Dr. Salah-Eddin Al-Batran
IMAB362 is a chimeric monoclonal against claudin 18.2—a tight junction protein that is expressed by several solid cancers, and, notably, in gastric cancer, gastroesophageal junction carcinomas, and pancreatic and biliary duct cancers.
FAST was a randomized, phase II study of patients whose disease had high claudin 18.2 expression based on an accompanying test—the Claudetect 18.2. To be eligible for the study, at least 40% of patients’ tumor cells had to show an immunohistochemical (IHC) expression of at least 2+. Of 686 IHC-assessable patients, 334 patients tested positive for the claudin 18.2 cut-off and 161 were treated after random assignment to two arms: 77 in the IMAB362 plus EOX arm and 84 in the standard EOX arm. An additional 85 patients were treated in a third arm, added later to evaluate IMAB362 at a higher dose.
The standard chemotherapy was epirubicin, oxaliplatin, and capecitabine (EOX) administered at standard dosages. IMAB362 was administered as a loading dose of 800 mg/m2 and then at 600 mg/m2 on day 1 and given subsequently every 3 weeks. Patients in the third arm were given 1,000 mg/m2 of IMAB every 3 weeks.
Median progression-free survival (PFS), the primary endpoint of the study, was significant for patients who received IMAB362 compared with EOX only (7.9 months vs. 4.8 months, respectively; HR 0.47, 95% CI [0.31, 0.70]; p = 0.0001). Similarly, the median PFS in the arm that received the higher dose of IMAB362 was also significantly greater at 7.1 months compared with 4.8 months in the EOX arm (p = 0.001). In addition, median overall survival (OS) was significantly prolonged with IMAB362 treatment at 13.2 months compared with 8.4 months in the EOX arm (HR 0.51, 95% CI [0.36, 0.73]; p = 0.0001).
In the subpopulation of patients with tumors that had very high claudin 18.2 expression (70% or greater tumor cell expression), Dr. Al-Batran reported an even greater OS benefit with IMAB362 treatment compared with EOX only (16.7 vs. 9.0 months, respectively; HR 0.45; p < 0.0005). In this subgroup, median PFS was 7.2 in the IMAB362 arm compared with 5.6 months in the EOX only arm (HR 0.36, p < 0.0005).
Patients who received IMAB362 also showed a higher objective response rate (ORR) at 39% compared with 25% in the EOX arm. The most frequent adverse events in the IMAB362 arm were nausea, vomiting, and neutropenia. The latter may be a cumulative effect, Dr. Al-Batran said. “Patients receiving IMAB362 were on chemotherapy for a longer time and had a longer follow up,” he told the ASCO Daily News.
Discussant Peter C. Enzinger, MD, of the Dana-Farber Cancer Institute, indicated that these are promising improvements in survival with minimal increased toxicity. “But, do we just move to a phase III study?” he asked.
He suggested that some questions may need to be addressed before that happens. First, although patients whose disease had high CLDN18.2 expression showed more pronounced clinical benefit, he wanted to see the clinical benefits for patients whose tumors expressed low CLDN18.2 levels or no CLDN18.2. This may identify the ideal cut-off point, Dr. Enzinger said.
Dr. Enzinger also noted that clinical outcomes for patients who received EOX only did not compare with patients who received EOX in the REAL 2 study (median OS, 11.2 months; ORR, 47.9%). “Why did the control arm not measure up?” he asked. He opined that perhaps EOX is not the best backbone for an international study.
Finally, he questioned whether highly emetogenic epirubicin as part of EOX is the best partner for IMAB362 if nausea and vomiting are its primary side effects. He suggested FOLFOX or FOLFIRI as other options.
“Although the results of the FAST study are promising, we need additional data and some tinkering before moving to a phase III study,” Dr. Enzinger concluded.
– Alexander Castellino, PhD