Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study.

BACKGROUND: HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification. METHODS: This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing. FINDINGS: Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths. INTERPRETATION: 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. FUNDING: Zymeworks.

Population pharmacokinetics of zanidatamab, an anti-HER2 biparatopic antibody, in patients with advanced or metastatic cancer.

PURPOSE: To characterize the pharmacokinetics (PK) of zanidatamab including evaluation of the impact of intrinsic and extrinsic patient factors. To investigate alternative dosing regimens to improve caregiver convenience and reduce zanidatamab wastage. METHODS: Serum zanidatamab concentrations were obtained from 305 patients with advanced or metastatic breast cancer, gastroesophageal adenocarcinoma (GEA), biliary tract cancer, and other HER2-expressing cancers from four ongoing phase I and II clinical trials. Zanidatamab PK were described using population methods. The exposure of alternative dosing regimens and the impact of dose delay was estimated by model simulation. RESULTS: A two-compartment model with parallel linear and nonlinear clearance from the central compartment adequately described zanidatamab PK. At the recommended dose regimens of 20 mg/kg Q2W and 30 mg/kg Q3W, zanidatamab clearance was primarily linear at steady state. At steady state, 30 mg/kg Q3W zanidatamab returns within 10% of the steady state trough after 2 subsequent doses following either a 1-week or 2-week dose delay. Statistically significant covariates included in the final model were body weight, sex, albumin, GEA cancer type, baseline tumor size, and presence of post-baseline anti-drug antibodies, all of which resulted in less than 30% impact on exposure. Model simulation predicts weight-based and two-tiered flat dosing will result in similar exposure and variability. CONCLUSION: The identified significant covariates were not considered clinically meaningful. Both weight-based (30 mg/kg Q3W) and two-tiered flat dosing (1800/2400 mg Q3W, 70 kg threshold) strategies are expected to provide similar exposures of zanidatamab.

Hydroxychloroquine usage in US patients, their experiences of tolerability and adherence, and implications for treatment: survey results from 3127 patients with SLE conducted by the Lupus Foundation of America.

The majority of patients with SLE in the USA have been prescribed hydroxychloroquine (HCQ). Given more recent guidelines, the availability of only one strength (200 mg tablets) may limit the flexibility and ability to accurately dose patients with lupus. The Lupus Foundation of America undertook a survey to assess the current landscape of HCQ tolerability and adherence.