Plexxikon announces Phase 1 extension study results of PLX4032 in metastatic colorectal cancer

Plexxikon announced today the results of a Phase 1 extension study in metastatic colorectal cancer that showed clinical activity of PLX4032 as a single agent in this hard-to-treat patient population. PLX4032 (RG7204) is a novel, oral small molecule targeting an oncogenic BRAF mutation found in over 50 percent of melanomas, about 10 percent of colorectal cancers and eight percent of all solid tumors. PLX4032 is being co-developed by Roche and Plexxikon under their 2006 collaboration agreement. The data are being presented in a poster session (Abstract # 3534) at the 2010 Annual Meeting of the American Society for Clinical Oncology (ASCO) meeting in Chicago, IL, by Scott Kopetz, MD, an oncologist at the University of Texas MD Anderson Cancer Center in Houston, TX.

“The biology of BRAF activation in patients with colorectal cancer is clearly more heterogeneous than in melanoma, especially as evidenced by the mixed response in some patients. We are evaluating combination trials that may offer improved efficacy in this subset of metastatic colorectal cancer patients with very poor prognoses.”

The BRAF-activating mutation in colorectal cancer patients is associated with distinct clinical and pathologic features with a very poor prognosis. In the Phase 1 extension study, 21 colorectal cancer patients who tested positive for the BRAF mutation were enrolled. All but one had received prior therapy for metastatic disease. Most patients (71 percent) had received three or more prior therapies.

Of the 19 patients evaluable for response, data showed:

• 1 confirmed partial response (≥ 30 percent shrinkage by RECIST criteria)
• 4 minor responses (≥ 10% shrinkage)
• 2 of 3 patients who had repeat FDG-PET scan imaging achieved metabolic response concordant with tumor shrinkage by RECIST criteria

In addition, 5 of the 19 patients had mixed responses (with both regressing and progressing lesions).

The data reported also showed median progression-free survival of 3.7 months, with one patient still on study.

PLX4032 was generally well tolerated. Dose-limiting toxicities were rare, and the most common toxicities were Grades 1 or 2, including fatigue, diarrhea, rash and arthralgia. Four patients developed cutaneous squamous cell carcinoma (keratoacanthoma subtype), which were managed by local excision.

"We are encouraged to see this signal of PLX4032/RG7204 clinical activity as a single agent in refractory metastatic colorectal cancer, with data suggesting mutant BRAF as a target for treatment in this population," said K. Peter Hirth, chief executive officer of Plexxikon. "The biology of BRAF activation in patients with colorectal cancer is clearly more heterogeneous than in melanoma, especially as evidenced by the mixed response in some patients. We are evaluating combination trials that may offer improved efficacy in this subset of metastatic colorectal cancer patients with very poor prognoses."

In an earlier extension study in metastatic melanoma patients, reported at the ECCO/ESMO conference in September 2009, PLX4032 demonstrated a 30 percent or greater tumor shrinkage in 70 percent of patients, and showed some response in nearly all patients. Drug-related adverse events were predominantly mild in severity, including rash, joint pain, photosensitivity and fatigue. Cutaneous squamous cell carcinoma (keratoacanthoma subtype) was observed in approximately 20 percent of patients and removed by excision while treatment with PLX4032 was continued.

Approximately 700 first-line patients are currently being enrolled for a Phase 3 ("BRIM 3") clinical trial of PLX4032 for metastatic melanoma. A Phase 2 ("BRIM2") trial in previously treated melanoma patients has completed enrollment, and data will be presented at a medical conference later this year.