Patritumab deruxtecan (HER3-DXd), an antibody drug conjugate consisting of a monoclonal antibody to HER3 attached to a topoisomerase I, demonstrates anti-tumour activity across various EGFR TKI resistance mechanisms in heavily pretreated, metastatic/locally advanced, EGFR-mutated non-small cell lung cancer (NSCLC).

 EGFR-directed TKIs are standard of care for patients with EGFR-mutated NSCLC. However, the development of various resistance mechanisms commonly leads to progression. Platinum-based chemotherapy following EGFR TKI failure has limited efficacy. Patritumab deruxtecan (HER3-DXd) is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. HER3 is expressed in 83% of NSCLC tumours [1]. Dr Jänne Pasi (Dana Farber Cancer Institute, MA, USA) presented efficacy and safety data from an ongoing phase 1 study (NCT03260491) of HER3-DXd in patients with locally advanced or metastatic EGFR-mutated NSCLC who had failed on prior EGFR TKI therapy [2].

A total of 57 patients were included, who had a median of 4 prior anti-cancer treatments; 100% had prior EGFR TKI, median treatment duration was 5.5 months, and treatment was ongoing in 18 patients (32%). Participants were treated with HER3-DXd 5.6 mg/kg IV Q3W and followed-up for a median of 10.2 months. At data cut-off, confirmed objective response rate was 39% (n=22: 1 complete responder, 21 partial responders, 19 with stable disease) with 14/22 responses occurring within 3 months of starting HER3-DXd. Disease control rate was 72%. Median duration of response was 6.9 months, and median progression-free survival was 8.2 months. Anti-tumour activity was observed across diverse mechanisms of EGFR TKI resistance, including those not directly related to HER3 (EGFR C797S, MET or HER2 amplification, and BRAF fusion).

Among patients with a history of brain metastases and prior platinum-based chemotherapy, objective response rate was 37%. HER3-DXd had a manageable safety profile and a low rate of discontinuation due to adverse events. The most common grade ≥3 adverse events were thrombocytopenia (30%), neutropenia (19%), and fatigue (14%). Drug-related interstitial lung disease by central adjudication occurred in 4 patients (7%; 1 grade ≥3 [2%]; no grade 5); 6/57 pts (11%) had adverse events associated with treatment discontinuation (none were due to thrombocytopenia). Based on these results, the phase 2 HERTHENA-Lung01 trial of HER3-DXd in patients with EGFR-mutated NSCLC after failure of EGFR TKI and platinum-based chemotherapy has been initiated (NCT04619004).

  1. Scharpenseel H, et al. Sci Rep 2019; 9: 7406.
  2. Pasi AJ, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). ASCO 2021 Virtual Meeting, abstract 9007.

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