Patritumab Deruxtecan in EGFR-Mutated NSCLC
The HER3-directed antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) appears promising for treatment of advanced EGFR-mutated non–small cell lung cancer (NSCLC) according to findings from the phase 2 HERTHENA-Lung01 clinical trial presented during the 2023 World Conference on Lung Cancer.1,2
About Patritumab deruxtecan (HER3-DXd)
Patritumab deruxtecan is a type of medication known as an Antibody Drug Conjugate. It is comprised of 3 components: an anti-HER3 monoclonal antibody, patritumab, that is linked (connected) to a chemotherapy (topoisomerase I inhibitor) payload, and an exatecan derivative, through a tetrapeptide-based cleavable linker. The ADC targets the HER3 receptor and delivers the chemotherapy payload to destroy the cancer cell.
Why HER3?
HER3 (human epidermal growth factor 3) is a small protein receptor on the surface of some cancer cells. When HER3 is "turned on" it causes the cells to grow and reproduce. HER3 belongs to the HER family of receptors which includes HER1/EGFR/erbB1, HER2/erbB2, and HER4/erbB4. HER3 alone lacks or has minimal cancer-causing activity but frequently works with other receptor tyrosine kinases in cancer cells to activate facilitate cancer cell growth. HER3 is expressed in more than 40% of lung cancers. Elevated expression of HER3 has been observed in a wide variety of human cancers and is associated with a worse survival. Research implicates HER3 activation as a major cause of treatment failure in cancer therapy.3,4
Results from the HERTHENA-Lung01 clinical trial were reported at the September 2023 World Conference on Lung Cancer – 30% of heavily pretreated patients with advanced EGFR-mutated NSCLC that had previously been treated with an EGFR TKI responded to treatment with patritumab deruxtecan. The median duration of response was 6.4 months, the median overall survival was 12 months, and patients with cancer that had spread to the central nervous system responded to treatment.1
Patritumab deruxtecan was well tolerated – nausea, decreased appetite, constipation and low blood counts were the major reported side effects. Interstitial lung disease occurred in 5.3% and was not severe.
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There are several ongoing clinical trials evaluating patritumab deruxtecan in patients with EGFR-mutated NSCLC after progression on third-generation EGFR TKI therapy, in combination with Tagrisso (osimertinib) in patients with EGFR-mutated NSCLC and in previously untreated patients.
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References
1. Yu HA, Goto Y, Hayashi H, et al. Patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC following EGFR TKI and platinum-based chemotherapy: HERTHENA-Lung01. Presented at: 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore.
2. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor–mutated non–small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. Published online September 10, 2023. doi:10.1200/JCO.23.01476
3. Steuer CE, Hayashi H, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR-activating mutations. J Clin Oncol. 2022;40(suppl 16):9017. doi:10.1200/JCO.2022.40.16_suppl.9017 4. Yonesaka K. HER2-/HER3-rargeting antibody-drug conjugates for treating lung and colorectal cancers resistant to EGFR inhibitors. Cancers (Basel). 2021;13(5):1047. doi:10.3390/cancers13051047
5. Patritumab deruxtecan demonstrated clinically meaningful and durable responses in patients with EGFR-mutated metastatic non-small cell lung cancer in HERTHENA-Lung01 phase 2 trial. News release. Daiichi Sankyo. September 10, 2023. Accessed September 10, 2023. https://daiichisankyo.us/press-releases/-/article/patritumab-deruxtecan-demonstrated-clinically-meaningful-and-durable-responses-in-patients-with-egfr-mutated-metastatic-non-small-cell-lung-cancer-in-
