Updated safety data from a randomized Phase 2 trial of Hedgehog pathway inhibitor GDC-0449 vs. placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer

Novelties from the ESMO 12th World Congress on Gastrointestinal Cancer (30 June-3 July 2010, Barcelona, Spain)

GDC-0449 is an Hedgehog pathway inhibitor which has clinical activity in advanced basal cell carcinoma and preclinical activity in colorectal cancer (CRC). The most common single agent toxicities seen in phase I trials of GDC-0449 include mild-to-moderate fatigue, anorexia, muscle spasms, alopecia and dysgeusia. The primary objective of the trial led by Dr J Bendell of the Sarah Cannon Research Institute, Nashville, USA was to compare the progression free survival (PFS) of FOLFOX-bevacizumab or FOLFIRI-bevacizumab plus either GDC-0449 or placebo in previously untreated metastatic CRC patients. Safety data from this trial were presented at the ESMO 12th World Congress on Gastrointestinal Cancer in Barcelona.

Patients were randomized 1:1 to receive GDC-0449 150 mg/day or placebo in combination with FOLFOX-bevacizumab or FOLFIRI-bevacizumab every 2 weeks. Between May 2008 and July 2009, 199 patients were randomized. As of October 1, 2009, 191 were safety evaluable; 121 FOLFOX-bevacizumab; 70 FOLFIRI-bevacizumab, 57% male; 26% received prior adjuvant chemotherapy. The primary objective of the trial was PFS. Secondary outcome measures included the measurement of Hedgehog protein expression in archival tissue and tracking of adverse events.

The trial did not meet its primary endpoint of extending the progression-free survival and despite these disappointing results in metastatic colorectal cancer, investigators remain encouraged about clinical development of GDC-0449 because the Hedgehog pathway is thought to act via different mechanisms of action in other tumor types. For example, proof of concept has already been shown in advanced basal cell carcinoma. Basal cell carcinoma is almost always the result of a specific mutation in a component of the Hedgehog pathway, an entirely different mechanism than that of metastatic colon cancer.

A randomized double-blind placebo-controlled Phase II trial in advanced ovarian cancer in a maintenance setting is evaluating the ability of GDC-0449 to slow the time to recurrence of cancer in patients whose disease is in complete remission, by impeding the residual cancer cells' ability to grow. Results from this study are expected during the second half of 2010.

Investigators were also encouraged by interim safety data from colorectal cancer study. The data demonstrated a safety profile that was reasonably consistent with that of the first-line metastatic colorectal cancer standard of care treatment of bevacizumab and FOLFOX or FOLFIRI chemotherapy. They believe that this safety profile may provide opportunities for GDC-0449 testing in combination with chemotherapy and other anticancer agents in other tumor types.