating weeks of ineffective treatment in nonresponders, according to a small study.

In patients with evidence of suppression of this biomarker, there was "the suggestion of a fairly dramatic effect" in progression-free survival, lead author Ryan B. Corcoran, MD, PhD, told Medscape Medical News. "There was a pretty striking separation of the progression-free survival curves."

Dr. Corcoran, a Damon Runyon clinical investigator from the Massachusetts General Hospital Cancer Center in Boston, spoke during a press briefing at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.

Recent developments in the treatment of melanoma have led to a huge focus on BRAF mutations, which are found in about half of all melanoma patients.

"Clearly, the first thing [clinicians] need to know is whether a [melanoma] patient has a BRAF mutation," said Lee Helman, MD, scientific director of clinical research at the National Cancer Institute in Bethesda, Maryland, who moderated the press briefing. Such patients have a "high likelihood" of responding to targeted therapy for some period of time, he said.

Targeted therapies include RAF inhibitors, such as vemurafenib (Zelboraf, Genentech) and dabrafenib (Tafinlar, GlaxoSmithKline), and the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline).

With BRAF mutations, clinicians have a "baseline" biomarker to use when selecting targeted therapy. However, up to 40% of patients with BRAF-mutant melanomas do not respond at all, which means they have "up-front" resistance to targeted therapy, said Dr. Corcoran.

He explained that the goal of this study was to find a "functional" biomarker that can rapidly identify treatment response, so that nonresponders can be switched to another targeted therapy or a therapy with a different mechanism of action, such as an immunotherapy.

About 15 to 20 potential mechanisms of resistance have been identified in BRAF-mutant melanoma, he noted. But the trick is to identify a common pathway downstream of BRAF in which these potential resistance signals all converge, providing a more universal indicator of resistance. "If you don't shut down this key pathway, then you are unlikely to get a response," he summarized.

The suppression of a marker in patients' tumor cells known as S6 phosphorylation (P-S6) might represent such a key pathway.

In their retrospective analysis, the researchers looked at 9 patients with BRAF-mutant melanomas who had undergone biopsies before and after the initiation of treatment with a RAF inhibitor.

Results showed that progression-free survival was better in the 6 patients who showed suppression of P-S6 after treatment than in the 3 who did not.

The patients who showed suppression of P-S6 had a 5-fold increase in progression-free survival.

"The patients who showed suppression of P-S6 had a 5-fold increase in progression-free survival," said Dr. Corcoran. The hazard ratio was 0.19 (95% confidence interval, 0.01 - 0.84; P = .03).

For patients with no suppression of P-S6, median progression-free survival was only "about 3 to 4 months," Dr. Corcoran reported. Median progression-free survival has not yet been reached in the 6 patients with suppressed P-S6.

In short, P-S6 suppression indicates sensitivity to treatment, and lack of suppression indicates resistance to treatment. But "the results certainly need to be confirmed in larger studies," said Dr. Corcoran.

Dr. Helman said he likes what he has seen so far. "We might have a better way of very quickly identifying patients who are not going to benefit [from initiated targeted therapy] and moving them on to other therapy."

The monitoring of P-S6 in patients was enabled by quantitative immunofluorescence. The lab technology allows for assessment of P-S6 in individual cancer cells, Dr. Corcoran explained. A minimally invasive fine-needle aspiration is used to biopsy the patient's melanoma.

This method has the potential to predict who will respond in the first week of treatment.

The technology could be used to dramatically reduce the time required to assess treatment response. "This method has the potential to predict who will respond in the first week of treatment," and possibly within 1 day, said Dr. Corcoran. Currently, melanoma patients typically receive a standard radiographic assessment of targeted therapy response at 6 to 8 weeks.

In addition to identifying up-front resistance to targeted therapy, this biomarker assessment could eventually help clinicians monitor the common phenomena of acquired resistance to these drugs.

Changes in P-S6 suppression might indicate in "real time" which responders have had their P-S6 levels recover and, therefore, their resistance to a targeted therapy, Dr. Corcoran explained.

Some of the study authors are employees of Genentech.

2013 International Conference on Molecular Targets and Cancer Therapeutics: Abstract C137. Presented October 22, 2013.


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