Assistant Managing Editor

Plexxikon Inc.'s and Roche AG's melanoma drug PLX4032 (RG7204) continued its streak of stellar data, with results from an open-label Phase II trial showing a 52 percent response rate in patients with previously treated disease with the BRAF V600E mutation, and the companies are planning to open an access program to answer growing patient demand for the drug ahead of approval.

PLX4032 has been generating significant buzz since last year, when promising Phase I data prompted Berkeley, Calif.-based Plexxikon and partner Roche to move straight into pivotal testing. By the time results from the Phase I extension cohort, published in an August 2010 issue of the New England Journal of Medicine, detailed the remarkable 81 percent response rate, both the single-arm Phase II study and a randomized, controlled Phase III trial were well under way. (See BioWorld Today, Sept. 30, 2009, and Aug. 27, 2010.)

Data from the Phase II trial, presented at the Society for Melanoma Research meeting in Sydney, Australia, "confirmed what we saw in Phase I, that the majority of patients saw a tumor response," Gideon Bollag, senior vice president of research at Plexxikon, told BioWorld Today. "We're very optimistic about the role of the drug in melanoma."

Roche spokeswoman Amy Berry echoed that sentiment. "We're very pleased and very encouraged by the data."

Results also showed progression-free survival of 6.2 months, compared to historical PFS for melanoma patients of about two months. Median duration of response was 6.8 months, and, as of data collection, median overall survival had not yet been reached.

The Phase II trial enrolled 132 patients. Data as of Sept. 27, 2010, showed that three patients had confirmed complete responses, while 66 had confirmed partial responses, defined as tumor shrinkage of at least 30 percent. Thirty-nine patients had stable disease.

In terms of safety, the most common drug-related adverse events were rash, photosensitivity, hair loss and joint pain. Twenty-six percent of patients in the trial developed cutaneous squamous cell carcinoma, a side effect that Bollag called "manageable."

"There is a risk management plan in place," he said. "My understanding is that the lesions are excised in a dermatologist's office and then patients continue on treatment."

With such strong Phase II data, the question is whether Roche and Plexxikon could file for accelerated approval. The FDA has not been crazy about giving its blessing based on single-arm studies – just ask Genzyme Corp. and Vion Pharmaceuticals Inc., who failed to win accelerated approval based on single-arm trials for acute myeloid leukemia drugs Clolar (clofarabine) and Onrigin (laromustine), though Allos Pharmaceuticals Inc.'s Folotyn (pralatrexate) and Gloucester Pharmaceuticals Inc.'s Istodax (romidepsin) had better luck in T-cell lymphoma. (See BioWorld Today, Sept. 28, 2009, and Nov. 9, 2009.)

Nothing has been decided yet, though Roche's Berry said the firms are keeping in close contact with regulatory authorities and "everything is being talked about."

In the meantime, the Phase III BRIM 3 study is ongoing, with about 680 previously untreated BRAF mutation-positive metastatic melanoma patients targeted for recruitment. That study is designed to test PLX4032 vs. dacarbazine, with overall survival as the primary endpoint. Secondary measures will look at PFS, best overall response rate, time to response, duration of response and time to treatment failure, as well as safety parameters.

Enrollment in that trial is progressing well, but the impressive Phase I data left many melanoma patients clamoring for access to the drug outside of clinical studies. The outcry was enough to prompt Roche and Plexxikon to begin discussions with global health authorities, and an expanded access program is expected to open by the end of this year to get PLX4032 to advanced melanoma patients who previously have received drugs for BRAF V600E mutation disease, Berry said. "Our plan is to get it to patients as soon as possible."

Melanoma has proved a tough disease for drug developers in the past, with notable failures such as Genta Inc.'s Bcl-2 targeting antisense drug Genasense (oblimersen) and tyrosine kinase inhibitor Nexavar (sorafenib) from Onyx Pharmaceuticals Inc. and Bayer AG. But there have been bright spots in the space of late, with Bristol-Myers Squibb Co.'s ipilimumab, acquired through its acquisition of Medarex Inc., showing promising survival data in a pivotal study earlier this year. (See BioWorld Today, June 8, 2010.)

Ipilimumab is under FDA review for previously treated patients with advanced disease, with a PDUFA data of March 26, 2011.

Earlier in development, there's Provectus Pharmaceuticals Inc., which also reported promising Phase II data at the Sydney conference showing that 49 percent of metastatic melanoma subjects had an objective response when treated with PV-10, an injectable formulation of Rose Bengal. The Knoxville, Tenn.-based company also reported that 71 percent of patients in the 80-subject trial achieved locoregional disease control in their injected lesions. Mean PFS among patients achieving objective response was 11.7 months.

Also coming down the pipeline is Vical Inc.'s Allovectin-7, a melanoma vaccine in Phase III development, as well as Celldex Therapeutics Inc.'s antibody-drug conjugate CDX-011, which demonstrated positive results in Phase II testing. And ZymoGenetics Inc. recently disclosed a successful Phase II trial for its recombinant interleukin 21 drug against metastatic melanoma.

Plexxikon's drug is designed to target specifically patients with BRAF-V600E mutations, which make up about 50 percent to 60 percent of all melanoma cases. When the company signed its potential $700 million partnership with Basel, Switzerland-based Roche in 2006, it entered a separate deal with Roche's diagnostics division to co-develop a test for identifying patients with that particular BRAF mutation. (See BioWorld Today, Oct. 5, 2006.)

The goal is to get the diagnostic test cleared for approval at the same time as the drug, Berry said, adding that "the personalized medicine aspect is something we're really proud of."

PLX4032, which stems from Plexxikon's Scaffold-Based Drug Discovery Platform, is set to start a combination trial in melanoma with an oral, small-molecule MEK inhibitor from Roche. The companies also plan to pursue the drug in other BRAF-mutant cancers such as thyroid and colorectal cancers.