Colorectal cancer (CRC) is one of the leading causes of global cancer deaths, with over 1.9 million annual cases (1). Traditional chemotherapies often have many drawbacks, such as limited efficacy combined with severe systemic side effects like nausea and fatigue, which impact the patient's quality of life. Antibody-drug conjugates offer an alternative therapeutic approach by combining a monoclonal antibody specific to CRC cells that ferries a potent chemotherapeutic payload directly to the tumor.
Oncologist Manish Sharma from South Texas Accelerated Research Therapeutics (START) is the lead investigator of an ongoing clinical trial for CRC to test ABBV-400, a new CRC antibody-drug conjugate developed by AbbVie.
“It's been very collaborative [working with AbbVie],” said Sharma. “They bring us these great drugs to offer to our patients.”
The antibody-drug conjugate ABBV-400 combines a CRC-specific antibody called telisotuzumab with the chemotherapeutic drug, which is a topoisomerase I inhibitor that blocks tumor growth. Results from the recent Phase 1 trial demonstrated that the treatment reduced tumor size in patients not responding to other chemotherapy regimens. Sharma and his global team of collaborators are excited about the study’s preliminary results and hope that ABBV-400 could be a new drug for CRC as well as other cancer types.
How do clinicians currently treat colorectal cancer?
Treatment is dependent on the stage of progression. I mostly see stage IV CRC, which is a metastatic disease where the cancer started in the colon or rectum and has now spread to other areas of the body, including the liver, lungs, and lining of the belly.
The standard of care for stage IV CRC includes chemotherapy drugs such as 5-fluorouracil and oxaliplatin (FOLFOX) or 5-fluorouracil and irinotecan (FOLFIRI). Often, doctors combine these drugs with biologics. Some of these include bevacizumab, which is an antibody that targets vascular endothelial growth factor, and cetuximab and panitumumab, which are monoclonal antibodies that target a protein called epidermal growth factor receptor.
What is ABBV-400, and how does it work?
ABBV-400 is an antibody-drug conjugate that consists of the antibody telisotuzumab, which binds to the protein c-Met expressed in CRC cells and the chemotherapy payload topoisomerase I inhibitor, which blocks cell growth and kills cancer cells. When telisotuzumab binds to c-Met positive cancer cells, it causes the internalization of the topoisomerase I inhibitor.
Who are the patients receiving ABBV-400 in the Phase 1 trial?
We’re testing this drug on those who do not have any other treatment options. It's notable that when we give them ABBV-400, even after they've had FOLFOX/FOLFIRI and potentially other therapies, we see tumor reductions in about 16 percent of the patients from a cohort of 122 patients with CRC. This is exciting because these patients would otherwise have no options to reduce tumor size.
There's a very human component to this research, where we get to know the patients and their families. It's very rewarding to see the patient benefit from the drug treatment and see their tumors shrink.
- Manish Sharma, South Texas Accelerated Research Therapeutics
How did you feel when you saw those positive results?
I was thrilled to see the drug work. There's a very human component to this research, where we get to know the patients and their families. It's very rewarding to see the patient benefit from the drug treatment and see their tumors shrink. We’re helping people live longer, which makes this work gratifying. The overall goal of drug development is to get better therapies for our current patients as well as for patients in the future.
What sort of feedback have you heard from patients?
The people I took care of personally were thrilled to be part of the study. They felt the benefits, and you could show them the pictures of the CT scans where tumors were shrinking. They understood that this clinical trial would go on to provide benefits for other patients too.
What do you plan to do next?
One thing that we're looking at next, within the context of this study, is the combination of ABBV-400 with another drug called bevacizumab. This is an FDA-approved therapy for CRC, so by combining these two, we may improve outcomes even further. There's some preclinical data to support that as well. We're also looking at ABBV-400 and other tumor types, which are separate clinical trials that have built off of the knowledge that we gained from this trial. Now that we know how to dose the drug and how often to give it, we can use this knowledge to propel the drug forward, even studying other diseases like pancreatic cancer.
This interview has been condensed and edited for clarity.
Reference
- Morgan, E. et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN.Gut 72, 338–344 (2023).
