Roche/Genentech is seeking a broad label in metastatic melanoma for the just-filed oral BRAF inhibitor vemurafenib (formerly PLX4032) and priority review, which could possibly enable a U.S. launch at the end of 2011.

Having an indication that does not specify first- or second-line use would put vemurafenib on par with Bristol-Myers Squibb Co.'s CTLA-4 inhibitor Yervoy (ipilimumab), which was cleared at the end of March, becoming the first drug approved for the disease in a decade (Also see "Yervoy Approval Has Shifted Development Landscape For Melanoma" - Pink Sheet, 4 April, 2011.). The Yervoy application was supported by one pivotal Phase III trial in previously treated patients, but the drug wound up receiving a broad label for metastatic melanoma (Also see "Yervoy Cuts To The Head Of The Line: Ipilimumab Has Unrestricted Label" - Pink Sheet, 28 March, 2011.).

The application for vemurafenib, which was developed by the biotech Plexxikon, now owned by Daiichi Sankyo, is supported by two trials, one in first-line therapy and one in previously treated patients.

Unlike Yervoy, vemurafenib is a personalized medicine. It's geared as a treatment for the roughly half of metastatic melanoma patients who test positive for the BRAF V600 mutation. A companion diagnostic to test for the mutation has been developed by Roche Molecular Systems, and has also been submitted for approval.

As a personalized therapy for the tough-to-treat disease, the drug has been widely described as a game-changer in melanoma.

Announcement of the filing with FDA's Center for Drug Evaluation and Research came on May 11, following a submission at the end of April. Genentech confirmed that it is seeking priority review, which if all went well would mean approval in the U.S. six months from the end of April.

Genentech said the companies want to be ready for a commercial launch if the application winds up getting approved at the six-month point. Through the Plexxikon acquisition, Daiichi has co-promotion rights in the U.S. ([See Deal]).

The companies are seeking a broad label for vemurafenib in metastatic melanoma, based on the results from two pivotal studies - the Phase II BRIM 2 and Phase III BRIM 3 trials- which tested the drug in previously treated and previously untreated patients respectively.

Around the same time the drug was submitted for approval, Roche submitted a pre-market approval application for the cobas 4800 BRAF V600 Mutation Test with the Center for Devices and Radiological Health. The hope is that the drug and diagnostic will be cleared at about the same time.

Though there is no mandate for the CDER and CDRH to approve a drug and diagnostic concurrently, there is precedent for this approach, Genentech pointed out. In October, a gastric cancer indication for Roche's Herceptin (trastuzumab) was cleared simultaneously with a companion diagnostic (Also see "Roche's Challenge With Herceptin Gastric Cancer Claim Will Be Companion Dx Use" - Pink Sheet, 21 October, 2010.).

In Europe, an application for the drug was filed for the same indication with the European Medicines Agency by Roche in early May.

In the EU, diagnostics receive a "Conformité Européenne" (CE) mark through self-certification and demonstration of clinical validity is not required. Roche is on track to obtain CE mark certification in the third quarter of 2011.

Vemurafenib And Ipilimumab: Competing Or Complementary?

If approved, vemurafenib would offer an alternative to ipilimumab, though given the different and likely complementary mechanisms of action, there is expectation that the drugs can be used in combination. The companies are still in talks regarding a trial testing vemurafenib and ipilimumab together, Genentech said.

The two drugs will really only compete in BRAF V600 mutation-positive patients. The detailed results on the performance of each will be unveiled at the American Society of Clinical Oncology annual meeting in June.

For ipilimumab, the full results of the second Phase III trial, in first-line patients, will be released. Bristol already announced that it met the survival endpoint in that trial.

Detailed results of the BRIM3 study of vemurafenib will also be presented at ASCO. The study compared vemurafenib to dacarbazine in 675 previously untreated patients with unresected BRAF V600 mutation-positive locally advanced metastatic melanoma. The companies have already disclosed that overall survival and progression-free survival endpoints were met in this study and that safety was in line with previously released studies.

In the Phase II BRIM2 study of 132 patients with BRAF V600 mutation positive metastatic melanoma, vemurafenib met the primary endpoint of overall response rate. The drug was shown to shrink tumors in 52% of trial participants and those on the study drug had a median progression-free survival of 6.2 months. More details on this trial are also expected at ASCO.

- Emily Hayes (e.hayes@elsevier.com)

Roche's Vemurafenib Filed With Companion Diagnostic In Tow

More from Archive

More from Pink Sheet