Tissue agnostic study shows activity of ADCs in solid tumours with HER2 activating mutations

Results from an open-label, multicentre, phase II study presented at the ESMO Congress 2023 (Madrid, 20–24 October) add to the growing bank of evidence supporting the benefits of the antibody–drug conjugate (ADC), trastuzumab deruxtecan (T-DXd), in the treatment of solid tumours with HER2-activating mutations, particularly for pre-treated patients with limited therapy options and often a poor prognosis. In recent breast cancer studies, the demonstration that second-generation ADCs have extensive activity across a broad spectrum of disease subtypes has clearly provided the rationale for testing these compounds in different solid tumours. The tissue agnostic DESTINY-PanTumour01 study investigated T-DXd (5.4 mg/kg every 3 weeks) in patients with a range of solid tumours harbouring pre-specified activating HER2 mutations who had failed on previous systemic therapy. Patients with HER2-overexpressing breast and gastric cancers or HER2-mutated non-small-cell lung cancer were excluded from the study.

As presented at the Congress, the 102 patients treated with T-DXd had received a median of 3 prior lines of therapy (range 1–13) (Abstract 654O). The median follow-up was 8.6 months (range 1.5–22.1). The primary endpoint of objective response rate (ORR; by RECIST 1.1 according to independent central review [ICR]) was 29.4% (95% confidence interval [CI] 20.8–39.3). The median duration of response was not reached and 54.2% of responders remained in response by ICR at 18 months. The median progression-free survival was 5.4 months (95% CI 2.7–7.1). In the most common tumour types, that is breast (n=20), colorectal (n=20) and biliary tract (n=19) cancers, the ORRs were 50.0%, 20.0% and 10.5%, respectively.

Potentially drug-related grade ≥3 adverse events (AEs) were reported in 25.5% of patients and 7.8% of patients discontinued T-DXd due to potentially drug-related AEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 11 patients (10.8%); one event was grade 3 and two were grade 5.

In the trial, positive responses were observed across HER2 expression levels, including HER2 immunohistochemistry score = 0 tumours, thus supporting a non-biomarker driven use of ADCs in solid tumours.

In recent years, the emergence of HER2-low expression as a heterogeneous group in breast cancer has prompted the need for novel definitions in clinical practice to interpret HER2 results and distinguish different clinical entities within this subgroup. The ESMO expert consensus statements on the definition, diagnosis, and management of HER2-low breast cancer aim to address several biological and clinical questions to reach a consensus on optimal treatment for these patients (Ann Oncol. 2023;34:645–659). According to the experts, fine tuning of the HER2-low pathologic diagnosis, along with accumulation of additional clinical data, will allow the benefits of novel anti-HER2 ADCs to be fully unlocked in the coming years, and possibly inform the targeting of HER2-low expression in other tumour types.