German CatuNeo Trial of Catumaxomab Fails to Meet Primary Endpoint in Gastric Cancer

German CatuNeo Trial of Catumaxomab Fails to Meet Primary Endpoint in Gastric Cancer

Dr. Florian Lordick presents Abstract 4 during Oral Abstract Session A.
Final results of the randomized phase II CatuNeo trial conducted in patients with peritoneal carcinomatosis from gastric cancer provide mixed results (Abstract 4). The bispecific anti-EpCAM/anti-CD3 monoclonal antibody yielded a 27% macroscopic complete remission (mCR) rate in patients who received intraperitoneal application of the agent prior to intravenous chemotherapy, which exceeded the 20% threshold set to gauge whether the therapy is promising for further study. However, as presenter Florian Lordick, MD, of the University Cancer Center Leipzig, in Germany, explained, the trial was closed prematurely with a reduced sample size after catumaxomab became unavailable in the European Union (EU).

The company that manufactures catumaxomab decided to discontinue marketing the agent for commercial reasons, and it has not been available in the EU since 2014.

“The study’s small sample size and the premature termination of the study make it difficult to interpret the data,” said discussant Stephen Leong, MD, of the University of Colorado Cancer Center.

Catumaxomab features a unique molecular design. One arm of the monoclonal antibody is designed to bind to EpCAM, a cell adhesion molecule abnormally expressed on the surface of epithelial cells in the vast majority of epithelial tumors. The other arm of catumaxomab binds to CD3, which is found on the surface of T cells. In addition, the tail of catumaxomab, the functional Fc domain, can simultaneously recruit and activate Fcγ receptor–positive accessory cells, including macrophages, natural killer cells, and dendritic cells. In theory, the trifunctional structure of the antibody causes a wealth of immune cells to flock to the tumor site, enhancing the efficiency of tumor-cell killing.

Intraperitoneal catumaxomab had previously been shown to be effective for the treatment of malignant ascites from EpCAM-positive epithelial tumors and was approved for this indication by the European Commission in 2009. As such, it seemed logical to test whether administering intraperitoneal catumaxomab prior to intravenous chemotherapy might help to reduce the likelihood of peritoneal metastasis given that the peritoneal surface is a prime destination for wayward gastric cancer cells that have broken free of the primary tumor.

CatuNeo was open to patients with gastric cancer and peritoneal carcinomatosis (classified according to Gilly stages P1-4) identified following laparoscopy. Patients were randomly assigned to receive escalating doses of intraperitoneal catumaxomab (10, 20, 50, and 150 µg on days 0, 3, 7, and 10, respectively) followed 7 days later by six cycles of FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) or to FLOT alone. A second laparoscopy was then performed to assess the primary endpoint—the mCR rate. If macroscopic disease remained, gastrectomy and peritonectomy were allowed to achieve complete resection of all malignant lesions.

Although the statistical plan was to enroll 42 patients, 21 in each arm, only 31 patients entered into the trial before it was closed prematurely. Of the 15 patients assigned to the catumaxomab arm, 14 received at least one catumaxomab dose and 12 received all four doses.

The addition of catumaxomab prior to FLOT did not significantly increase the macroscopic CR rate over FLOT alone (27% vs. 19%; p = 0.69). In addition, no significant differences between the catumaxomab-FLOT and FLOT arms were found for median progression-free survival (6.7 vs. 5.4 months; HR 0.85, 95% CI [0.35, 2.05]; p = 0.71) or median overall survival (13.2 vs. 13.0 months; HR 0.98, 95% CI [0.45, 2.13]; p = 0.97) based on a median follow-up duration of 52 months.

Overall, catumaxomab was fairly well tolerated for an agent that targets a molecule found on all epithelial cells. It did not increase the toxicity profile of FLOT, although it was associated with some grade 3/4 adverse events prior to administration of FLOT. The most frequent of these included abdominal pain (31%), fever (23%), and nausea (15%). Elevated liver enzymes were also somewhat common (gamma-glutamyltransferase elevations in 31%; bilirubin elevations in 23%). Four patients (29%) developed serious adverse events during catumaxomab administration.

A phase II trial was undertaken to explore the potential benefit of postoperative intraperitoneal catumaxomab after resection of peritoneal metastases from gastric carcinoma. However, this trial, like CatuNeo, was stopped early when the agent became unavailable.

 

– Kara Nyberg, PhD