When added to standard chemotherapy, IMAB362, a chimeric monoclonal antibody against the claudin 18.2 protein, reduced the risks for disease progression and death by 50% compared with standard chemotherapy alone as first-line treatment for patients with advanced or recurrent gastric cancer and gastroesophageal junction carcinomas, according to data presented at ASCO 2016.
The data, from the international, randomized phase 2 FAST trial, provide “a strong rationale for pursuing this approach in a confirmatory phase 3 study,” said Salah-Eddin Al-Batran, MD, Director, Institute of Clinical Cancer Research, Nordwest Hospital, Frankfurt Am Main, Germany.
First-in-Class Monoclonal Antibody
The IMAB362 antibody is a first-in-class chimeric immunoglobulin G1 backbone antibody that is highly specific for claudin 18.2, which is a major structural component of tight junctions that is broadly expressed by various cancers, including biliary duct, pancreatic, and gastric cancers.
In combination with chemotherapy, IMAB362 enhances T-cell infiltration of tumors and induces proinflammatory cytokines, thereby modifying the microenvironment of the tumor.
The FAST trial was conducted in patients with gastric, esophageal, or gastroesophageal junction adenocarcinoma who tested positive for claudin 18.2 using the CLAUDETECT18.2 test. No previous chemotherapy for advanced disease was allowed.
The patients were randomized to IMAB362 plus epirubicin, oxaliplatin, and capecitabine (EOX) chemotherapy (N = 77) or to EOX only (N = 84). IMAB362 was administered as a loading dose of 800 mg/m2 followed by 600 mg/m2 on day 1 and every 3 weeks thereafter. A third arm consisting of 85 patients was later added to explore the feasibility of a higher dose of IMAB362 (1000 mg/m2 every 3 weeks).
The median progression-free survival (PFS), which was the primary end point, was 7.9 months in the IMAB362 plus EOX arm compared with 4.8 months in the EOX-only arm, which corresponded to a 53% improvement in PFS with IMAB362 (P = .001). In arm 3 (which received the higher dose of IMAB362), the median PFS was 7.1 months, a 49% improvement versus EOX alone (P = .001).
The median overall survival (OS) was extended significantly when IMAB362 was added to the EOX regimen compared with EOX alone (13.2 months vs 8.4 months, respectively; hazard ratio [HR], 0.51; P = .001).
In patients with very high expression of claudin 18.2 (who were defined as patients with 2+/3+ claudin 18.2 staining in ≥70% of tumor cells), the PFS and OS benefit of IMAB362 was even greater. In this subgroup, the median PFS was 7.2 months in the IMAB362 plus EOX arm versus 5.6 months in the EOX-only arm (HR, 0.36; P ≤.005), and the median OS was 16.7 months in patients receiving IMAB362 plus EOX versus 9.0 months with EOX only (HR, 0.45; P ≤.005).
Treatment with IMAB362 was well-tolerated. A slight increase in the rate of grade 3 or 4 neutropenia was seen with IMAB362 plus EOX versus EOX only (32.5% vs 21.4%, respectively), in addition to grade 1 or 2 vomiting (55.8% vs 34.5%) and grade 3 or 4 vomiting (10.4% vs 3.6%).
Phase 3 Considerations
Peter C. Enzinger, MD, Clinical Director of the Center for Esophageal and Gastric Cancer, Dana-Farber Cancer Institute, Boston, MA, noted some considerations before moving to a phase 3 study.
“Before we declare victory, let us not forget rilotumumab,” he cautioned. Rilotumumab showed improvement in OS of 5.4 months in a phase 2 study of patients with high levels of MET expression, but failed to meet its primary end point in a follow-up phase 3 study, and its development was halted.
Second, the benefit of IMAB362 in patients with low or no claudin 18.2 expression is unclear from the data presented, said Dr Enzinger.
He added that the control arm in the FAST trial did not perform as well as in patients who received EOX chemotherapy in the REAL 2 study, in which the median OS was 11.2 months with EOX. Finally, highly emetogenic epirubicin may not be the best chemotherapy partner for IMAB362.