Despite the fact that many gastrointestinal tumors, including colorectal cancer, are driven by WNT signaling, there have been no therapies approved by the FDA that target this signaling pathway to date. One compound that was shown to disrupt WNT signaling in preclinical studies is CGX1321, which blocks secretion of the WNT ligand and is a potent, selective O-acyltransferase Porcupine inhibitor, having a 50 percent inhibitory concentration (IC50) of 0.45 nM. Other preclinical studies found that CGX1321 reduced the growth of tumors bearing inactivating RNF43 mutations or RSPO fusions.
"Activation of WNT signaling promotes tumor growth but is also associated with an immunosuppressive tumor microenvironment," noted Marios Giannakis, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute.
In an interview with Oncology Times, he discussed some preliminary results from a Phase I/Ib trial evaluating CGX1321 as monotherapy or in combination with the anti-PD-1 monoclonal antibody pembrolizumab. "CGX1321 has demonstrated potent inhibition of the WNT pathway with a manageable side effect profile," Giannakis stated. He presented a poster session on his research at the 2023 ASCO Annual Meeting (Abstract 3514).
First-in-Human Trials
There were two different first-in-human trials evaluating CGX1321: one in the U.S. (NCT02675946) and one in China (NCT03507998). The Phase I study included dose-escalation and dose-expansion cohorts for CGX1321 monotherapy, while the Phase Ib study evaluated the combination of CGX1321 plus pembrolizumab.
"Primary objectives included safety, tolerability, and identification of the recommended dosages and schedules for CGX1321 alone and in combination with pembrolizumab," Giannakis explained.
Among the secondary study objectives were determination of pharmacokinetics, pharmacodynamics, and antitumor activity of CGX1321 as a single agent or together with immune checkpoint blockade. For the expansion cohorts, as a monotherapy, CGX1321 was orally dosed at 18 mg once daily for 21 days of a 28-day cycle. In combination with pembrolizumab, oral dosage occurred on 14 days of each 21-day cycle.
Research Results
A total of 77 patients had been enrolled in this study by January 1, 2023, including the following: 38 in the CGX1321 monotherapy dose-escalation phase with solid tumors, 17 with colorectal or small bowel cancer bearing RSPO fusions or with pancreatic cancers and RNF43 inactivating mutations in the monotherapy dose-expansion phase, 17 with microsatellite-stable colorectal cancer in the CGX1321 plus pembrolizumab dose-escalation phase, and five with microsatellite-stable colorectal or small bowel cancer with RSPO fusion in the combination therapy dose-expansion phase.
For patients having gastrointestinal tumors bearing RSPO fusions, CGX1321 monotherapy showed a disease control rate of 77 percent. In contrast, for patients having tumors with unknown or undetected RSPO fusion status, the disease control rate was 2.6 percent.
For patients having gastrointestinal tumors bearing RSPO fusions, the combination of CGX1321 plus pembrolizumab had an objective response rate of 33 percent and a disease control rate of 83 percent. For those having unknown or undetected RSPO fusion status, the objective response rate was 0 percent and the disease control rate was 10 percent.
"CGX1321 displayed a reasonable safety profile, with the majority of adverse events being Grade 1 or 2," Giannakis observed. "Importantly, a common adverse event noted in other trials of WNT inhibitors, dysgeusia, was mostly Grade 1," he added. One of the major on-target toxicities is bone resorption, which could be managed prophylactically by treatment with zoledronic acid or denosumab.
Concerning the results, Giannakis noted, "CGX1321 monotherapy led to durable stable disease specifically in GI tumors with RSPO fusion, accompanied by significant ctDNA responses." When asked about other interesting findings within their study, he replied, "We also observed responses in patients who had microsatellite stable tumors with RSPO fusion that were treated with the combination of pembrolizumab and CGX1321."
Noting future directions for this inhibitor, Giannakis concluded, "These promising results warrant larger randomized trials in cancers with upstream WNT activating mutations."
Richard Simoneaux is a contributing writer.