Novel Antibody-Drug Conjugate Shows Promise in Advanced Gastric Cancer

Gastric Cancer: Gastric CancerThe first-in-class antibody-drug conjugate CMG901 targeting claudin 18.2 (CLDN18.2) may be a potential new treatment option for patients with claudin 18.2-positive gastric or gastroesophageal junction (GEJ) cancer. Updated results from a dose-expansion trial in patients with advanced gastric/GEJ cancer show a confirmed overall response rate (ORR) of 42 percent and median progression-free survival (PFS) of 4.8 months after 6 months of follow-up. Overall survival (OS) was not reached, with an OS rate of 56.4 percent at 9 months. “CMG901 demonstrated promising clinical efficacy in patients with CLDN18.2-positive gastric/GEJ cancer. Clinical activity was observed across all subgroups,” said lead author Rui-Hua Xu, MD, PhD, President of Sun Yat-sen University Cancer Center in Guangzhou, China, at the November 2023 American Society of Clinical Oncology (ASCO) Plenary Series (Abstract 434420). Recent progress in the management of gastric/GEJ cancer has not included targeted therapy. CLDN18.2 is a promising therapeutic target for advanced gastric/GEJ cancer. Its expression represents the largest subgroup of gastric cancer, Xu noted. CMG901, a potential first-in-class CLDN18.2-targeted antibody-drug conjugate carrying monomethyl auristatin E, has demonstrated potent anti-tumor activity. Initial results from a dose-escalation Phase I trial showed a manageable safety profile and preliminary efficacy. Study Details At the ASCO Plenary session, Xu presented results from the first trial to assess the efficacy and safety of CMG901 for patients with advanced gastric/GEJ cancer. This study in China consisted of a dose-escalation phase (part A; dose range 0.3-3.4 mg/kg) and a dose-expansion phase (part B; doses of 2.2, 2.6, and 3.0 mg/kg) to evaluate the safety, tolerability, and anti-tumor activity of CMG901 in patients with advanced gastric/GEJ cancers and other solid tumors. Primary endpoints were safety and tolerability, as well as maximum tolerated dose (MTD) for part A, and ORR and recommended Phase II dose in part B. MTD was not reached during the dose-escalation phase. A total of 113 patients (6 patients from part A and 107 patients from part B) received CMG901 at doses of 2.2-3.0 mg/kg. Of the 89 CLDN18.2-positive patients with at least one post-treatment scan, the confirmed ORR was 42 percent. For all 93 CLDN18.2-positive patients, the median PFS was 4.76 months after a median follow-up of 5.98 months. “ORR was similar across different subgroups, including patients with ECOG PS of 1 or peritoneal metastasis—subgroups known to have a poor prognosis,” Xu said. Objective responses were observed regardless of the number of prior lines of therapies, including in patients with three or more prior lines. Similar ORR was observed regardless of prior taxane or anti-programmed death-1 therapy. Most common treatment-emergent adverse events (TEAEs) were anemia (62.8%), vomiting (57.5%), and hypoalbuminemia (57.5%). Neutrophil count decreased (18.6%) and anemia (13.3%) were the most frequent Grade ≥3 TEAEs. “The results of this study show CMG901 was active in this heavily pretreated population with a manageable safety profile. CMG901 appears to be a promising therapeutic agent for CLDN 18.2-expressing gastric/GEJ cancers, an area of high unmet medical need,” Xu explained. “These results provide a strong rationale to further explore CMG901 as an antibody-drug conjugant in CLDN18.2-expressing gastric/GEJ cancer.” Pamela Kunz, MD, ASCO Expert in Gastrointestinal Cancers and Associate Professor of Internal Medicine (Medical Oncology) at the Yale Medical Center, noted, “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 and 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.” Discussant Elizabeth Smyth, MD, Consultant at Oxford University Hospital NHS Foundation Trust, commented, “These results provide more reasons to be optimistic about CMG901. The follow-up is short—6 months—and there were many censored patients, but OS is good compared to most second-line or third-line standards.” In terms of adverse events, neutropenia and hypoesthesia were dose-related. The relationship to prior oxaliplatin/taxane therapy is important for neuropathy. “CMG901 appears to have promising activity in this Asian-only gastric cancer trial and requires validation in international populations. We also need to know how best to use this modality in gastroesophageal cancer,” Smyth concluded. Mark L. Fuerst is a contributing writer.