Optimism Surrounds Claudin 18.2 ADC

Although some progress has been made of late in treating patients newly diagnosed with gastric and gastroesophageal (GEJ) cancers, overall progression-free survival (PFS) hovers around 7 months—and overall survival (OS) around 14 to 16 months—with currently approved therapies. Researchers are optimistic that a potential new treatment for the diseases is on the horizon, given the results of a phase I trial of CMG901 (KYM Biosciences), a first-in-class antibody–drug conjugate (ADC) targeting claudin 18.2 (CLDN18.2).

CLDN18.2 is “not an uncommon biomarker” in gastric and GEJ cancers, said Samuel Klempner, MD, of Massachusetts General Hospital in Boston, MA, who described the target during the November session of the American Society of Clinical Oncology Plenary Series. He noted that in the phase III SPOTLIGHT and GLOW trials assessing zolbetuximab (Astellas), an investigational CLDN18.2-targeted mAb, 38.4% of participants were CLDN18.2-positive. “It's a large portion of our patients.”

Because CLDN18.2 is a validated target and a largely tumor-restricted antigen, researchers launched a trial testing whether the ADC CMG901—composed of an anti-CLDN18.2 antibody, a protease-cleavable linker, and a toxic MMAE payload to inhibit cell division—could safely target tumor cells and extend survival. (Under a license agreement signed in February, AstraZeneca will research, develop, manufacture, and commercialize the agent, renamed as AZD-901.)

Rui-Hua Xu, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented results from the dose-expansion phase of the trial, which included 113 patients—all Asian—with solid tumors refractory to standard therapy and moderate-to-strong CLDN18.2 expression on at least 5% of tumor cells. They had received a median of two prior therapies.

The researchers tested three doses of CMG901: 2.2 mg/kg, 2.6 mg/kg, and 3.0 mg/kg. The confirmed overall response rates (ORR) were 42%, 24%, and 38%, respectively. After a median follow-up of 6 months, the median duration of response (DOR) was 7.2 months.

For the three doses, respectively, median PFS, median OS, and 9-month OS rates were 4.8 months, not reached, and 70.7%; 3.3 months, 8.5 months, and 46.9%; and 14.5 months, not reached, and 56.3%.

Asked about the lack of a dose-related response, Xu commented, “We do not exactly have an explanation for this.”

Regarding safety, all 113 patients had treatment-emergent adverse events (AE), Xu reported. About 64% had AEs deemed grade 3 or higher. Eight percent of patients discontinued treatment due to AEs, most commonly anemia, vomiting, hypoalbuminemia, weight loss, and nausea.

“These results provide a strong rationale to further explore CMG901 as an ADC in claudin 18.2–expressing gastric or gastroesophageal cancer,” Xu declared.

Discussant Elizabeth Smyth, MD, of Oxford University Hospitals NHS Foundation Trust in the UK, said that survival with CMG901 is “much better than what we see with standard-of-care second-line and third-line treatments.”

Yet she noted several limitations of the trial. “One key issue…was that patient selection for the trial was quite permissive” because moderate-to-strong CLDN18.2 expression was allowed on as a few as 5% of tumor cells. However, 83% of participants had that level of CLDN18.2 expression on at least 20% of cells. In addition, the trial lacked data on when CLDN18.2 status was assessed, which “could be important due to biomarker plasticity and epitope decay,” she said.

That the study was conducted only in China offered another reason to be cautious when assessing CMG901. “As we've seen with gastric cancer, [drugs] sometimes work differently inside and outside of Asia,” she said.

Even so, “what I see here as reassuring is that there are very few immediate progressions,” Smyth added, noting that the median DOR of 7.2 months compares favorably with the median DOR of 3.9 months for patients who received only chemotherapy in the Asian DESTINY-GASTRIC01 study. “We're getting control of the disease early, which is important for maintaining patient symptom control and performance status.” –Suzanne Rose

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