A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer.

Berlin J, Bendell JC, Hart LL, Firdaus I, Gore I, Hermann RC, Mulcahy MF, Zalupski MM, Mackey HM, Yauch RL, Graham RA, Bray GL, Low JA
Clin Cancer Res. 2013 19 (1): 258-67

PMID: 23082002 · DOI:10.1158/1078-0432.CCR-12-1800

PURPOSE - Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).

EXPERIMENTAL DESIGN - Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.

RESULTS - A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.

CONCLUSIONS - Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.

MeSH Terms (23)

Adult Aged Aged, 80 and over Anilides Antibodies, Monoclonal, Humanized Antineoplastic Combined Chemotherapy Protocols Bevacizumab Camptothecin Colorectal Neoplasms Female Fluorouracil Humans Leucovorin Male Maximum Tolerated Dose Middle Aged Neoplasm Metastasis Organoplatinum Compounds Proto-Oncogene Proteins Proto-Oncogene Proteins p21(ras) Pyridines ras Proteins Treatment Outcome

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