Nick Mulcahy

April 18, 2013

WASHINGTON, DC — Is intermittent dosing a solution to the universal problem of resistance to the targeted therapy vemurafenib (Zelboraf, Roche/Genentech) that melanoma patients develop within months of starting treatment?

The concept is not proven, but it is worth studying, said Darrin Stuart, PhD, from the Novartis Institutes for Biomedical Research in Emeryville, California.

"Some sort of drug holiday, to me, makes sense," Dr. Stuart told reporters at a press briefing here at the American Association for Cancer Research 104th Annual Meeting.

He explained that 2 new sets of data from his team at Novartis offer some evidence that suspending treatment can slow disease progression.

In the first, a study of mice demonstrated that drug resistance was prevented with intermittent treatment. In the second, a retrospective review of melanoma patients demonstrated that the growth of vemurafenib-resistant tumors slowed after the cessation of treatment.

In other words, there could be some clinical value to intermittent dosing or starting and stopping treatment, Dr. Stuart said.

Clinicians should not try this at home.

However, a vemurafenib expert discouraged any use of the drug outside of labeling. "Clinicians should not try [intermittent dosing] at home," said Keith Flaherty, MD, from the Massachusetts General Hospital Cancer Center in Boston.

"Until proven otherwise, continuous-dose therapy is the standard of care," he told Medscape Medical News.

Dr. Flaherty was not involved with the research presented by Dr. Stuart, but he was an investigator for BRIM-3, the pivotal phase 3 clinical trial of vemurafenib that was the basis for the drug's approval.

There is a "high bar to be cleared" for any would-be clinical trial of an interrupted dosing schedule, he told Medscape Medical News.

"We know that there are short-term and overall survival benefits from giving BRAF inhibitors as continuous treatment," said Dr. Flaherty, referring to the class of drug that includes vemurafenib. BRIM-3 results, presented in 2012, demonstrated that the median overall survival was longer in the vemurafenib group than in the chemotherapy group (13.6 vs 9.7; hazard ratio, 0.70; P < .001).

Findings Explored

At the press briefing, Dr. Stuart discussed his team's mouse study (Nature. 2013;494:251-255), which showed that when melanoma cells are subjected to vemurafenib, they make more of the BRAF protein and eventually become resistant. This was unexpected because BRAF is the target of the drug. The researchers hypothesized — and then found — that the drug-resistant tumors in mice would shrink when vemurafenib was removed.

That study produced some intriguing results. "Strategies that we may not have even thought about may turn out to be very relevant," said Maurie Markman, MD, in his Medscape Markman on Oncology blog. "In this case, we find that a tumor that is first inhibited by a drug may become dependent on the drug, and subsequent withdrawal of that drug may result in a further positive effect," explained Dr. Markman, who is from the Cancer Treatment Centers of America in Philadelphia, Pennsylvania.

But the "clinical rationale" for the idea of intermittent drug dosing comes from a set of patients who were treated in clinical trials at the Royal Marsden Hospital in London, United Kingdom, Dr. Stuart reported.

He and his colleagues retrospectively identified 42 patients from the clinical trials database who stopped treatment because of progressive disease.

For 19 of these patients, computed tomography scans were available at 3 timepoints: prior to stopping vemurafenib, when progressive disease was diagnosed and vemurafenib was stopped, and after vemurafenib was stopped and prior to the initiation of further therapy. The researchers used these scans to determine total tumor volume.

In 14 of the 19 patients, tumor growth rate slowed after the cessation of vemurafenib, Dr. Stuart reported.

However, as Dr. Flaherty pointed out, the researchers did not emphasize the fact that "only a small subset" of patients with vemurafenib-related resistance actually had stabilization/regression of disease after the suspension of treatment.

In other words, it was more impressive statistically to focus on patients who had decreased disease progression (relatively reduced tumor growth rate) than on those who had their disease stop or regress.

It is unclear whether the observation from that small subset can "support the idea of an interrupted schedule of vemurafenib," Dr. Flaherty said.

Dr. Stuart is an employee of Novartis. Dr. Flaherty reports serving as a consultant to Roche.

American Association for Cancer Research (AACR) 104th Annual Meeting. Abstract LB-144. Presented April 8, 2013.


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