Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer.

Abstract

PURPOSE:

Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC.

EXPERIMENTAL DESIGN:

Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work.

RESULTS:

In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints.

CONCLUSIONS:

Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC.

• Authors: Eric Van Cutsem, Cathy Eng, Elzbieta Nowara, Anna Swieboda-Sadlej, Niall C Tebbutt, Edith Mitchell, Irina Davidenko, Joe Stephenson, Elena Elez, Hans Prenen, Hongjie Deng, Rui Tang, Ian McCaffery, Kelly S Oliner, Lisa Chen, Jennifer Gansert, Elwyn Loh, Dominic Smethurst, Josep Tabernero
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 16 Pg. 4240-50 (Aug 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24919569 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• KRAS protein, human
• Proto-Oncogene Proteins
• rilotumumab
• Panitumumab
• ganitumab
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Colorectal Neoplasms (drug therapy, mortality, pathology)
• Female
• Follow-Up Studies
• Humans
• Liver Neoplasms (drug therapy, mortality, secondary)
• Male
• Middle Aged
• Mutation (genetics)
• Neoplasm Recurrence, Local (drug therapy, mortality, pathology)
• Neoplasm Staging
• Panitumumab
• Prognosis
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Survival Rate
• Young Adult
• ras Proteins (genetics)