With positive read-outs from trials over the last two years and approval of two new agents for the disease, Yervoy and Zelboraf, the field is already looking to new agents and combination trials to improve patient outcomes and survival.
With positive readouts from trials over the last two years and approval of two new agents-ipilimumab (Yervoy) and vemurafenib (Zelboraf)-for the disease, the field of melanoma treatment is already looking to new agents and combination trials to improve on patient outcomes and survival. At this year’s Melanoma International Congress in Tampa, presented by the Society for Melanoma Research, researchers presented the latest updates on three of these trials.
Uwe Trefzer of the department of dermatology at Charit Berlin in Germany presented the phase IIA BREAK-2 trial of the BRAF kinase inhibitor, GSK2118436 (GSK436) in patients with BRAF mutation-positive (V600E/K) metastatic melanoma. The GSK compound is on the heels of the Roche BRAF inhibitor that was approved by the FDA for treatment of BRAF-mutated (V600E) late-stage and inoperable melanoma on August 17, 2011.
Dr. Trefzer presented data of the open-label, single-arm trial with GSK436 which was administered to patients until disease progression. Ninety-two patients were enrolled in the trial, 76 harboring the V600E BRAF mutation and 16 with the V600K BRAF mutations, and patients received an oral 150 mg dose of GSK436 twice daily.
The overall response was 59% for the V600E cohort and 13% for the V600K cohort. The progression-free survival was 27 weeks for the V600E group and the 6-month overall survival rates were 75% and 69% for the V600E and V600K cohorts, respectively. All patients had stage 4 disease, with the vast majority having extensive metastatic tumors and all were pre-treated but had not had prior BRAF or MEK (mitogen-activated protein/extracellular signal-regulated kinase) inhibitors.
Serious adverse events that were drug related occured in 18% of patients and 14% of patients had dose decreases due to an adverse event. The most common adverse events were pyrexia, arthralgia, hyperkeratosis, fatigue, headache, and naseau. The most common serious adverse events were the presence of squamous cell carcinoma and basal cell carcinoma. Both of these types of lesions are frequent for BRAF inhibitor treatment, do not develop into advanced disease, and are easily excised. The phase III monotherapy trial with this compound is underway and fully accrued with results expected in 2012.
The melanoma field is also moving toward combination therapies, including combined treatment with two oral agents that both target the MAP kinase pathway, which is upregulated in approximately 50% of melanomas. Dr. Keith Flaherty from the Dana Farber Cancer Institute presented a third late-breaking abstract, an update on the phase I/ II study of the combination GSK436 plus GSK212 in metastatic melanoma patients with a BRAF mutation who had progressed on a prior BRAF inhibitor.
The progression-free survival was 3.5 months for the 26 patients analyzed. Both drugs were given at their maximum dose, 150 mg twice daily of GSK436 and once-daily 2 mg of GSK212. The combination shows improved rates of skin lesions such as the basal cell carcinoma seen with BRAF inhibitor monotherapy. Skin toxicity frequency (predominantly rash) was 29% for the 65 patients analyzed. 2% of patients exhibited the squamous cell carcinoma seen with BRAF inhibitor monotherapy. The most frequent adverse events were pyrexia, skin lesions, fatigue, nausea, and chills.
“I think it is very encouraging because we can see some responses in this population of patients. Of course, it is too early, and we do not know how long they will respond yet,” commented Dr. Caroline Robert of the Institut Gustave Roussy in Paris, France. “It is one of the best combinations we have today,” she added.
The randomized phase II portion of the trial is ongoing in patients with no prior exposure to either a BRAF or MEK inhibitor and a phase III registrational trial is currently being planned by GSK.