Overcoming Resistance to Targeted Therapies in EGFR-Positive Patients

Juhi Kunde, MA, LUNGevity Science Writer

In 2004, after the discovery of mutations in the EGFR gene in lung cancer, the FDA approved a targeted therapy that increased survival in EGFR-positive NSCLC patients. However, the tumors inevitably became resistant to the treatment, and the cancer returned unchecked.

To understand what was causing the cancer to come back, researchers studied the genomic changes in the tumors that had recurred. What they found was surprising! Tumor cells are shrewd—they were developing additional mutations that allowed the tumor to survive and thrive. Researcher developed new drugs (third-generation treatment options) to target these new mutations, with the goal of overcoming drug resistance.

One third-generation treatment, osimertinib (Tagrisso®), is currently FDA-approved. This drug has had excellent results, and is also now approved for first-line treatment for patients with advanced-stage EGFR-positive NSCLC.

Eventually, though, whether patients begin with this third-generation therapy or progress through other treatments to end up on it, their cancers also become resistant to this treatment.

Exciting Early Progress in Overcoming Resistance

Zosia Piotrowska, MD, a lung cancer oncologist and researcher at Massachusetts General Hospital, is poised to help. “I was a first-year fellow around the time that third-generation EGFR targeted therapies were in clinical development. It was revolutionizing the way we treated patients. After seeing the importance of drug development first-hand, I was inspired to develop even better therapies for patients,” says Dr. Piotrowska.

Dr. Piotrowska began studying biopsy and blood samples taken from patients before and after treatment with osimertinib. “By comparing the genes in the samples taken at these different times, my team and I were searching for genomic changes that could be causing the drug resistance.”

Their results, published earlier this year in Cancer Discovery, were exciting. Dr. Piotrowska and her team found that a secondary type of driver mutation, known as a RET-fusion, was likely to be causing resistance in two of the 41 NSCLC EGFR-positive patients in the study. The team was able to successfully overcome drug resistance in both patients with a combination of osimertinib and BLU-667, a RET-fusion targeted therapy.

The Research Continues

Dr. Piotrowska was awarded a three-year Career Development Award from LUNGevity Foundation in 2017 to continue her critical research.

“I am so grateful to LUNGevity for the financial and collaborative support of my research career, as well as for the emotional and educational support they provide to my patients,” she says. “I attended the 2018 HOPE Summit and saw the incredible work LUNGevity does for the lung cancer community. I am proud to be part of the LUNGevity community.”

Over the next two years, Dr. Piotrowska will continue her research to understand the underlying mechanisms of drug resistance in EGFR-positive NSCLC. She has already begun enrolling patients in a clinical trial, and will continue to study biopsy samples to identify other avenues to overcome drug resistance.

 “It’s hard to say when this work will become available to patients,” notes Dr. Piotrowska. “In some cases, like our experience with RET-fusions, findings from patient biopsies can be used to design a new treatment in just a few months, while in other cases it can take much longer to develop new therapies. I expect the discoveries to come faster and faster, and I know that researchers will work hard to get them out quickly to the patients who need them.”



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Juhi Kunde, MA, is a science writer for LUNGevity. Juhi Kunde

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