Zr-89 Trastuzumab PET monitors radioimmunotherapy for gastric cancer

For patients testing positive for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer undergoing treatment with the tyrosine kinase inhibitor afatinib, therapy monitoring using PET and the radiopharmaceutical Zr-89 Trastuzumab can effectively assess tumor activity and improve staging of disease, according to research published online April 11 in The Journal of Nuclear Medicine.

Yelena Y. Janjigian, MD, from the gastrointestinal oncology service and department of medicine at Memorial Sloan-Kettering Cancer Center in New York City, and colleagues, investigated the use of Zr-89 trastuzumab PET as a monitoring technique used in conjunction with therapeutic afatinib for HER2 positive gastric cancer in animal models. Results of the study showed Zr-89 trastuzumab provided excellent assessment of radioimmunotherapy with afatinib.

“Afatinib demonstrated antitumor activity in HER2-positive gastric cancer in vivo,” wrote the authors. “ Zr-89 trastuzumab PET specifically delineated HER2-positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib.”

HER2–positive esophagogastric cancer is detected in an estimated 200,000 people every year across the globe. The FDA and EU have approved treatment with trastuzumab for patients with HER2-positive esophagogastric cancer, but there are challenges with regard to complete blockade of EGFR and HER2 kinase activity and potential activation of other erbB receptors. 

Afatinib (BIBW 2992) is currently in phase II and III clinical trials for the treatment of breast, lung, head and neck cancers. The drug is considered a strongly selective and irreversible inhibitor for tyrosine kinase receptors of the erbB family, including EGFR, HER2 and HER4. This is the first study exploring the drug for treatment of HER2–positive esophagogastric cancer.

Researchers tested trastuzumab, afatinib and a combination of the two in an NCI-N87 xenograft model. Immunohistochemistry revealed HER2 gene amplification. Treatment evaluation showed HER2–positive esophagogastric tumors were refractory to trastuzumab, but that monotherapy with afatinib triggered “dramatic” tumor volume regression within four days of administering the drug and almost complete resolution of tumors after 21 days. Assessment with PET imaging and Zr-89 trastuzumab followed reductions in tumor size and downregulation of total HER2, p-HER2, total EGFR and p-EGFR as treatment with afatinib progressed. A comparison with F-18 FDG showed relatively little change in uptake, indicating that Zr-89 trastuzumab is superior for monitoring afatinib.

"Zr-trastuzumab tumor uptake decreased, especially over the first 14 days of treatment, mirroring reduction in tumor weight and decrease in total HER2 as measured by immunoblot and immunohistochemistry," concluded the authors. "Zr-89 trastuzumab displayed remarkable potential to noninvasively measure the functional effects of afatinib, affording an early predictor of response within and as early as 7 days of therapy, compared with 18F-FDG," they added.

Further studies are required in humans to prove the efficacy of this imaging technique as a means for monitoring afatinib radioimmunotherapy.