Zanidatamab Plus Chemo Displays Early Activity in HER2+ Metastatic Gastroesophageal Adenocarcinoma

Rob Iannone, MD, MSCE

The combination of zanidatamab (ZW25) and standard chemotherapy demonstrated activity when used as a first-line treatment for patients with HER2-positive metastatic or advanced gastroesophageal adenocarcinoma, according to preliminary results from a phase 2 trial (NCT03929666) presented at the 2023 Gastrointestinal Cancers Symposium.¹

At a median follow-up of 26.5 months (interquartile range [IQR], 17.8-32.4), those who received zanidatamab plus chemotherapy in the form of CAPOX, mFOLFOX6, or 5-fluorouracil (5-FU) and cisplatin (n = 38) achieved a confirmed objective response rate (ORR) of 79% (95% CI, 63%-90%), which included a complete response (CR) rate of 8% and a partial response (PR) rate of 71%; 13% of patients achieved stable disease (SD) and 8% experienced disease progression (PD). The disease control rate (DCR) in the total population was 92% (95% CI, 79%-98%), and the median duration of response (DOR) was 20.4 months (95% CI, 8.3-not estimable [NE]).

“We are very encouraged by the data from this phase 2 trial, which demonstrate zanidatamab administered with chemotherapy is a highly active treatment regimen and resulted in significant and durable tumor response in the first-line setting for patients with advanced HER2-expressing metastatic gastroesophageal adenocarcinoma,” Rob Iannone, MD, MSCE, executive vice president, global head of Research and Development of Jazz Pharmaceuticals, stated in a news release.² “These results showcase zanidatamab’s potential as a foundational treatment for patients with HER2-positive metastatic gastroesophageal adenocarcinoma, and we look forward to additional data in 2024 from the ongoing pivotal phase 3 [HERIZON-GEA-01] trial [NCT05152147] that may support US and global regulatory filings.”

HER2 overexpression is observed in about 20% of cases of gastric, esophageal, and gastroesophageal cancers but HER2-targeted options remain limited.¹ The bispecific antibody, zanidatamab, is directed at ECD4 and ECD2 of HER2. The agent has unique binding properties and mechanisms of action such as boosted receptor clustering, internalization, and downregulation vs trastuzumab (Herceptin). The agent also stimulates immune-mediated responses, such as antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity.

The open-label phase 2 study enrolled patients with unresectable, locally advanced, recurrent, or metastatic HER2-experssing metastatic gastroesophageal adenocarcinoma. Patients were required to have an ECOG performance status of 0 or 1. They were excluded if they previously received HER2-targeted therapies or systemic treatment except for prior neoadjuvant or adjuvant therapy 6 months or more from study treatment.

All patients received zanidatamab at 30 mg/kg or 1800/2400 mg intravenously every 3 weeks in combination with CAPOX (n = 18) or mFOLFOX6 (n = 18) or 5-FU and cisplatin (n = 2). Physician’s choice of chemotherapy was given for 6 or more cycles.

Patients received treatment until disease progression, intolerable toxicity, or other discontinuation criteria were met. Notably, patients who discontinued chemotherapy were permitted to continue zanidatamab alone.

The primary end point of the trial was confirmed ORR. Key secondary end points included safety, DCR, DOR, progression-free survival (PFS), and overall survival (OS).

Data from an unlocked database were extracted on October 17, 2022. Forty-one percent (n = 19) of all patients remained on treatment with zanidatamab. Those who discontinued (59%; n = 27) did so because of disease progression (n = 20), adverse effects (AEs; n = 5), physician decision (n = 1), or other (n = 1).

The median patient age was 58 years (range, 26-82), and 85% were male. Thirty-seven percent of patients were Asian, 61% were White, and 2% were unknown. Ninety-three percent of patients were non-Hispanic or Latino. Regarding performance status, 57% had a status of 0, and 43% had a status of 1.

Primary tumor locations included esophageal (24%), gastroesophageal junction (35%), and gastric (41%). Eighty-three percent of patients had stage IV disease at initial diagnosis. Ninety-one percent of patients had HER2-positive disease per central testing; 80% of patients were immunohistochemistry (IHC) 3-positive and 11% were IHC 2-positive/fluorescence in situ hybridization–positive.

Additional data showed that patients treated with zanidatamab plus CAPOX experienced a confirmed ORR of 89% (95% CI, 65%-99%), which comprised CR and PR rates of 11% and 78%, respectively; 11% of patients had SD. In this group, the DCR was 100% (95% Ci, 82%-100%), and the median DOR was 10.4 months (95% CI, 5.7-NE).

In those who received zanidatamab with mFOLFOX6, the confirmed ORR was 67% (95% CI, 41%-87%), which included CR, PR, SD, and PD rates of 6%, 61%, 17%, and 17%, respectively. The DCR was 83% (95% CI, 59%-96%), and the median DOR was NE (95% CI, 2.8-NE). Both patients who received zanidatamab and 5-FU/cisplatin experienced PRs, with a median DOR that was NE (95% CI, 6.8-NE).

Among all patients, the median PFS was 12.5 months (95% CI, 7.1-NE), and the median OS was NE (95% CI, 23.6-NE). Moreover, the 12-month OS rate was 88% (95% CI, 73%-95%) and the 18-month OS rate was 84% (95% CI, 68%-93%).

All patients treated with zanidatamab and any of the 3 chemotherapy regimens who were evaluable for safety (n = 46) experienced at least 1 any-grade treatment-related AE (TRAE); 61% had at least 1 grade 3 or higher TRAE. Serious TRAEs of any grade occurred in 17% of patients; grade 3 or higher serious TRAEs occurred in 17% of patients. Any-grade TRAEs led to treatment discontinuation in 7% of patients, and grade 3 or higher TRAEs resulted in discontinuation of 2% of patients.

The most common TRAEs included diarrhea (any grade, 93%; grade ≥3, 35%), nausea (78%; 7%), peripheral neuropathy (61%; 0%), fatigue (43%; 4%), decreased appetite (43%; 0%), vomiting (33%; 9%), hypokalemia (28%; 15%), stomatitis (24%; 0%), decreased neutrophil count (22%; 7%), hypomagnesemia (20%; 2%), dysgeusia (20%; 0%), acute kidney injury (7%; 4%), and decreased white blood cell count (15%; 7%).

Any-grade TRAEs of special interest included infusion-related reaction (22%) and decreased ejection fraction (4%). No grade 3 or higher TRAEs of special interest were reported.

Antidiarrheal prophylaxis was implemented after the first 25 patients were treated. Prior to the addition of antidiarrheal prophylaxis, the rate of grade 3 or higher diarrhea was 52% (n = 13/25); the rate following the use of prophylaxis was 14% (n = 13/21). Treatment-related grade 3 or higher diarrhea occurred primarily during cycle 1, and the median duration of events in all cycles was 3 days (IQR, 2-5).

"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,” said Elena Elimova, MD, lead trial investigator and a medical oncologist at Princess Margaret Cancer Centre, stated in a news release.² “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.”

References

1. Elimova E, Ajani J, Burris H, 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
2. 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 February 8, 2023. https://investor.jazzpharma.com/news-releases/