Patritumab deruxtecan, a potential first-in-class HER3 directed antibody drug conjugate, could have more anticancer activity in combination with a EGFR-tyrosine kinase inhibitor (EGFR-TKI): a new paper on Clinical Cancer Research shows that EGFR-TKIs increase HER3 expression thus enhancing anticancer activity of HER-3 targeting patritumab deruxtecan.
The study has been conducted on tumor samples obtained from patients with EGFR-mutated non-small cell lung cancer treated with EGFR-TKI, the standard first line therapy for these tumors. All tumors eventually acquire resistance to EGFR-TKIs and when it happens, treatment options are limited. However, clinical trials have demonstrated that the HER3-targeting antibody–drug conjugate patritumab deruxtecan has some benefits in patients with EGFR-mutated non-small cell lung cancer: that’s why authors tried to understand the mechanisms regulating the expression of patritumab deruxtecan target, HER3, and to verify if there could be a way to enhance its anticancer activity by modifying HER3 expression. Data shows an augmented HER3 expression in EGFR- mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples, moreover in vitro testing also showed that EGFR-TKI directly increased HER3 expression and enhanced the anticancer activity of patritumab deruxtecan.
The findings, authors say, highlights a rational for combination therapy with EGFR-TKI and patritumab deruxtecan because the first treatment, even inducing resistance, could enhance the anticancer activity of the second: HER3 expression was increased by EGFR-TKI therapy and augmentation was likely mediated by PI3K/AKT/mTOR signaling. In December 2021 the US Food and Drug Administration has granted breakthrough therapy designation to patritumab deruxtecan for the treatment of patients with metastatic or locally advanced EGFR-mutated non-small cell lung cancer with disease progression on or after treatment with a third-generation tyrosine kinase inhibitor and platinum-based therapies.