Treatment with ensituximab (NPC-1C), a chimeric IgG1 monoclonal antibody, induced stable disease in nearly half of patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) without contributing significant toxicity.
Overall survival (OS) was comparable with, or somewhat better, than that seen with other late-line regimens. “But the toxicity profile is what stands out,” said Richard D. Kim, MD, of Moffitt Cancer Center and Research Institute in Tampa, Florida. “These patients are much sicker than patients receiving first-line treatment, and toxicity profile does matter with them,” Kim said in an interview withTargeted Oncology.
Ensituximab is an analog of the MUC5AC-related tumorassociated antigen, but it does not react with MUC5AC antigen in nonmalignant tissue. It targets an MUC5AC variant with specificity to CRC, attacking the tumors through antibodydependent cellular cytotoxicity. The compound was developed from a colon cancer vaccine that was in development in the 1980s, explained Philip M. Arlen, MD, CEO of Precision Biologics, Inc, Rockville, Maryland, the manufacturer.
“This unique antibody was not developed in a lab with recombinant proteins. It was a biologically functional process,” he said.
Approximately 60% of patients with CRC express the MUC5AC variant. This could serve as a biomarker to select patients for the treatment, Kim noted. An earlier phase I study established the maximum tolerated dose of ensituximab at 3 mg/kg IV every 2 weeks. Using this dose, investigators conducted the single-arm, open-label, multicenter phase II trial of adults with mCRC who progressed after at least 2 lines of standard chemotherapy. An immunohistochemistry- based companion diagnostic assay was used to select eligible patients whose tumors express the target in >20% of tumor cells.
The study enrolled 53 patients, with 48 patients evaluable for the primary endpoint, OS. Patients were heavily pretreated, and had failed an average of 5 prior lines of therapy, including chemotherapy, cetuximab, panitumumab, regorafenib, and aflibercept, and a number of investigational agents.
Median OS for patients who received at least 2 doses of ensituximab at 3 mg/kg was 6.8 months. “We assumed an OS of about 7 months, and we almost got there. We basically hit our goal,” Kim said.
Of the 48 subjects evaluable for response, 15 (31%) remained alive as of December 31, 2015. Response (measured by Response Evaluation Criteria In Solid Tumors [RECIST]) was evaluated in 37 patients, 13 of whom received more than 4 doses. Despite advanced disease in this population, 18 subjects (48.6%) exhibited stable disease in target lesions at the end of the first course (day 57), the researchers reported.
The only grade 3/4 adverse event (AE) seen in more than 1% of patients was anemia, which occurred in 3 patients (1.3%). Hyperbilirubinemia and fatigue were seen in 2 patients each, and nausea, vomiting, diarrhea, headache, and hypoxia were observed in 1 patient each. The most common grade 1/2 AEs were fatigue (10.6%), anemia (10.2%), and nausea (4.9%). “The main point is that the drug was very well tolerated,” Kim emphasized. “Grade 3/4 toxicity was very rare.”
The investigators hope to conduct a larger phase III trial of the drug in various combinations and are evaluating the immune correlates of response in the current study.
“If we could come up with a combination in the refractory setting, with a low toxicity profile, that could really move the needle in this field,” Arlan commented.