Marios Giannakis, MD, PhD, medical oncologist, clinical investigator, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, assistant professor of medicine, Harvard Medical School, discusses preliminary efficacy data from a phase 1 study conducted in the United States (NCT02675946); and in China (NCT03507998) of CGX1321 with or without pembrolizumab (Keytruda) in advanced gastrointestinal (GI) tumors.

The phase 1/1b study is a first-in-human trial of the novel highly-potent and -selective O-acyltransferase porcupine inhibitor CGX1321. The trial consisted of a phase 1 ose-escalation portion and a dose-expansion portion, Giannakis explains. The coprimary end points of the trial included safety, tolerability,  identification of the recommended phase 2 dose (RP2D), and dosing schedules, Giannakis states.

The RP2D for CGX1321 was identified at 18 mg daily for 3 weeks on and 1 week off. Additionally, the agent was evaluated in patients with 

altered GI cancers as a monotherapy and in combination with pembrolizumab during the dose-expansion portion of the study.

A total of 77 patients were evaluated, including 38 patients with solid tumors in the single-agent CGX1321 dose-escalation cohort, and 19 patients with microsatellite stable (MSS) CRC 

in the CGX1321/pembrolizumab escalation cohort. Additionally, 18 patients with 

altered colorectal cancer (CRC) or small bowel cancer (SBC) were in the single-agent expansion cohort, and 10 patients with MSS GI tumors were in the combination expansion cohort. 

CGX1321 was well-tolerated and had significant inhibitory activity in 

-mutated tumors, Giannakis reports. Patients who received CGX1321 monotherapy experienced sustained stable disease and significant ctDNA reduction, with a disease control rate (DCR) of 77%, Giannakis states. This was seen in those with GI tumors displaying 

 fusions. In tumors that did not have these alterations, the DCR was 0%, Giannakis continues. In the combination arm, DCR was 83% for patients with MSS tumors. Notably, a DCR of 33% was observed in patients with 

Although these preliminary results highlight the importance of targeting the WNT pathway in these specific tumor types further evaluation of this agent in a larger sample of patients with 

-activating mutations is needed, Giannakis concludes.

Dr Giannakis received institutional research funding from Janssen Servier; he has a patent pending on biomarkers of immune response.

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Marios Giannakis, MD, PhD, discusses preliminary efficacy data from a phase 1 study of CGX1321 with or without pembrolizumab in advanced gastrointestinal tumors.

Marios Giannakis, MD, PhD

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Dr Giannakis on the Initial Efficacy of CGX1321 With or Without Pembrolizumab in GI Cancers