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.

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

“…However, in vitro effects of IGF-1R agents appear to have, at best, static in colon cancer cell lines as reported by Garcia-Carbonero and colleagues (31). Furthermore, as reported by Cutsem and colleagues, the addition of an IGF-1R inhibitor, ganitumab, to the EGFR inhibitor panitumumab did not increase response rate in patients with advanced colon cancer as compared with panitumumab alone (32). Therefore, it is unlikely the marked clinical effect observed in the case was due to ceritinib inhibition of IGF-1R.…”

Current and Future Approaches to Target the Epidermal Growth Factor Receptor and Its Downstream Signaling in Metastatic Colorectal Cancer

“…There was no significant association between tumor MET expression in IHC and PFS or OS. 107 Because of the lack of survival benefit, there are no plans to continue development of rilotumumab in CRC.…”

“…Baseline circulating IGF-1 or IGF-2 protein levels were also not predictive of effect. 107 Dalotuzumab (MK-0646) is a humanized antieIGF-1 receptor IgG1 mAb that was shown to reduce activity of the PI3K/AKT pathway. 135 A total of 345 KRAS wild type mCRC patients were randomized to receive cetuximab/irinotecan with placebo, dalotuzumab weekly, or dalotuzumab every other week.…”

Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies

“…Despite this promising preclinical evidence, recent clinical trials in patients with KRAS wild-type colorectal cancer have shown that combined therapy with anti-EGFR and anti-IGF1R antibodies did not improve response compared with EGFR-targeted monotherapy (47,48). The reasons for these discrepancies are currently not fully understood, and there is still considerable discussion about the validity of IGFs and IGF1R as viable therapeutic targets in cancer.…”