Use of a New Blood Test to Identify Response to Targeted Treatment in Patients With EGFR Mutated Lung Cancer. Evaluation in a Multicenter Study

Background Non-small celled lung cancer (NSCLC) is one of the most common cancers in the world, and Denmark has one of the highest incidences of approximately 3800 new patients each year who are diagnosed with NSCLC, and the overall prognosis is very poor.

The EGF (epidermal growth factor) system with its known receptors and related proteins are known to play an active role in the development of cancer. In non-small cell lung cancer (NSCLC) especially EGFR has been studied. Inhibition of EGFR is associated with prolonged survival especially in patients with mutations in the EGFR (EGFR M+) 10-15% of the patients with NSCLC harbor a mutation in the tumor's EGFR. This receptor is the target for treatment with the tyrosine kinase inhibitor (TKI) erlotinib. The response rate for erlotinib treatment in EGFR M+ NSCLC is around 75% as opposed to response rates around 30% for treatment with traditional chemotherapy.

Recently, resistance mechanisms that cause progression on TKI treatment has been elucidated. The most common is the T790M mutation in EGFR, but other mechanisms such as increased MET and HER3 expression is also described. It is estimated that T790M mutations in EGFR accounts for 50% of the cases with TKI resistance development. With the exception of HER3 and MET, which is estimated to represent less than 5% of the cases with the development of resistance, are the mutations which cause the remaining 50% of cases, resistance remains unknown. The revelation of further resistance mutations hampered by the problems of obtaining biopsies when progression occurs.

Identification of EGFR M+ is done on a tumor biopsy, which can be difficult to retrieve. Furthermore a biopsy only provides information about a certain part of the one tumor site, that is tested. The investigators know that tumors especially in NSCLC is a very heterogenous group. A blood test provides us with e more overall information about the tumor mass of each specific patient. However tumor DNA is also present in blood of cancer patients in the form of circulating free DNA. A new blood based test identifies EGFR M+ in plasma, which makes it possible to monitor the level of EGFR M+ in the patient's blood during treatment. This enables both a closer monitoring of the treatment with erlotinib and a closer study of the resistance mechanisms that almost inevitably develop during treatment.

A pilot study with 23 EGFR M+ NSCLC patients demonstrated that the quantity of EGFR M+ in plasma correlates to the response to treatment and might be used to predict disease progression. In this study resistance mutations were detected between 20-300 days prior to clinical evidence of disease progression via CT scans.