In a Chinese phase I trial (KYM901) reported in The Lancet Oncology, Ruan et al found that CMG901—a first-in-class claudin 18.2–targeting antibody-drug conjugate—had manageable toxicity and activity in patients with advanced gastric or gastroesophageal junction (GEJ) cancer. CMG901 comprises a humanized anticlaudin 18.2 antibody linked to the microtubule-disrupting agent monomethyl auristatin E.
Study Details
In the multicenter trial, 27 patients (14 with pancreatic cancer) were enrolled in a dose-escalation phase, and 107 patients with gastric or GEJ cancer were enrolled in a dose-expansion phase between December 2020 and February 2023. Patients received intravenous CMG901 every 3 weeks at 0.3 to 3.4 mg/kg in the dose-escalation phase and 2.2 to 3.0 mg/kg in the dose-expansion phase until disease progression or unacceptable toxicity. The primary outcome measures were adverse events and dose-limiting toxic effects in the dose-escalation phase and objective response rate and recommended phase II dose in the dose-expansion phase.
Key Findings
In the dose-escalation phase, a dose-limiting toxicity (grade 3 pancreatitis) occurred in one patient at 2.2 mg/kg; the maximum tolerated dose was not reached in the dose-escalation phase. Adverse events of any grade were reported in all 27 patients in the dose-escalation phase, most commonly vomiting (70%), decreased appetite (59%), proteinuria (59%), and anemia (56%). Drug-related grade ≥ 3 adverse events occurred in five patients (19%).
In the dose-expansion phase, grade ≥ 3 adverse events occurred in 73 patients (68%), most commonly decreased neutrophil count (21%), anemia (14%), and vomiting (10%). Serious adverse events of any grade were reported in 50% of patients in the dose-expansion phase. One treatment-related death occurred, as a result of cerebral hemorrhage.
At a median follow-up of 9.0 months (interquartile range = 4.4–12.9 months), among 113 patients with gastric or GEJ cancer in the 2.2 to 3.0 mg/kg cohort across both dose-escalation and dose-expansion phases, confirmed objective response was achieved in 32 (28%, 95% confidence interval [CI] = 20%–38%); median response duration was 7.9 months (95% CI = 5.3–10.0 months). Among 109 patients with gastric or GEJ cancer in the efficacy analysis set (at least one post-dose imaging evaluation and no major protocol deviations), confirmed objective response was achieved in 32 (29%, 95% CI = 21%–39%).
Based on overall safety, activity, and pharmacokinetics of CMG901, 2.2 mg/kg was the proposed recommended phase II dose.
The investigators concluded: “CMG901 showed a manageable safety profile and had promising antitumor activity in patients with advanced gastric or [GEJ] cancer.”
Rui-Hua Xu, MD, and Dong-Sheng Zhang, MD, of Sun Yat-sen University Cancer Center, Guangzhou, are the corresponding authors of The Lancet Oncology article.
Disclosure: The study was funded by KYM Biosciences. For full disclosures of all study authors, visit The Lancet Oncology.
