A new phase 2 clinical trial led by University of Colorado Cancer Center member Robert Lentz, MD, may offer hope for patients with metastatic colon cancer for whom standard therapy is no longer effective. Lentz is mentored by Wells Messersmith, MD, associate director of clinical services at the CU Cancer Center.
“Colorectal cancer is the third most common and third most deadly cancer among both men and women in the U.S.,” says Lentz, assistant professor of medical oncology at the CU School of Medicine. “And while chemotherapy and biologic therapy are effective in many patients, once those no longer work, there are not many effective treatment options. The problem is made worse by the fact that about 95% of patients with colorectal cancer do not respond to already-approved immune therapy drugs. We really need to identify a way to generate an anti-tumor immune response in order to improve the lives of these patients.”
The power of three
That effort is aided by the CU-led, multisite trial of a new medication called evorpacept (ALX148), used in combination with cetuximab and pembrolizumab, commonly used immunotherapy drugs in cancer treatment.
Evorpacept specifically blocks a protein called CD47, which is found on the surface of most cells in the body. CD47 is known as the “don’t eat me signal,” as its primary function is to signal immune cells called macrophages not to eat them. Diseased or aged cells have lost enough CD47 that macrophages see them as OK to consume. Researchers have found that CD47 is overexpressed in tumor cells, however, as the tumor looks to protect itself against the immune system. When CD47 is blocked by evorpacept, cetuximab and pembrolizumab are able to prime the immune system to go in and destroy the cancer cell.
“This is a novel combination that attempts to achieve an effective immunotherapy treatment where it has not succeeded in the past,” Lentz says.
Patients in the study are being enrolled across five sites, including UCHealth University of Colorado Hospital. They receive treatment once a week, and it takes at least nine weeks to see a response — ideally tumor shrinkage or tumor stability. Messersmith and Lentz hope to have the study fully enrolled in early 2023, with early data on safety and efficacy to follow by the end of 2023. The trial also includes a two-year overall survival follow-up to determine the longer-term effectiveness of the medication.
Benefit for patients
The CU Cancer Center was a site for the first-in-human clinical trial of evorpacept, which closed last year.
“It's always our goal to give our patients access to novel therapies years before they're approved and available,” says Messersmith, division head of medical oncology and chief medical officer of oncology services at UCHealth. “We have many cases of patients who were put on hospice, told there were no other options, and then we're able to get them on a clinical trial and basically save their life.”
That’s the hope with the evorpacept trials, he says, which have the added advantage of being developed in collaboration with other academic cancer centers. The current trial is being run through the Academic GI Cancer Consortium, a group of about more than 20 gastrointestinal malignancy-focused centers across the U.S.
“The idea is that these academic centers can team up and do larger trials together than they could do alone,” Messersmith says. “We do that through master contracts, and through relationships with companies like ALX Oncology, which manufactures evorpacept.”
Another benefit of clinical trials, Messersmith says, are the educational opportunities they provide for students, fellows, and residents. In the case of the evorpacept study, Lentz wrote the protocol and began his research when he was a fellow.
“It's been a great training experience for him, and he's actually been on some of our formal NCI training grants — called “T32” and “K12” — which have supported his effort,” Messersmith says. “The nice thing about it is that when the project's done, not only are you helping patients and advancing the field, but you've also developed a cancer researcher from a student into a faculty member.”
Lentz says working on the study has been a great opportunity for him, especially because he’s been able to track its development all the way from an early concept to the point where the first patient has actually received treatment.
“Over the next few months, the chance that some patients will respond to this is very gratifying,” he says. “It’s been a great educational experience not only in terms of scientific concepts and clinical and translational research, but also the nuts and bolts of developing a clinical trial. I think that all of those skills will set me up for success in order to lead future trials down the road.”