HER3-Targeted Patritumab Deruxtecan in Treatment-Resistant EGFR-Mutant Lung Cancer

In around 15% of non-small cell lung cancers, which account for 85% of lung cancers, EGFR mutations are present. However, this proportion can vary depending on factors such as ethnicity, geographic location and smoking habits. For example, EGFR mutation rates may be higher in Asian populations, ranging from 30-50%.

An EGFR mutation is a change in the epidermal growth factor receptor (EGFR) gene and is common in certain cancers, particularly lung cancer. It promotes the uncontrolled growth and spread of cancer cells, which is why treatments targeting EGFR, known as anti-EGFR agents , can often be effective. Over time, however, patients may become resistant to targeted drugs directed against EGFR.

Drug options are limited for patients with advanced EGFR-mutant lung cancer once resistance to treatment develops. Against this background, the 2023 World Conference on Lung Cancer featured the phase II HERTHENA-Lung01 clinical trial, which investigated patritumab deruxtecan (HER3-DXd) , a new anti-HER3 antibody-drug conjugate. Published alongside the conference on September 10, 2023 in the Journal of Clinical Oncology , this study presents promising results for these patients.

Japanese biotechnology company Daiichi Sankyo is developing patritumab deruxtecan (HER3-DXd). The same company also developed a drug previously approved by the FDA (US Food and Drug Administration) for HER2-positive breast, stomach and lung cancers, namely trastuzumab deruxtecan (Enhertu) , a targeted therapy.

Why Target HER3 in EGFR-Mutant Lung Cancer?

EGFR (epidermal growth factor receptor) and HER3 (human epidermal growth factor receptor 3) actually belong to the same receptor family and work together in many biological processes. In patients with EGFR-mutant lung cancer, EGFR-targeted treatments may lose their effectiveness over time, or patients may become resistant to them. Cancer cells then often continue using other pathways or receptors to grow and spread.

HER3 may be one of these alternative pathways. HER3 can interact with EGFR and create an active pathway in cells that have become resistant to EGFR inhibition. Targeting HER3 could therefore provide a new treatment option for patients who have become resistant to EGFR-targeted therapies.

This treatment strategy illustrates the complexity of cancer biology and how alternative pathways can be targeted in patients who develop resistance to treatment.

The mechanism of action of patritumab deruxtecan (HER3-DXd) is shown below:

Study Details

The study enrolled 225 patients between February 2021 and February 2022 in North America, Europe, East Asia, Southeast Asia and Australia. All patients had previously received EGFR tyrosine kinase inhibitor therapy and platinum-based chemotherapy. The primary endpoint was the confirmed objective response rate assessed by independent central review.

Response Rates

• At a median follow-up of 18.9 months, an objective response was observed in 67 of the 225 patients (29.8%).
• In addition, disease remained stable in 99 patients (44%).
• The median duration of response was 6.4 months, and
• 43% of patients had a response lasting 6 months or longer.

Response in Patients With and Without Brain Metastases

• Among 115 patients with a history of brain metastases, the objective response rate was 28.7% and the median duration of response was 5.5 months.
• Among 110 patients without a history of brain metastases, the objective response rate was 30.9% and the median duration of response was 6.9 months.

Side Effects

The most common side effects included thrombocytopenia (21%), neutropenia (19%) and anemia (14%). The treatment-related death rate was 2%.

Conclusion

HERTHENA-Lung01 addresses patients with advanced EGFR-mutant non-small cell lung cancer who have developed resistance to EGFR-targeted drugs. The study investigated HER3-DXd (patritumab deruxtecan) as a new treatment candidate for this group and found that it favorably affected the course of the disease and elicited responses even in treatment-resistant patients. This suggests that it could become a promising new treatment option, particularly for patients with EGFR-mutant lung cancer who have become resistant to previous therapies.