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

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 RSPO- or RNF43-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 RSPO- or RNF43-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 WNT-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 RSPO 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 RSPO fusions, Giannakis details.

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 WNT-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.