IMAB362 is an innovative antibody drug candidate being developed by Ganymed for the treatment of gastroesophageal cancer. IMAB362 represents a unique opportunity to transform solid cancer treatment by benefiting a far higher proportion of patients (up to 80%) than other anticancer antibodies while mitigating the threats of side effects.
IMAB362 is the first-in-class drug candidate that is selective and specific for the tight junction protein Claudin-18.2 (CLDN18.2). This unique target is responsible for regulating paracellular permeability and sealing the space between epithelial and endothelial cellular sheets. Its expression is restricted to differentiated stomach cells only and is absent from all other tested healthy tissues. CLDN18.2 is however overexpressed in up to 80% of gastrointestinal adenocarcinomas (primary and metastasized)1 and 60% pancreatic tumors2 in addition to other solid cancers.
This makes IMAB362 the first antibody that is cancer cell selective while having little or no effect on healthy cells, thus reducing the risk of toxicity. This represents a great advantage over other anticancer therapies that target both cancerous and healthy cells resulting in unwanted side effects.
Gastroesophageal cancer is currently the second leading cause of cancer related deaths worldwide. The 5-year survival rates are 28% for advanced gastric cancer and 3.7% only for metastasized gastric cancer.
IMAB362 has received orphan drug designation in the US and Europe for gastric cancer and will soon enter into phase III clinical development for gastroesophageal cancer.
Key Findings Phase IIb FAST Study
Results of a Phase IIb (FAST) study showed that IMAB362 significantly extended median overall survival in patients with advanced gastric cancer when added to standard chemotherapy. Furthermore, IMAB362 nearly doubled survival in patients with the highest levels of Claudin18.2. The study included 161 patients with advanced or recurrent gastric or gastroesophageal junction cancer with a specific minimal level of Claudin18.2 in the tumor. Claudin18.2 levels were assessed from tumor biopsy specimen using the validated CE-marked diagnostic assay CLAUDETECT®18.2. Patients were then randomly assigned to receive standard chemotherapy (epirubicin, oxaliplatin and capecitabine) with IMAB362 (800/600 mg/m2) or chemotherapy alone. Moreover, an additional 85 patients were treated in an added exploratory arm with a higher IMAB362 dose.
Compared to chemotherapy alone, IMAB362 extended the median time to disease progression from 4.8 to 7.9 months (HR 0.47, p=0.0001) and the median overall survival from 8.4 to 13.2 months HR 0.51, p=0.0001). Among the patients with the highest levels of Claudin18.2, the median overall survival was 16.7 months with IMAB362 and 9 months with chemotherapy alone (HR 0.45, p<0.0005).
Treatment with IMAB362 was well tolerated during the study. Vomiting (34.5% of patients with grade 1/ 2 and 3.6% with grade 3/4 in the control arm versus 55.8% of patients with grade 1/ 2 and in 10.4% with grade 3/4 in the IMAB362 arm) and low blood counts (neutropenia; 21.4 % of patients with grade 1/ 2 and 21.4 % with grade 3/4 in the control arm versus 23.4% of patients with grade 1/ 2 and in 32.5% with grade 3/4 in the IMAB362 arm) were slightly more common in the IMAB362 group. The rates of severe adverse effects were not increased with IMAB362 compared to chemotherapy alone.
Key Finding Phase IIa MONO Study
IMAB362 also showed strong evidence for single agent anticancer activity in a Phase IIa clinical (MONO) study in patients with CLDN18.2-positive, metastatic, refractory or recurrent advanced gastroesophageal cancer. Patients treated with IMAB362 showed a disease control rate of 48% with 19% of patients undergoing partial remission and 29% achieving stable disease state based on a set of 21 per protocol treated patients. The median Progression Free Survival (PFS) was 102 days (95% CI), ranging from 70 to 146 days. Patients with clinical benefits had a median PFS of 262 days as compared to a median PFS of 70 days for patients with disease progression. Nine patients continued treatment beyond 5 cycles due to clinical benefit. IMAB362 was safe and well tolerated during the study.
Phase I Pilot Study Completed
An additional Phase I (PILOT) study has been recently completed to explore the safety and efficacy of IMAB362 in combination with immunomodulation agents in patients with advanced gastrointestinal adenocarcinomas (ClinicalTrials.gov Identifier: NCT01671774). Results will be presented soon.
Pancreatic cancer is one of the deadliest cancers with a one-year relative survival rate of less than 20% and a five-year survival rate of less than 4%. In non-clinical studies, IMAB362 efficiently lysed CLDN18.2 positive pancreatic cell lines in vitro and significantly reduced tumor size and increased survival of in vivo xenograft mouse models injected with CLDN18.2 positive human pancreatic adenocarcinoma cells. IMAB362 has received orphan drug designation in Europe and the US for pancreatic cancer Ganymed is planning to initiate clinical studies in the future. This would allow IMAB362 to treat a patient population where there is an extremely high medical need for more effective therapies.
Many cancers are highly heterogeneous diseases comprising of small subpopulations of patients that specifically express one or another drugable target. Impressive response rates have been observed with some anticancer drugs even if their target is expressed in only a small percentage of patients.
CLDN18.2 expression has been observed in distinct subsets of individuals with non-small cell lung carcinoma (<5%), ovarian cancer (<10%), and colon cancer (<5%). CLDN18.2 is also found in several forms of biliary ductal carcinomas which are uncommon, but serious types of cancers. Line extension of IMAB362 into these indications may provide these subgroups of patients with important therapeutic benefits and broaden the use of IMAB362 in cancer treatment.