SAN FRANCISCO – Combining monoclonal antibodies that target different cellular signaling pathways may improve antitumor activity in patients with metastatic colorectal cancer, according to the first results of an ongoing, randomized, phase II trial.
Dr. Eric Van Cutsem
The combination of panitumumab (Vectibix, which targets the epidermal growth factor receptor [EGFR] and inhibits its downstream signaling) plus investigational rilotumumab (AMG-102, which targets hepatocyte growth factor [HGF] and inhibits downstream c-Met signaling) yielded a better objective response rate than did panitumumab alone (31% vs. 21%).
In contrast, the combination of panitumumab plus investigational ganitumab (AMG-479, which targets the insulinlike growth factor I receptor [IGF-IR] and inhibits downstream signaling through the PI3K/AKT and MAPK pathways) improved little on the rate that was seen with just panitumumab (22% vs. 21%).
"This is the first study to show promising evidence of the efficacy by an HGF inhibitor, rilotumumab, ... when combined with panitumumab in patients with pretreated metastatic colorectal cancer ... [of] KRAS wild type," lead investigator Dr. Eric Van Cutsem told attendees at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.
"Preclinical studies indeed have indicated that there is a complex interdependence between the HGF/c-Met and the IGF-IR and EGFR pathways," he noted, explaining the trial’s rationale. "Combinations of agents that block these receptors are being investigated for their potential to generate additive or synergistic anticancer effects."
To be eligible for the trial, patients had to have metastatic colorectal cancer with wild-type KRAS (because mutations in KRAS confer panitumumab resistance); progression during or after prior irinotecan- and/or oxaliplatin-based chemotherapy; a glycosylated hemoglobin level of 8% or less; a good performance status; and no previous EGFR, c-Met, or IGF-IR inhibitor therapy.
The patients were randomly assigned in nearly equal numbers to receive panitumumab (6 mg/kg every 2 weeks) in combination with placebo, with rilotumumab (10 mg/kg every 2 weeks), or with ganitumab (12 mg/kg every 2 weeks).
All three antibodies are manufactured by Amgen. Panitumumab is approved by the Food and Drug Administration for the treatment of EGFR-expressing metastatic colorectal cancer that has progressed during or after conventional chemotherapy. The other two antibodies are investigational.
The trial’s primary end point was the objective response rate as determined with modified RECIST (Response Evaluation Criteria in Solid Tumors). "It’s important to mention that all responses were required to be confirmed at least 4 weeks after response criteria were first met," noted Dr. Van Cutsem, head of digestive oncology at the University Hospital Gasthuisberg in Leuven, Belgium.
Median follow-up was 6.9 months, as of the data cutoff for the analyses reported. Some 58% of the 142 patients enrolled were men, and the average age was about 58 years. Nearly two-thirds had metastases in the liver plus other sites. About a third had received three or more prior lines of therapy.
All of the responses were partial ones. The median duration of response was 3.7 months with panitumumab alone, 5.1 months with panitumumab plus rilotumumab, and 3.7 months with panitumumab plus ganitumab. The corresponding values for the disease control rate (complete response, partial response, and stable disease) were 56%, 71%, and 61%.
The median duration of progression-free survival was 3.7 months with panitumumab. This compared with 5.2 months with panitumumab-rilotumumab and 5.3 months with panitumumab-ganitumab.
"In general, the safety and toxicity was acceptable in all three arms of this study," commented Dr. Van Cutsem. The overall rate of grade 3/4 adverse events was 52% with panitumumab alone and higher with panitumumab-rilotumumab (71%) and with panitumumab-ganitumab (63%).
Although the nature of these grade 3/4 events was generally similar across groups, the addition of rilotumumab to panitumumab increased the rate of rash (from 8% to 29%), and the addition of ganitumab to panitumumab increased the rate of hypomagnesemia (from 2% to 15%).
"We hope to report in future meetings and manuscripts further details and especially also analysis of biomarkers for response in serum and tissue samples that have been collected and that are underway," Dr. Van Cutsem concluded.
"I am very proud to say ... that we do have movement forward," said discussant Dr. Johanna C. Bendell, director of GI oncology research with the Sarah Cannon Research Institute in Nashville, Tenn. "Targeting the c-Met or HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer in this small study."
Targeting both EGFR and Met signaling has been tapped with marked clinical benefit in patients with non–small cell lung cancer who have high Met expression (Ann. Oncol. 2010;21[suppl. 8]:viii7 [abstract LBA15]), she noted. But those whose tumors had low Met expression actually fared worse when they were given dual therapy than when they were given anti-EGFR therapy alone.