In a phase I dose-escalation and expansion study reported in The Lancet Oncology, Funda Meric-Bernstam, MD, and colleagues found that zanidatamab, a novel bispecific monoclonal antibody directed against two nonoverlapping domains of HER2, showed activity in locally advanced or metastatic HER2-expressing or HER2-amplified solid tumors.

Funda Meric-Bernstam, MD

Study Details

The international multicenter study enrolled patients between September 2016 and March 2021. In the dose-escalation phase, 46 patients received zanidatamab at doses of 5 to 30 mg/kg at intervals of 1, 2, or 3 weeks. In the expansion phase, 86 patients received zanidatamab at the recommended dose for further testing, including 22 with biliary tract cancer, 28 with colorectal cancer, and 36 with other cancers (excluding breast and gastroesophageal cancers).

Dose-Escalation Phase

During dose escalation, no dose-limiting toxicities were identified, and no maximum tolerated dose was reached. The recommended dose for the expansion cohort was 20 mg/kg every 2 weeks. The most commonly reported treatment-related adverse events of any grade were diarrhea (52%, all grade 1–2), infusion reactions (43%, all grade 1–2), and diarrhea (20%, all grade 1–2). A total of five grade 3 events were observed (consisting of fatigue, decreased appetite, arthralgia, hypertension, and hypophosphatemia).

Expansion Phase

Among all 86 patients receiving 20 mg/kg of zanidatamab every 2 weeks, confirmed objective responses (all partial) were observed in 31 (37%, 95% confidence interval [CI] = 27%–49%), including in 8 (38%) of 21 with biliary tract cancer, 10 (38%) of 26 with colorectal cancer, and 13 (36%) of 36 with other cancers. Stable disease was observed in an additional 37% of all patients (24%, 38%, and 44% of the three respective groups). Median response durations were 6.9 months (95% CI = 5.6–16.7 months) among all responders, including 8.5 months, 5.6 months, and 9.7 months among those with biliary tract, colorectal, and other cancers, respectively. 

Median progression-free survival was 5.4 months (95% CI = 3.7–7.3 months) among all patients, including 3.5, 6.8, and 5.5 months among patients with biliary tract, colorectal, and other cancers.

The most common treatment-related adverse events of any grade were diarrhea (43%, all grade 1–2 [except for grade 3 in 1 patient]), infusion reactions (34%, all grade 1–2) and nausea and fatigue (9% each, all grade 1–2). Overall, six treatment-related grade 3 adverse events were observed in 4 (3%) of 132 patients in the study; no grade 4 events or treatment-related deaths occurred.

The investigators concluded, “These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies.”

Dr. Meric-Bernstam, of the Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Zymeworks. For full disclosures of the study authors, visit thelancet.com.