On August 17, 2011 the FDA announced that it had approved the oral targeted therapy vemurafenib (Daiichi Sankyo/Plexxikon/Roche’s Zelboraf; also known as PLX4032) for first-line treatment of metastatic and unresectable melanomas. The drug is indicated for use in patients whose tumors carry the BRAFV600E) mutation. Approximately 50% of melanoma patients have tumors that carry this mutation.
Vemurafenib was approved together with a test called the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Diagnostics). This is a companion diagnostic designed to determine if a patient’s melanoma cells carry the BRAF(V600E) mutation and thus patients can benefit from therapy with the drug.
Vemurafenib and the companion BRAF(V600E) diagnostic test were approved earlier than scheduled. They had been reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists. The original goal PDUFA (Prescription Drug User Fee Act) review dates for vemurafenib and the companion diagnostic were October 28, 2011 and November 12, 2011, respectively.
The Biopharmconsortium Blog has been following the veurafenib story since March 2010. See this January 23, 2011 article, and the links to earlier articles that it contains.
There are now two drugs approved for the treatment of advanced melanoma in 2011 that demonstrate an improvement in progression-free and overall survival, when before there were none. The other drug, the immunomodulator ipilimumab (Medarex/Bristol-Myers Squibb’s [BMS’s] Yervoy), was discussed in a March 30, 2011 article on our blog.
The FDA granted early approval for vemurafenib on the basis of the results of the pivotal Phase 3 trial known as BRIM-3. In a previous article on this blog, we discussed a report of an interim analysis of this trial in January 2011. The results of the trial were published in the June 30, 2011 issue of the New England Journal of Medicine. Earlier Phase 1 and 2 clinical trails of the drug had show response rates of over 50% in advanced melanoma patients whose tumors bore the BRAF(V600E) mutation.
In the BRIM-3 trial, researchers compared vemrafenib to dacarbazine (the previous standard of care) in 675 patients with previously untreated metastatic melanoma that had the BRAF(V600E) mutation. Patients were randomized to receive either vemurafenib or dacarbazine. Co-primary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety.
Patients receiving vemurafenib had a 74% reduction in the risk for progression (or death), compared with patients receiving dacarbazine. Mean progression-free survival was 5.3 months in the vemurafenib group, compared with 1.6 months in the dacarbazine group. At 6 months, estimated overall survival was 84% in the vemurafenib group and 64% in the dacarbazine group. The median survival of patients receiving vemurafenib has not been reached, while the median survival for those who received dacarbazine was 8 months.
Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse effects in patients receiving vemurafenib were joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity to the sun. Approximately 26% of patients developed cutaneous squamous cell carcinoma, which was managed with surgery. Patients treated with vemurafenib should avoid sun exposure.
FDA approval of the cobas 4800 BRAF V600 mutation test was also based on data from the BRIM-3 trial. Patient tumor samples were tested with the diagnostic in order to select patients for the trial.
The complete response rate seen with vemurafenib has been only 0.9%. The great majority of patients experience tumor regrowth due to drug resistance. As we have discussed in previous article on this blog (for example, our January 23, 2011 article), researchers are hard at work developing combination therapies designed to overcome this resistance. As discussed in our June 8, 2011 blog article, research aimed at developing such combination therapies was extensively discussed at the 2011 ASCO meeting. We have also outlined strategies for overcoming vemurafenib resistance via design of multitargeted combination therapies in our June 2011 book-length report, Multitargeted Therapies: Promiscuous Drugs and Combination Therapies.
2011 has brought good news to patients who have or may develop late-stage melanoma, their families and friends, and to physicians who treat these patients. When previously there had been no FDA approved therapies that can produce improved survival in patients with this deadly disease, now there are two. We hope that research aimed at designing combination therapies to overcome drug resistance will result in even greater ability to control this disease, and that new therapies for still intractable forms of cancer will emerge in the next several years.