A first-in-class, claudin 18.2 (CLDN18.2)-targeted antibody-drug conjugate may be a new treatment option for patients with advanced gastric/gastroesophageal junction (GEJ) cancers, according to data presented by Xu et al during the ASCO Plenary Series: November 2023 Session (Abstract 434420).
Results of a phase I trial of CMG901, a potential first-in-class CLDN18.2-targeted antibody-drug conjugate carrying monomethyl auristatin E, demonstrated promising clinical efficacy in patients with CLDN-18.2-positive, second-line gastric/gastroesophageal junction cancers. With a median follow-up of 6 months, the median progression-free survival for patients treated with the agent was 4.8 months, and the 9-month overall survival rate was 56%.
“Based on the results in this study, it was found that CMG901 was active in this heavily pretreated population, with a manageable safety profile”, said lead study author Rui-hua Xu, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China. “CMG901 appears to be a promising therapeutic agent for CLDN 18.2-expressing gastric and gastroesophageal junction cancers—an area of high unmet medical need.”
Rui-hua Xu, MD, PhD
As Dr. Xu reported, gastric cancer has a substantial disease burden globally, particularly in Asia. Although there has been recent progress in the management of gastric and gastroesophageal junction cancer, said Dr. Xu, there have been limited gains in targeted therapy.
However, CLDN18.2, a protein found in approximately 40% to 60% of gastric adenocarcinoma cases, is a clinically validated target. CMG901 has demonstrated potent antitumor activity in preclinical studies.
This is the first trial to assess the efficacy and safety of CMG901 for patients with advanced gastric or gastroesophageal junction cancers.
Phase I Study Design
The phase I trial included a dose-escalation phase (part A) and a dose-expansion phase (part B) to evaluate the safety, tolerability, and antitumor activity of CMG901 in patients with advanced gastric/gastroesophageal junction cancers and other solid tumors. CLDN18.2 expression was not required for study entry in part A, but CLDN18.2 expression of at least 2+ membrane-staining intensity in at least 5% of tumor cells was required for gastric/gastroesophageal junction cancers in part B.
CMG901 was administrated intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoints were safety and tolerability and maximum tolerated dose for part A, and objective response rate and recommended phase II dose in part B.
Potential Clinical Efficacy
As Dr. Xu reported, maximum tolerated dose was not reached during dose escalation. A total of 113 patients received CMG901 at doses of 2.2 to 3.0 mg/kg.
Of 89 patients with CLDN18.2-positive disease and at least one posttreatment scan, the confirmed objective response rate was 32.6%, with 70% of these patients experiencing disease control. For all 93 patients with CLDN18.2-positive disease, the median progression-free survival was 4.8 months after a median follow-up of 6 months, and 25% remain on CMG901 as of data cutoff. The median overall survival was not reached, with a 9-month overall survival rate of 56%.
“Among patients who responded to CMG901, the median duration of response was about 7 months,” said Dr. Xu. “The progression-free and overall survival [results] are encouraging for this heavily pretreated patient population.”
Objective responses were observed regardless of number of prior lines of therapy, including patients who had received three or more prior lines. Antitumor activity of CMG901 was also seen in patients who had received prior anti–PD-1 and anti-CLDN18.2 therapy.
All 113 patients in the trial had at least one treatment-emergent adverse event, with 64% experiencing grade ≥ 3 treatment-emergent adverse events. Dose reductions and treatment discontinuations occurred in 13% and 8% of patients, respectively. There was one treatment-related death (due to cerebral hemorrhage). Vomiting and nausea were common, said Dr. Xu, although the majority of these events were grade 1 or 2.
ASCO Expert Perspective
Pamela Kunz, MD
Commenting on the study findings, ASCO Expert in gastrointestinal cancers Pamela Kunz, MD, Director of the Center for Gastrointestinal Cancers and Chief of GI Medical Oncology at Smilow Cancer Hospital and Yale Cancer Center, New Haven, said: “The recent phase III SPOTLIGHT and GLOW studies put CLDN18.2 on the map as a viable target for gastroesophageal cancer. It is one of the most exciting new targets for patients with advanced gastroesophageal cancer…. CMG901 represents a new way to interrogate this target. What’s exciting for patients is the potential for an entirely new class of therapies for advanced gastroesophageal cancer—we will all eagerly await future studies.”
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
