Zanidatamab Combinations Approved for HER2+ Gastroesophageal Cancers

FDA Approval for Zanidatamab in HER2–Positive Gastroesophageal Cancer

Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, both community medical oncologists and cohosts of the Oncology Brothers podcast, met with gastrointestinal (GI) medical oncologist Nataliya Uboha, MD, PhD, of University of Wisconsin School of Medicine and Public Health, to discuss the FDA approval of zanidatamab as frontline treatment for HER2–positive unresectable locally advanced or metastatic gastric, esophageal, or GEJ cancers. 

HERIZON-GEA-01 Data for Zanidatamab

The FDA approval for zanidatamab was based on the phase 3 HERIZON-GEA-01 trial. The study randomized patients with HER2–positive metastatic gastroesophageal adenocarcinoma to receive trastuzumab plus chemotherapy, zanidatamab plus chemotherapy, or zanidatamab plus tislelizumab and chemotherapy. 

The median PFS was 12.4 months (95% CI, 9.8-18.5) with zanidatamab, tislelizumab, and chemotherapy compared with 8.1 months (95% CI, 7-8.9) with trastuzumab plus chemotherapy (HR, 0.63; 95% CI, 0.51-0.78; P < .0001). The median OS was 26.4 months (95% CI, 21.5-30.3) with zanidatamab, tislelizumab, and chemotherapy compared with 19.2 months (95% CI, 16.8-21.8) with trastuzumab plus chemotherapy (HR, 0.72; 95% CI, 0.57-0.9; P = .004). The triple combination therapy had a particularly impressive median duration of response of over 20 months, which has not been achieved in this population before, Dr. Uboha said.

Compared with trastuzumab plus chemotherapy, zanidatamab plus chemotherapy significantly improved PFS, but the OS difference was not statistically significant at time of analysis. The PFS benefit with zanidatamab plus chemotherapy was primarily driven by the HER2 immunohistochemistry (IHC) 3+ patient subgroup, according to the FDA announcement.

Interpreting the Zanidatamab FDA Label

Based on HERIZON-GEA-01 analyses, the FDA approved zanidatamab plus chemotherapy for patients with HER2 IHC3+ score, and approved zanidatamab plus tislelizumab and chemotherapy for patients with HER2 IHC 3+ score or HER2 IHC 2+ score plus a positive in situ hybridization test.

Dr. Rohit Gosain asked Dr. Uboha if PD-L1 testing has any role in guiding patient selection for tislelizumab. Current data support using the tislelizumab–containing regimen regardless of PD-L1 score, which is distinct from findings for other anti-PD-1 agents in the metastatic setting, Dr. Uboha said. In her practice, she plans to offer the triple-class regimen to all patients who are eligible for immunotherapy. 

Side Effects of Zanidatamab

The most common side effects of zanidatamab reported in HERIZON-GEA-01 were diarrhea, nausea, vomiting, decreased appetite, anemia, peripheral sensory neuropathy, weight decrease, infusion-related reactions (IRRs), neutropenia, hypokalemia, thrombocytopenia, and hand-foot syndrome. Dose interruptions may be needed.

Dr. Uboha noted that the majority of patients in the trial received capecitabine–based chemotherapy, although FOLFOX (leucovorin [folinic acid], fluorouracil, and oxaliplatin) is more commonly used in the US. In real-world practice, zanidatamab plus tislelizumab with FOLFOX may show lower rates of diarrhea. In addition, the biweekly administration schedule for FOLFOX allows for closer monitoring, which may allow oncologists to catch patients with worsening diarrhea and adjust supportive care as needed, Dr. Uboha said. 

Both zanidatamab and tislelizumab are associated with diarrhea, but the presentation is notably different for each agent. Zanidatamab–related diarrhea typically occurs during the first few treatment cycles, and patients are often able to continue on the drug with dose modifications and supportive care, said Dr. Uboha. Comparatively, tislelizumab–related diarrhea tends to occur in later treatment cycles, similar to other immunotherapies profiles.

IRRs occurred in 25% of patients of either zanidatamab arm. In Dr. Uboha’s clinic, IRRs are usually managed by pausing the infusion and administering rescue medication, then resuming the infusion at a lower rate. Patients may need the lower rate for several infusions, but many are able to increase to the normal rate as treatment continues, Dr. Uboha added. 

Biomarker Testing in Gastroesophageal Cancers

Closing the discussion, Dr. Uboha emphasized that biomarker testing in patients with gastroesophageal adenocarcinoma is crucial, and its importance will only continue to grow as more novel biomarker-based therapies are developed. Fortunately, many relevant biomarkers for upper GI cancers like HER2 are based on IHC testing, which has a short turnaround for results. Given that HER2 expression can change over time, it’s important to repeat testing frequently, especially if patients progress on zanidatamab or other anti-HER2 therapy, Dr. Uboha finished.