Zanidatamab, With Biparatopic Binding to HER2, Shows 84% OS in Phase 2 Study of Gastroesophageal Adenocarcinoma

Gastroesophageal adenocarcinoma (GEA), which include cancers in the esophagus and stomach, is the fifth most common diagnosis worldwide—although deaths from GEA are more common in Asian countries than in the United States.^1,2 Because of the heterogeneity of these cancers, treatment has been challenging, although HER2 has emerged as a target in approximately 20% of these patients.³

Treatment options to target HER2 in GEA remain limited. Trastuzumab with chemotherapy is considered the standard of care, based on phase 3 results of the ToGA trial (NCT01041404), published in 2010.⁴ More recently, trastuzumab with chemotherapy and pembrolizumab (Keytruda) as approved for first-line use in advanced metastatic gastric/gastroesophageal junction cancer in May 2021, following results of the phase 3 KEYNOTE-811 study (NCT03615326).⁵

Now an investigational therapy promises a new way to target HER2 while still using chemotherapy combinations. On January 19, 2023, at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI), investigators presented data from a phase 2 trial (NCT03929666) for zanidatamab, a new bispecific antibody. When used with chemotherapy, the therapy showed an 18-month overall survival (OS) rate of 84% (95% CI, 68%-93%); the 12-month OS rate was 88% (95% CI, 73%-95%). The median OS had not been reached after 26.5 months of follow-up. Median progression-free survival was 12.5 months (95% CI, 7.5-not estimable [NE]).⁶

“Gastroesophageal adenocarcinoma represents one of the most frequent tumor types worldwide and, tragically, a leading cause of cancer-related deaths. Compared [with] what has historically been reported for OS with the current approved standard of care, the OS findings from the combination of zanidatamab and chemotherapy in this trial are very compelling," Elena Elimova, MD, MSc, lead trial investigator and a medical oncologist at Princess Margaret Cancer Centre in Toronto, Canada, said in a statement.⁷ “HER2 has been recognized as a predictive biomarker for these cancers, and it is promising to see a treatment targeting this expression exhibit strong and durable antitumor activity when administered with chemotherapy.”

Data presented in May 2022 during Digestive Disease Week showed a steep rise in rates of esophageal cancers between 2012 and 2019, which are rising alongside increased rates of colorectal cancer among young adults and increased rates of obesity and gastroesophageal reflux disease.⁸ However, although observational studies show that abdominal obesity can be a predictor of chronic disease, the connections between abdominal obesity and GEA are not fully understood.⁹

Zanidatamab is being developed by Zymeworks, which reached a licensing agreement with Jazz Pharmaceuticals in October 2022 to develop and market the therapy.¹⁰

Novel mechanism. Zanidatamab uses biparatopic binding, which means the drug simultaneously binds to 2 distinct, nonoverlapping HER2 epitopes: ECD2 and ECD4. According to material presented by Zymeworks during the JP Morgan Healthcare Conference prior to ASCO GI, the molecular design of zanidatamab “results in HER2 binding across range of expression levels (from low to high),” and allows for “HER2 receptor crosslinking, clustering, internalization, and downregulation.”¹¹ These multiple mechanisms increase removal of HER2 protein, which promotes antitumor activity.

Study design and responses. The phase 2 trial is an ongoing, open-label study of patients who had not received prior systemic therapy for metastatic GEA. A total of 46 patients were enrolled between August 29, 2019, and February 18, 2022, with data cutoff of July 28, 2022. The primary objective was to evaluate antitumor activity. Patients received zanidatamab and physician’s choice of chemotherapy options: 20 received CAPOX (capecitabine-oxaliplatin), 2 received FP (5-fluorouracil and cisplatin), and 24 received mFOLFOX6 (modified folinic acid, fluorouracil, and oxaliplatin). The median age was 58 years; 85% of the patients were men; and 42 (91%) had HER2+ tumors, based on central testing.⁶

According to the abstract, of 38 response-evaluable patients with HER2+ tumors, confirmed objective response rate was 79% (95% CI, 63%-90%) and disease control rate was 92% (95% CI, 79%-98%); 3 patients achieved complete response. The median duration of response was 20.4 months (95% CI, 6.8-NE), and 57% of patients had an ongoing at the time of data cutoff.

Adverse events. Treatment-related adverse events (TRAEs) occurring in at least 25% of patients were diarrhea, nausea, peripheral sensory neuropathy, decreased appetite, fatigue, vomiting, and hypokalemia. Diarrhea was the most common grade 3 or higher TRAE, lasting a median of 3 days, with most events occurring in the first cycle. The incidence of grade 3 or higher events was 56% in 25 patients who did not receive antidiarrhea prophylaxis vs 14% in 21 patients who did. There were no treatment-related deaths.⁶

Regulatory status. Previously, the FDA granted breakthrough therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified biliary tract cancer (BTC), along with 2 fast-track designations for zanidatamab: 1 as a single agent for refractory BTC and 1 in combination with standard of care chemotherapy for first-line GEA. Zanidatamab has received FDA orphan drug status for the treatment of patients with BTC and GEA. The phase 3 HERIZON-GEA-01 trial (NCT05152147), which is evaluating zanidatamab with physician’s choice of chemotherapy with or without the PD-1 inhibitor tislelizumab (BeiGene) for first-line treatment of patients with advanced HER2+ metastatic GEA, is currently enrolling.^7,12

References

1. Rawla P, Barsouk A. Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol. 2019;14(1):26-38. doi:10.5114/pg.2018.80001

2. Pourhoseingholi MA, Vahedi M, Baghestani AR. Burden of gastrointestinal cancer in Asia; an overview. Gastroenterol Hepatol Bed Bench. 2015;8(1):19-27.

3. Fong C, Chau I. HER2 inhibition in gastric cancer—novel therapeutic approaches for an established target. Cancers (Basel). 2022;14(15):3824. doi:10.3390/cancers14153824

4. Bang YJ, Van Custem E, Feyereislova A, et al; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label randomised controlled trial. Lancet. 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X

5. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed January 28, 2023. http://bit.ly/3jbEk6D

6. Elimova E, Ajani JA, Burris HA III, et al. Zanidatamab + chemotherapy as first-line treatment for HER2-expressing metastatic gastroesophageal adenocarcinoma (mGEA). J Clin Oncol. 2023;41(suppl 4):347. doi:10.1200/JCO.2023.41.3_suppl.347

7. Jazz Pharmaceuticals and Zymeworks announce 84% overall survival at 18 months from phase 2 trial evaluating zanidatamab in HER2-expressing metastatic gastroesophageal adenocarcinoma. News release. Jazz Pharmaceuticals. January 19, 2023. Accessed January 28, 2023. http://bit.ly/3WS7cyG

8. Alarming rise found in esophageal cancer and Barrett’s esophagus in middle-aged adults. News release. Digestive Disease Week. May 18, 2022. Accessed January 28, 2023. https://bit.ly/3XKKwBJ

9. Du X, Hidayat K, Shi BM. Abdominal obesity and gastroesophageal cancer risk: systematic review and meta-analysis of prospective studies. Biosci Rep. 2017;37(3).BSR20160474. doi:10.1042/BSR20160474.

10. Jazz Pharmaceuticals and Zymeworks announced exclusive license agreement to develop and commercialize zanidatamab, a HER2-targeted bispecific antibody. News release. Jazz Pharmaceuticals. October 19, 2022. Accessed January 28, 2023. http://bit.ly/3Dk14s0A

11. Zymeworks. JP Morgan Healthcare Conference. January 12, 2023. Accessed January 28, 2023. https://ir.zymeworks.com/events/event-details/jp-morgan-healthcare-conference-0

12. Tabernero J, Shen L, Elimova E, et al. HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. Future Oncol. 2022;18(29):3255-3266. doi:10.2217/fon-2022-0595