Results from a randomized phase II study indicate that adding the experimental antibody IMAB362, which targets the tight junction protein claudin18.2, to standard chemotherapy is more effective than chemotherapy alone in previously untreated patients with advanced gastric cancer. IMAB362 extended progression-free and overall survival by 3.1 months and 4.8 months, respectively.

Findings from FAST, an international multicenter phase II study, indicate that adding the experimental antibody IMAB362 (Ganymed Pharmaceuticals) to standard chemotherapy boosts the overall survival (OS) of previously untreated patients with advanced gastric cancer, compared to chemotherapy alone. The data were presented by Salah-Eddin Al-Batran, MD, director of Nordwest Hospital's Institute of Clinical Cancer Research in Frankfurt, Germany, during the American Society of Clinical Oncology's annual meeting in Chicago, IL, June 3–7.

IMAB362 is a first-in-class antibody targeting claudin18.2, which belongs to a family of tight junction proteins. Claudin18.2 is “abundantly expressed” in 70%–90% of gastric, pancreatic, and biliary duct cancers, Al-Batran said, but not in normal tissue—with the exception of the stomach lining. Once IMAB362 binds claudin18.2, it unleashes antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), both of which mediate tumor destruction: ADCC recruits various immune cells, including macrophages and monocytes; CDC works through a group of proteins called the membrane attack complex.

In this study, 161 patients with advanced gastric, esophageal, or gastroesophageal junction adenocarcinomas were randomized to receive first-line chemotherapy—epirubicin, oxaliplatin, and capecitabine (EOX)—alone or with IMAB362. None of the patients had received prior therapy for their disease, and all had claudin18.2 expression, determined by immunohistochemistry, in at least 40% of their tumor cells. Compared to EOX alone, IMAB362 extended the median progression-free survival (PFS) from 4.8 months to 7.9 months, and the median OS from 8.4 months to 13.2 months.

Notably, when the investigators did a subset analysis of patients with claudin18.2 expression in 70% or more of their tumor cells, they found that adding IMAB362 to EOX nearly doubled the median OS from 9.0 months to 16.7 months. “It seems that patients with higher levels of claudin18.2 derive more benefit from IMAB362,” Al-Batran said. “We haven't assessed its performance in those with only low claudin18.2 levels [<40%], though, so we can't exclude its potential efficacy there.”

IMAB362 was largely well tolerated, although neutropenia and nausea/vomiting were more common—the latter likely due to claudin18.2′s presence in the stomach lining, Al-Batran observed.

“I think our findings provide a strong rationale for a confirmatory phase III study of this antibody plus chemotherapy in GI [gastrointestinal] adenocarcinomas,” he concluded.

“Before victory is declared, let's not forget rilotumumab [Amgen]—in phase II, it was associated with increased OS of patients with advanced MET-positive gastric cancer,” cautioned Peter Enzinger, MD, clinical director of the GI malignancy program at Dana-Farber Cancer Institute in Boston, MA. “Unfortunately, it failed to meet the same primary endpoint in phase III and further development was halted.”

Enzinger suggested determining the ideal cutoff for claudin18.2 expression in subsequent studies of IMAB362, and including an arm for claudin18.2-negative patients to confirm the antibody's mechanism of action. He also wondered if epirubicin, being highly emetic, was perhaps not the best partner for IMAB362, given the latter's primary toxicity.

“Overall, these are promising initial results, but additional data are required, along with some tinkering [of the study design] before IMAB362 is moved to phase III,” Enzinger said. –Alissa Poh

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.