Improving Precision Therapies for Non-Small Cell Lung Cancer

Grantee: Pasi Jänne, MD, PhD
Institution: Dana-Farber Cancer Institute in Boston
Area of Focus: Cancer Drug Discovery 
Grant Term: 7/1/17 to 6/30/22

“Lung cancers that harbor EGFR gene mutations are treated with EGFR inhibitors, including the drug osimertinib, but they inevitably develop drug resistance. As such, there is a need to develop new therapies to combat drug resistance.
“In this study, we evaluated an HER3 antibody drug conjugate (called HER3-DXd) as a treatment approach for drug-resistant cancers.
“We observed that HER3-DXd is effective in EGFR-inhibitor drug-resistant models. We further note, that osimertinib treatment increases the membrane expression of HER3, resulting in enhanced internalization of HER3-DXd and increased efficacy in vitro and in vivo.  Our findings suggest that the combination of osimertinib and HER3-DXd may be an effective combination treatment strategy for EGFR-mutant cancers.”

The Challenge: The epidermal growth factor receptor (EGFR) gene provides instructions for making a protein with the same name. Several mutations in the EGFR gene have been associated with certain types of cancer, including lung cancer. The gene is mutated in about 15 to 20% of non-small cell lung cancers (NSCLC), and specifically in a form of NSCLC called adenocarcinoma. These mutations are most common in people with lung cancer who have never smoked.

The gene changes result in an EGFR protein that is always “turned on,” allowing it to constantly receive signals to grow and survive and leading to the formation of a tumor.

Lung cancers with EGFR gene mutations usually respond to drugs that specifically target and inhibit the EGFR protein, causing the tumor to shrink and improving survival. Osimertinib (Tagrisso) is the preferred first line EGFR inhibitor of choice for the most common EGFR-mutant cancers. The problem is that sooner or later these drugs stop working.

The Research: American Cancer Society Clinical Research Professor, Pasi A. Jänne, MD, PhD, was one of the co-discoverers of EGFR mutations and has led the development of therapeutic strategies for patients with EGFR- mutant lung cancer. He and his team tested a new treatment strategy for NSCLC in mice, hoping it would have longer-lasting anti-tumor effects.

Their hypothesis was that targeting the human epidermal growth factor receptor 3 (HER3) protein might improve the effectiveness of EGFR inhibitor drugs.

They evaluated an antibody drug conjugate (called HER3-DXd), which is an antibody directed at HER3 (commonly expressed in EGFR-mutant cancers) linked to a chemotherapeutic agent (topoisomerase I inhibitor). In addition to its evaluation for EGFR mutant NSCLCs, this drug is currently being evaluated for HER3 positive metastatic breast cancer and metastatic colorectal cancer.

The team transplanted patient-derived lung cancer specimens into mice to test the anti-tumor effects of HER3-DXd, including lung cancers that had previously developed treatment resistance.

They found that HER3-DXd was well tolerated by mice. The reduced size of the transplanted lung cancers in mice positively correlated with the dose of the drug, and the team observed anti-tumor effects even for NSCLCs that previously had developed drug resistance. But the results were variable, prompting the team to their next strategy—testing a combination treatment.

The team subsequently discovered that treating EGFR-mutant cancers with osimertinib, results in an increase in the total HER3 protein on the cell surface. This increase enhances the efficacy of HER3-DXd both in cells in culture and in mouse models. 

Why does it matter? These promising preclinical data have led to the initiation of a Phase I clinical trial – a study done in humans – combining osimertinib with HER3-DXd. The study involves advanced NSCLC patients previously treated with osimertinib and those who haven’t been treated with an EGFR inhibitor.