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.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

E. Van Cutsem reports receiving a commercial research grant from Amgen Inc. C. Eng and N. Tebbutt report receiving commercial research grants from and are consultants/advisory board members for Amgen Inc. I. McCaffery and D. Smethurst were employees of and have ownership interest (including patents) in Amgen Inc. K. Oliner, L. Chen, J.L. Gansert are employees of Amgen Inc. E. Loh is an employee of and has ownership interest (including patents) in Amgen Inc. J. Tabernero is a consultant/advisory board member for Amgen Inc. No potential conflicts of interest were disclosed by the other authors.

©2014 American Association for Cancer Research.

Figures

Figure 1

Kaplan–Meier curves for PFS (central review) in patients treated with panitumumab plus rilotumumab (AMG 102;A) and panitumumab plus ganitumab (AMG 479; B) versus panitumumab plus placebo.

Figure 2

Kaplan–Meier curves for OS in patients treated with panitumumab plus rilotumumab (AMG 102; A) and panitumumab plus ganitumab (AMG 479; B) versus panitumumab plus placebo.

Figure 3

Effect of low (≤50%) and high (≥50%) cytoplasmic MET IHC staining (≥1 +) on OS in patients treated with panitumumab plus placebo (A) and panitumumab plus rilotumumab (AMG 102; B).