MILAN – Hope for patients with melanoma who develop brain metastases may be on the horizon with the finding that a novel targeted agent reduces the size of multiple brain lesions.
Data from a phase I/II study in 10 patients show that all but one of the participants treated with the oral agent GSK2118436 experienced a partial or complete response, with overall reductions in the size of brain metastases ranging from -20% to -100%.
"These are extremely promising results," said Dr. Caroline Robert of Institut Gustave-Roussy, Villejuif, France, who was asked to comment on the study at the annual congress of the European Society for Medical Oncology.
GSK2118436 inhibits a specific mutation (V600) in the BRAF gene that is present in around 50% of melanomas and "locks BRAF into its active conformation," study investigator Dr. Georgina V. Long explained. The researcher, from Melanoma Institute Australia and Westmead Hospital in Sydney, added that the mutation enhances cancer cells' ability to proliferate, grow, and survive and that GSK2118436 disrupts this unwanted activity.
The positive effect of the novel agent in treating brain metastases was first seen about a year ago, Dr. Long said in an interview: "We had an inkling at the end of 2009, and that's when we really pushed to do a formal, prospective study of the brain cohort."
The melanoma brain cohort consisted of 10 patients with one or more brain lesions of at least 3 mm in size who were asymptomatic and who had not received any prior treatment specifically for their brain lesions. The median age of recruited patients was 59 years, 90% had the V600E mutation in the BRAF gene, and 30% had more than three brain metastases.
Gadolinium-enhanced and T1-weighted magnetic resonance imaging showed that twice-daily oral dosing (150 mg) of GSK2118436 resulted in reductions in brain lesions that correlated to extracranial tumor responses.
The tolerability was very similar to that presented recently at the American Society of Clinical Oncology (J. Clin. Oncol. 2010;28(15s):Abstr 8503). Grade 3/4 adverse events reported in the brain cohort included pyrexia/chills, fatigue, dehydration, nausea, in one patient each, and anemia in two patients.
Patients remained on treatment for a relatively short period of time, however, and it is too early to tell if GSK2118436 is likely to have any effect on the very poor overall survival of patients who develop brain metastases, which is currently around 16 weeks from the time that brain involvement in diagnosed.
"We need to do the phase II study in more patients to get better data," Dr. Long said. A phase II trial has already been started in patients who do not have brain metastases, now it is time to set up a similar trial in those that do, she added.
The phase II brain cohort trial should start recruitment early in 2011 and accruing enough patients should not be an issue. "In melanoma, brain metastases is a major problem; 15%-20% of patients have them at baseline, and nearly three-quarters develop them eventually. It is the cancer where brain metastases are a major problem, more so than any other cancer," commented Dr. Long.
Dr. Long's travel expenses to present the study data were paid for by GlaxoSmithKline, the study's sponsor. She also participated in a phase I advisory board in 2009. Dr. Long's coauthors have received consultancy fees and research report from the company, and three were current employees of GSK with stock ownership. Dr. Robert had no relevant conflicts of interest.