Trastuzumab Deruxtecan in Solid Tumours Harbouring HER2 Mutations

1. The objective response rate for trastuzumab deruxtecan was 29.4%.

2. Treatment-emergent adverse event grade 3 or higher was seen in 51% of patients.

Evidence Rating Level: 2 (Good)

Study Rundown: HER2, a tyrosine kinase receptor, can be overexpressed in some cancers enabling the use of HER2-directed therapies. Trastuzumab deruxtecan comprises an antibody targeting HER2 coupled with a topoisomerase I inhibitor that demonstrated anti-cancer activity across various HER2 mutations. This study further investigates it efficacy across multiple solid tumors harboring activating HER2 mutations. The primary endpoint was objective response rate (ORR), and secondary endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The median follow-up duration was 8.61 months. The ORR was 29.4%, which was seen across a variety of HER2 mutations. Median DoR was 11.0 months and the DCR at 6 weeks was 75.5%. Median PFS was 5.4 months, with PFS at 6 months was 41.4% and at 12 months was 30.9%. Median OS was 10.9 months. The OS at 6 months was 67.6% and at 12 months was 46.3%. The median number of treatment cycles was 5.0. With regards to safety, 51% of patients had treatment-emergent adverse event grade 3 or higher, and the most common events included anaemia (16%) and decreased neutrophil count (8%). The strength of this study included the variety of outcome measures, and the limitations included the small sample size and limited follow-up duration. Overall, this study found that trastuzumab deruxtecan had some efficacy in patients with solid tumors containing HER2 mutations who have undergone extensive prior treatment.

Click to read the study in Lancet Oncology

Relevant Reading: Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors.

In-Depth [ prospective cohort]: This international, open-label, phase 2, basket study enrolled adults (n=102) with unresectable/metastatic solid tumors with specific HER2 mutations who have failed previous treatments, and started them on trastuzumab deruxtecan every 3 weeks until disease progression or safety concerns. The median follow-up duration was 8.61 months. The ORR was 29.4% (95%CI, 20.8-39.3), which was seen across a variety of HER2 mutations. Median DoR was 11.0 months (95%CI, 7.9-18.1) and the DCR at 6 weeks was 75.5% (95%CI, 66.0-83.5). Median PFS was 5.4 months (95%CI, 2.7-7.1), with PFS at 6 months was 41.4% (95%CI, 30.8-51.6) and at 12 months was 30.9% (95%CI, 20.6-41.8). Median OS was 10.9 months (95%CI, 8.3-14.9). The OS at 6 months was 67.6% (95%CI, 57.4-75.9) and at 12 months was 46.3% (95%CI, 35.7-56.3). The median number of treatment cycles was 5.0 (2.0-12.0). With regards to safety, 51% of patients had treatment-emergent adverse event grade 3 or higher, and the most common events included anaemia (16%) and decreased neutrophil count (8%). Overall, this study found that trastuzumab deruxtecan had some efficacy in patients with solid tumors containing HER2 mutations who have undergone extensive prior treatment.

Image: PD

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