Potential Therapy for Refractory Colon Cancer

Patients with advanced RAS/BRAF–wild-type colorectal cancer typically develop resistance to two leading EGFR inhibitors, the monoclonal antibodies cetuximab (Erbitux; Lilly Oncology) and panitumumab (Vectibix; Amgen). A recent study suggests that an investigational antibody mixture could provide a new therapeutic option for these tumors (Sci Transl Med 2016;8:324ra14).

Acquired resistance to cetuximab and panitumumab most often develops from mutations in genes downstream of EGFR, such as KRAS and BRAF. In about 20% of cases, however, it occurs through alterations in EGFR's extracellular domain (ECD) that disrupt drug binding.

Having previously identified seven EGFR ECD mutations, a team of researchers, including Sabrina Arena, PhD, and Alberto Bardelli, PhD, of the University of Torino in Italy, decided to explore whether MM-151 (Merrimack Pharmaceuticals) could circumvent these mutations. MM-151 contains three antibodies that recognize nonoverlapping epitopes of EGFR's ECD. This third-generation EGFR inhibitor is being evaluated in a phase I study of patients with solid tumors, including colorectal cancer, who have relapsed on anti-EGFR therapies.

To determine whether MM-151 overcomes resistance in vitro, the researchers modified a colorectal cancer cell line that is highly sensitive to cetuximab and panitumumab to generate a cell line panel expressing each of the different EGFR ECD mutations individually. Four mutations rendered cells resistant to both drugs; another two conferred resistance to just cetuximab. However, the cells were all vulnerable to MM-151.

The researchers then studied colorectal cancer cells that developed cetuximab resistance after the spontaneous emergence of EGFR ECD mutations. MM-151 suppressed proliferation and downstream signaling in these cells. Next, the scientists tested MM-151 in cells derived from a colorectal tumor that had been removed from a patient and transplanted into mice; these cells harbored one of the ECD mutations and were resistant to cetuximab and panitumumab. Once again, MM-151 curbed the proliferation of these cells.

To test the ability of MM-151 to overcome secondary resistance to cetuximab, Arena, Bardelli, and colleagues analyzed circulating tumor DNA from a subset of 11 patients with colorectal cancer enrolled in the phase I study of MM-151. They detected EGFR ECD mutations in circulating tumor DNA from two patients and found that the amount of mutant DNA decreased or stabilized during treatment with MM-151: One patient's tumor shrank, and the disease stabilized in the other patient. “I believe this might be a powerful new weapon to fight acquired resistance in colorectal cancer,” says Arena.

“The study suggests that MM-151 may have a positive clinical impact, in particular on tumor cells that would be otherwise resistant to conventional EGFR blockade with a single anti-EGFR antibody,” says Luis Diaz, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD, who wasn't connected to the study.

“The ability to use an antibody mixture to get around these mutations is novel and exciting,” adds Dustin Deming, MD, of the University of Wisconsin School of Medicine and Public Health in Madison. A similar oligoclonal antibody mixture, Sym004 (Symphogen), has already undergone phase I evaluation in refractory colorectal cancer and shrunk tumors in 44% of patients. “What this study shows is that there's a rationale to continue to investigate these therapies in colon cancer,” Deming says. –Mitch Leslie

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