A first-in-class, claudin 18.2 (CLDN18.2)-targeted antibody-drug conjugate may prove to be an effective treatment option for patients with advanced gastric or gastroesophageal junction cancer, according to data presented during the ASCO Plenary Series: November 2023.1 (The ASCO Plenary Series is presented bimonthly in an online session with an invited discussant and live Q&A. To learn more, visit ASCO.org.)
Results of a phase I trial of this agent, also called CMG901, demonstrated clinical efficacy in the second-line setting for some patients with CLDN18.2-positive gastric or gastroesophageal junction cancer. With a median follow-up of 6 months, the median progression-free survival was 4.8 months, and the 9-month overall survival rate was 56%.
“CMG901 appears to be a promising therapeutic agent for CLDN18.2-expressing gastric and gastroesophageal junction cancers—an area of high unmet medical need.”— Rui-Hua Xu, MD, PhD
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“Based on the results of 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, Guangzhou, China. “CMG901 appears to be a promising therapeutic agent for CLDN18.2-expressing gastric and gastroesophageal junction cancers—an area of high unmet medical need.”
Background
As Dr. Xu reported, gastric cancer is linked to a substantial disease burden globally, particularly in Asia. Although there has been recent progress in the management of gastric and gastroesophageal junction cancers, Dr. Xu added, 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, a potential first-in-class CLDN18.2-targeted antibody-drug conjugate carrying monomethyl auristatin E, has demonstrated antitumor activity in preclinical studies. This is the first trial to assess the efficacy and safety of CMG901 in patients with advanced gastric or gastroesophageal junction cancer.
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 or gastroesophageal junction cancer 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 or gastroesophageal junction cancer in part B.
KEY POINTS
- The phase I trial of CMG901, a potential first-in-class claudin 18.2 (CLDN18.2)-targeted antibody-drug conjugate, has demonstrated clinical efficacy in patients with CLDN18.2-positive gastric junction cancer.
- Treatment with CMG901 led to disease control in 70% of patients, with a manageable safety profile, according to the investigators.
CMG901 was administrated intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoints were safety/tolerability and maximum tolerated dose for part A and objective response rate and recommended phase II dose for part B.
Clinical Efficacy and Safety
As Dr. Xu reported, the maximum tolerated dose was not reached during dose escalation. A total of 113 patients received CMG901 at doses between 2.2 and 3.0 mg/kg.
Of 89 patients with CLDN18.2-positive tumors who had at least one scan after treatment, the confirmed objective response rate was 32.6%, with 70% experiencing disease control. For all 93 patients with CLDN18.2-positive tumors, the median progression-free survival was 4.8 months after a median follow-up of 6 months, and 25% remain on CMG901 treatment 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 survival and overall survival are encouraging for this heavily pretreated patient population.”
Objective responses were observed regardless of the number of prior lines of therapy, including patients with three or more prior lines. Antitumor activity of CMG901 was also found in patients with prior anti–PD-1 and anti-CLDN18.2 therapy.
All 113 patients had at least one treatment-emergent adverse event, with 64% experiencing grade 3 or higher treatment-emergent adverse events. Dose reductions and treatment discontinuations were reported in 13% and 8% of patients, respectively. There was one treatment-related death from cerebral hemorrhage.
Vomiting and nausea were common, according to Dr. Xu. However, the majority of these events were grade 1 or 2.
DISCLOSURE: Dr. Xu reported financial relationships with Astellas Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, HenRui, Junshi Biosciences, KYM Biosciences, Merck Serono, and Roche.
REFERENCE
1. Xu RH, Ruan DY, Zhang DS, et al: A phase 1 trial of claudin 18.2-specific antibody-drug conjugate CMG901 in patients with advanced gastric/gastroesophageal junction cancer. ASCO Plenary Series: November 2023 Session. Abstract 434420. Presented November 7, 2023.
