Invited discussant of the phase I trial of the claudin 18.2-specific antibody-drug conjugate CMG901 in advanced gastric or gastroesophageal junction cancer was Elizabeth Smyth, MD, of Oxford University Hospitals NHS Foundation Trust. She said CMG901 demonstrated “encouraging results,” but more work needs to be done to leverage its full potential.
Elizabeth Smyth, MD
“I am reassured by the very few immediate disease progressions,” Dr. Smyth continued. “This is targeted chemotherapy, so we’re getting control of the disease early, which is important for patient symptom control and maintaining performance status. The duration of response is better than we see with chemotherapy alone but not quite as good as we see with [fam-trastuzumab deruxtecan-nxki] in HER2-positive patients,” she added.
Cautious Optimism
Despite the antitumor activity, however, there are reasons for caution, she added. Dr. Smyth called the progression-free survival, including responders and nonresponders, “fairly average” except for at the higher dose. At 6 to 8 months, overall survival looks encouraging when we compare most second- and third-line options,” she added, “but this was a small number [of patients], and there was short follow-up.”
Dr. Smyth also noted this study is an Asia-only trial, which is common in gastric cancer. Drugs sometimes work differently inside and outside Asia, she added. “There is more work to do,” she continued. “This includes validation outside Asia, optimization of the biomarker to understand which patients truly benefit, and toxicity management.”
According to Dr. Smyth, however, the biggest question for CMG901 and other targeted agents is how best to use these different modalities to help patients with gastric cancer. “There are a couple of different factors we will need to think about in terms of designing our therapy approach,” she explained. “CLDN18.2 has a biphasic distribution: Approximately 40% of patients have high expression; 40% have very low expression; and 20% are somewhere in the middle.”
Dr. Smyth continued: “We will probably consider antibodies, which have low monotherapy activity, in combination with chemotherapy for high expressors. In contrast, antibody-drug conjugates may be used in low expressors and heterogeneous populations, especially if they have good cleavage and permeability. They are tough to combine with other chemotherapy drugs.”
According to Dr. Smyth, bispecific T-cell engagers could be an effective tool to activate the immune system, but their use may be limited to immunologically “hot” tumors. “Unlike bispecific T-cell engagers, which are off the shelf, CAR-T [chimeric antigen receptor T-cell therapies] may overcome innate immune evasion. However, these therapies are quite expensive and challenging to operationalize, so we will need to see prolonged benefits to justify their use outside very specific niches,” she concluded.
DISCLOSURE: Dr. Smyth reported no conflicts of interest.
