SAN FRANCISCO––Colorectal cancer patients treated with panitumumab plus rilotumumab (formerly called AMG 102) had a higher overall response rate than patients treated with panitumumab plus placebo in a randomized Phase II study reported here at the Gastrointestinal Cancers Symposium. The combination exceeded a predetermined Bayesian criterion for activity and thus warrants further study in this disease setting, the researchers said.
Rilotumumab is a monoclonal antibody that binds to the hepatocyte growth factor (HGF) and thereby blocks signaling in the c-Met pathway. Preclinical work indicates there is an interdependence between the HGF/c-Met pathway and the epidermal growth factor receptor (EGFR) pathway, which is blocked by panitumumab. Therefore, researchers hypothesized that a combination of rilotumumab and panitumumab may improve patient outcomes. The team also tested panitumumab with ganitumab (AMG 479), which blocks the insulin-like growth factor receptor (IGF-1R) and inhibits the PI3K/AKT pathway.
“This is the first study to show promising efficacy of an HGF inhibitor, rilotumumab, when combined with panitumumab in pretreated metastatic colorectal cancer patients,” said Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven in Belgium, who presented the study.
In the dose-finding portion of the study, the investigators tested a standard dose of panitumumab and 10 mg/kg of rilotumumab every two weeks. There were no dose-limiting toxicities reported in the first six patients. That dose was therefore set for the randomized Phase II portion of the study.
A total of 142 patients from 11 countries enrolled in the trial between June 2009 and February 2010. All patients had tumors with wild-type KRAS, which is critical for panitumumab activity. With a median follow-up of nearly seven months, the team reported that 31% of patients in the panitumumab-rilotumumab arm showed a partial response, compared with 21% in the panitumumab-placebo arm and 22% in the panitumumab-ganitumab. There were no complete responses in any trial arm.
Rather than just comparing the percentage of responses in the trial and deciding whether to move forward based on these data alone, the investigators used a Bayesian analysis that evaluated the data in the context of prior trial results.
With that approach, the estimation was that there was a 93% probability that the panitumumab-rilotumumab combination was better than panitumumab alone, which exceeded the prespecified boundary and indicated that the combination was promising. By contrast, the panitumumab-ganitumab combination showed only a 63% probability that the combination improved on monotherapy, which fell in the prespecified indeterminate range.
“This was a very good result,” Dr. Van Cutsem said, referring to the rilotumumab combination.
The median duration of response with the rilotumumab combination was 5.1 months compared with 3.7 months for panitumumab alone and 3.7 months for the ganitumab combination. Median progression-free survival showed a trend for improvement in both experimental arms at 5.2 months in the panitumumab-rilotumumab arm and 5.3 months in the panitumumab-ganitumab arm compared with 3.7 months in the panitumumab-placebo arm. The differences in progression-free survival did not reach statistical significance, however.
Adverse events increased in the combination arms, but Dr. Van Cutsem said they were within an acceptable range. There was more Grade 3/4 rash in the rilotumumab arm and more Grade 3/4 hypomagnesia in the ganitumab arm. Grade 3/4 diarrhea also increased in both combination arms.
These results may be a “glimpse of the future,” said Johanna Bendell, MD, Associate Director of Drug Development and Director of Gastrointestinal Cancer Research at Sarah Cannon Research Institute in Nashville, who discussed the abstracts. The results suggest that there might be new agents for colorectal cancer patients in the not too distant future, “which is what we desperately need,” Dr. Bendell said.
She complimented the team on their interesting study design, acknowledging that what they wanted and achieved was a quick estimate as to whether there was potential activity with the combinations, rather than definitive data.
She noted that other groups are also working on combination therapies that block c-Met and EGFR. For example, her colleague at Sarah Cannon Research Institute, David Spigel, MD, reported at the most recent European Society of Medical Oncology meeting that an antibody against c-Met, called MetMAb, in combination with erlotinib increased overall and progression-free survival in non-small cell lung cancer patients whose tumors had high c-Met expression (OT, 12/25/10 issue).
In that study, however, patients with low c-Met expression did better with erlotinib alone than with the combination.
“We do have movement forward,” Dr. Bendell concluded. “Targeting of the c-Met/HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer, as well as for lung cancer. We await more follow-up, but the early results look very interesting.”
Dr. Van Cutsem received research funding from Amgen, which owns the three antibodies used in the current study.
The Gastrointestinal Cancers Symposium is cosponsored by the American Society of Clinical Oncology, the American Gastroenterological Association Institute, the American Society for Radiation Oncology, and the Society of Surgical Oncology.