Transparency Submission

FDA Clearance: Zanidatamab [TRADENAME] is a HER2-targeted bispecific antibody being reviewed by the FDA for the treatment of patients with previously treated, unresectable, locally advanced, or metastatic HER2-positive biliary tract cancer. Under the Prescription Drug User Fee Act (PDUFA), FDA has set a target action date of November 29, 2024.

Rationale for Requested Change: As the FDA action date (PDUFA November 29, 2024) for zanidatamab is imminent, we respectfully provide evidence of zanidatamab in HER2-positive biliary tract cancer (BTC) from two clinical studies for panel consideration (1-3). Zanidatamab is supported by the largest BTC-specific data set to date for HER2-positive tumors and was studied in patients, the majority of whom received one line of prior systemic therapy. The response rates, durability of response, and tolerability of zanidatamab fulfill an unmet need for patients with advanced HER2+ BTC. Pivotal study (1,2): HERIZON-BTC-01 is a global, multi-center, single-arm, phase 2b trial of zanidatamab in patients with unresectable, locally advanced, or metastatic BTC with disease progression on previous gemcitabine-based therapy. Patients with HER2-amplified tumors were assigned by immunohistochemistry (IHC) score to Cohort 1 (HER2-positive: 2+ or 3+; 80 patients) or Cohort 2 (IHC 0 or 1+; 7 patients). At a median follow-up of 12.4 months, zanidatamab treatment in 80 HER2-positive patients from Cohort 1 resulted in 41.3% confirmed objective response rate (ORR) and 68.8% disease control rate (DCR) by independent central review, with median time to first response of 1.8 months (1). A similar response rate of 43% was observed among 21 patients who received prior checkpoint inhibitors (1). The above ORR and DCR of Cohort 1 were maintained at longer median follow-up of 21.9 months, with median duration of response at 14.9 months (2). Median progression-free survival (PFS) of Cohort 1 was 5.5 months, median overall survival (OS) was 15.5 months, and 12-month OS was 56.2% (2). Pivotal trial safety (2): In HERIZON-BTC-01, the most common treatment-related adverse events (TRAEs) in Cohorts 1 and 2 (N=87) at the longer median follow-up of 21.9 months were diarrhea (36.8%) and infusion-related reactions (33.3%). The majority of TRAEs were grade 1-2 (51.7% of patients); grade 3 TRAEs occurred in 19.5%* of patients; grade 4 TRAE occurred in one patient and no treatment-related death was reported. TRAEs led to treatment discontinuation in two patients (2.3%). Earlier Phase 1 study (3): The above results were consistent with an earlier Phase 1, multi-center, dose-escalation and expansion trial in 132 patients with locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumors. The report included 86 patients in the dose-expansion part, 22 of which had BTC with HER2 status of IHC 2+ or 3+. Among the BTC group, confirmed ORR was 38% and DCR was 62%. Median DOR was 8.5 months, while median PFS was 3.5 months. The most frequent TRAEs in the dose-expansion part were diarrhea (43%) and infusion reactions (34%). All TRAEs were grade 1-2 except one grade 3; no grade 4 TRAE or treatment-related death was reported. TRAEs led to treatment discontinuation in two patients (2%). *This value is not part of the original data presentation; however, it is supported by existing study data and has been added for clarity.