A study led by Winship Cancer Institute of Emory University offers new insight into what causes resistance to the non-small cell lung cancer (NSCLC) medication osimertinib that may prove valuable in developing more effective NSCLC therapies. Study results were reported August 8 at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer in Vienna, Austria.
"This real-world study improves our understanding of how resistance mutations to osimertinib emerge over time," says the study's principal investigator Suresh S. Ramalingam, MD, FACP, FASCO, Winship's executive director, "with new insights on when EGFR C797X mutations overtake MET amplifications as the most commonly acquired resistance mechanism."
EGFR C797X mutations happen from damage to the part of a cell's DNA carrying the "recipe" for EGFR (epidermal growth factor receptor) proteins. These proteins are involved in cells' division and survival. Sometimes mutations in the EGFR gene cause the proteins to be produced in higher than normal amounts in certain cancers, such as non-small cell lung cancer.
MET gene amplification means that there are extra copies of the cell growth gene MET in the body. Having extra copies of the MET gene indicates there are extra growth signals being sent to the cancerous cells. MET amplification is a predictive biomarker for some patients. A high number of copies of the MET gene could require a targeted therapy.
Osimertinib, sold under the brand name Tagrisso, is a medication used to treat non-small-cell lung carcinomas with EGFR mutations. It is a type of third-generation targeted therapy called tyrosine kinase inhibitor. "Although it is highly effective," says Ramalingam, "resistance invariably occurs in all patients."
When someone develops mutations, and resistance to osimertinib, most will have to change their drug therapy. "This involves switching to chemotherapy or enrolling in a clinical trial based on the specific resistance mechanism," says Ramalingam.
The study was a collaborative effort between Winship, Guardant Health and Blueprint Medicines. Guardant Health is a precision oncology company that uses proprietary tests, vast data sets and advanced analytics in its precision oncology efforts. Blueprint Medicines is a precision therapy company with a particular focus on therapies for people with cancer and blood disorders.
The study analyzed de-identified clinical and genomic data of more than 2,000 people who had an EGFR mutation and were being treated with osimertinib, drawn from the GuardantINFORM real-world evidence platform, which includes more than 65,000 adults with NSCLC. The study incorporated DNA results up to five years after patients initiated osimertinib therapy.
Altogether, the analysis found that EGFR C797X mutations were 1.25 times more common than MET amplification when osimertinib was used as a first-line therapy, and 2.4 times more common when used as a second-line therapy. MET amplifications were the most common resistance mutation in the first year of osimertinib treatment, and EGFR C797X mutations exceeded the rate of MET amplifications in years two through five.
Implications going forward
"We have made remarkable progress in improving outcomes for lung cancer patients," says Ramalingam. "With the advent of targeted therapies, patients are living longer and better, if their tumor bears a targetable driver mutation." He adds, "The next challenge is to understand mechanisms of resistance to targeted therapies and develop novel treatment approaches to overcome resistance."
Ramalingam says the study's results are "highly important" in highlighting the need to develop specific EGFR C797X inhibitors. "The analysis," he says, "characterizes the increased frequency of EGFR C79X mutations as patients are treated with first-line osimertinib for longer durations, reinforcing the need for next-generation EGFR inhibitors to address C797X-driven resistance."
He notes that in fact a fourth generation of EGFR inhibitors – with activity against C797X – are just entering the clinic. "These agents have an excellent pre-clinical profile," he says, adding, "A phase 1 trial of a fourth generation tyrosine kinase inhibitor will be opening soon at Winship."