Zanidatamab exhibits ‘promising’ efficacy in advanced HER2-positive biliary tract cancer



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CHICAGO — Zanidatamab exhibited durable antitumor activity among patients with previously treated advanced HER2-amplified biliary tract cancer, according to results of the phase 2B HERIZON-BTC-01 study presented at ASCO Annual Meeting.

More than half of patients who received zanidatamb (Jazz Pharmaceuticals/Zymeworks) monotherapy survived at least a year and median OS exceeded 15 months.

Graphic showing response rate in IHC 3+ tumors
Data derived from Pant S, et al. Abstract 4091. Presented at: ASCO Annual Meeting; May 31-June 4, 2024.

“These results are very promising,” researcher Shubham Pant, MD, MBBS, associate professor in the department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, told Healio. “Response rate is important but duration of response is a very critical factor, also. If a patient responds but relapses in 2 months, that’s not really clinically significant. To see these patients continue in response is encouraging.”

Background and methods

Biliary tract cancer is a heterogenous group of malignancies that includes gallbladder cancer, extrahepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma.

Patients with locally advanced or metastatic biliary tract cancer who experience disease progression after first-line treatment typically derive limited clinical benefit from subsequent therapies, according to study background. Only about 5% of patients respond to second-line chemotherapy, and median OS is approximately 6 to 9 months.

HER2 overexpression or gene amplification rates range from 4% to 5% for intrahepatic cholangiocarcinoma, 17% to 19% for extrahepatic cholangiocarcinoma, and 19% to 31% for gallbladder cancer. However, no HER2-targeted therapy is approved for biliary tract cancers.

A phase 1 trial showed zanidatamab — a HER2-targeted bispecific antibody — induced response among 41% of patients with HER2 overexpression, defined as 2+/3+ by immunohistochemistry (IHC).

In HERIZON-BTC-01, Pant and colleagues assessed zanidatamab monotherapy — dosed at 20 mg/kg via IV every 2 weeks — for patients with HER2-amplified, locally advanced unresectable or metastatic biliary tract cancer.

The study included 87 participants (median age, 64 years; 54% women; 66% Asian). Half (51.7%) had gallbladder cancer, 29.9% had intrahepatic cholangiocarcinoma and 18.4% had extrahepatic cholangiocarcinoma.

All patients had received gemcitabine-containing therapy, and they had received a median one (interquartile range, 1-2) prior line of therapy for locally advanced or metastatic disease. Protocol excluded patients who received prior HER2-targeted therapies.

Researchers assigned patients to one of two cohorts based on IHC status.

Cohort 1 included 80 patients with HER2-positive disease, defined as IHC2+/3+ status. Cohort 2 included seven patients with IHC0/1+ status.

Objective response rate per independent central review in cohort 1 served as the primary endpoint. Secondary outcomes included duration of response, PFS, disease control rate, OS and safety/tolerability.

Previously reported results

At last year’s ASCO, Pant presented results based on median follow-up of 12.4 months.

In cohort 1, researchers reported a 41.3% (95% CI, 30.4-52.8) confirmed ORR, with one (1.3%) complete response and 32 (40%) partial responses. Twenty-two patients (27.5%) exhibited stable disease and 24 (30%) developed progressive disease, equating to a disease control rate of 68.8% (95% CI, 57.4-78.7).

Median response duration was 12.9 months.

In cohort 2, no patients responded to treatment. One patient (14%) exhibited stable disease and three (43%) developed progressive disease.

Updated results

This year, Pant presented updated results from cohort 1 based on median follow-up of 21.9 months (range, 16-34).

The confirmed ORR remained 41.3%. One patient converted from a partial response to complete response during longer follow-up. Rates of stable disease, progressive disease and disease control remained unchanged with longer follow-up.

Median response duration increased to 14.9 months (95% CI, 7.4 to not reached).

The trial was not designed to assess treatment effects based on HER2 status; however, a preplanned subgroup analysis showed confirmed response rates of 51.6% among patients with IHC 3+ tumors and 5.6% among those with IHC 2+ tumors.

A majority of patients in cohort 1 remained alive at 6 months (80.3%) and 12 months (56.2%). Results showed median OS of 15.5 months (95% CI, 10.4-18.5) — which Pant characterized as “very promising” — with longer median OS among patients with IHC 3+ tumors than IHC 2+ tumors (18.1 months vs. 5.2 months).

Shubham Pant, MD, MBBS

Shubham Pant

“The differences in outcomes between IHC 3+ and IHC 2+ did not surprise me. As we’ve seen with other HER2-targeted agents, the more expression that is there, the more effective the drug is,” Pant said. “However, we did see some clinical benefit in the IHC 2+ group in terms of prolonged stable disease, which is very important.”

Safety results

Safety analyses that included both cohorts showed 84 patients (96.6%) experienced any treatment-emergent adverse event and 63 (72.4%) experienced treatment-related adverse events, the most common of which were diarrhea (36.8%), infusion-related reaction (33.3%), ejection fraction decrease (10.3%) and nausea (9.2%).

Eighteen patients (20.7%) experienced grade 3/grade 4 treatment-related adverse events, the most common of which were diarrhea (4.6%), ejection fraction decrease (3.4%), anemia (3.4%), anemia (3.4%) and increased aspartate aminotransferase (2.3%).

Five patients (5.7%) experienced confirmed cardiac events; three were grade 3/grade 4. One patient (1.1%) developed a grade 3/grade 4 non-infectious pulmonary toxicity.

No treatment-related deaths occurred. Two patients (2.3%) discontinued therapy due to treatment-related adverse events.

“This is a non-chemotherapy option, so patients can stay on it for a long time,” Pant said. “There are some side effects but they’re very easily managed.”

Implications and next steps

The results highlight the importance of next-generation sequencing to identify patients with biliary tract cancer who could derive benefit from targeted therapies, Pant said.

“There are approved drugs for patients with FGFR fusions or IDH1 mutations,” he said. “This is also important for HER2 amplification to identify patients who could be eligible for clinical trials.”

In April, Jazz Pharmaceuticals completed a rolling submission of a biologics license application to the FDA seeking accelerated approval of zanidatamab for previously treated unresectable, locally advanced or metastatic HER2-positive biliary tract cancer.

A randomized phase 3 trial — HERIZON-BTC-02 — is underway to evaluate zanidatamab in combination with standard therapy for first-line treatment of HER2-positive biliary tract cancer.

“It was exciting to see the efficacy signal with this agent in phase 1 and watch it move forward to phase 2,” Pant said. “Hopefully we’ll be able to carry that forward into phase 3. Obviously, speculation is always tricky — we need to run that trial and see how the data look — but I’m hopeful.”

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