In patients with chemotherapy-refractory metastatic colorectal cancer (mCRC), ensituximab (NPC-1C), a chimeric immunoglobulin IgG1 monoclonal antibody, produced stable disease in almost half the patients in a phase II study, without contributing toxicity.
Ensituximab Refractory Metastatic Colorectal Cancer
Richard D. Kim, MD
In patients with chemotherapy-refractory metastatic colorectal cancer (mCRC), ensituximab (NPC-1C), a chimeric immunoglobulin IgG1 monoclonal antibody, produced stable disease in almost half the patients in a phase II study, without contributing toxicity, investigators reported at the 2016 Gastrointestinal Cancers Symposium.
Overall survival (OS) was comparable with, or maybe 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 analogue of the MUC5AC-related tumor-associated 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 antibody-dependent 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 at 3.0 mg/kg IV every 2 weeks. Using this dose, investigators conducted this single-arm, open-label, multicenter phase II trial of adults with mCRC who progressed after at least two 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.
"This was a heavily pretreated population. Patients had failed an average of 5 prior lines of therapy, including chemotherapy, cetuximab and panitumumab, regorafenib, and aflibercept, and a number of investigational agents (but not TAS102, which was not available at the start of the study).
The 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," he said. "We basically hit our goal."
Of the 48 subjects evaluable for response, 15 (31%) remained alive as of December 31, 2015.
Response (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.
"But the main point is the drug was very well tolerated," he emphasized. "Grade 3/4 toxicity was very rare."
The only grade 3/4 adverse effect (AE) seen in more than 1% of patients was anemia, which occurred in three patients (1.3%). Hyperbilirubinemia and fatigue were seen in two patients each, and nausea, vomiting, diarrhea, headache and hypoxia were observed in one patient each.
The grade 1/2 events that were somewhat common were fatigue (10.6%), anemia (10.2%), and nausea (4.9%).
The investigators hope to conduct a larger phase III trial of the drug in various combinations. They are also 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.