A strand of DNA explosively breaking in the middle.

The History of Precision Medicine in Lung Cancer

As recently as twenty years ago, everyone diagnosed with metastatic lung cancer was treated the same way — with chemotherapy. Immunotherapy, targeted therapy, and other treatment advances that we today take for granted did not exist as therapy options.

Precision medicine, “a form of medicine that uses information about a person’s own genes or proteins to prevent, diagnose, or treat disease”, was not yet a part of lung cancer diagnosis and treatment.1

How did lung cancer treatment evolve?

How did lung cancer treatment evolve from this one-size-fits-all approach? Initially investigated and developed for breast cancer treatment, gefitinib (later known as Iressa) came on the lung cancer scene in the early 2000s. Initially, all that was known was that gefitinib inhibited the expression of EGFR, the epidermal growth factor receptor.

However, EGFR is a protein that is expressed in both normal cells and cancer cells and is necessary for many cellular processes. This means that many patients with lung cancer express EGFR in varying degrees. As a result, early lung cancer trials focused on giving gefitinib to any patient with recurring non-small cell lung cancer, with "objective response rates between 10 and 20%."2

The FDA approval of gefitinib...

These trials led to the accelerated FDA approval of gefitinib in May 2003, but only under specific conditions —  "as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies."3 It was pretty much considered a drug of last resort; most patients did not respond, but those who did often had significant improvements in symptoms. Soon after, in November 2004, erlotinib (Tarceva) was also approved as an EGFR inhibitor to treat patients who had progressed after at least one line of chemotherapy.

Also in 2004, researchers began to uncover an important difference between patients who responded to gefitinib and erlotinib and those who did not. They found that tumor tissue from the majority of responding patients had EGFR mutations (otherwise known as changes) in genes that caused production of EGFR to be abnormal and led to cancer growth. These mutations came to be known as “activating” or “sensitizing” mutations. This was a HUGE breakthrough because it meant that it might be possible to target specific treatment to patients with lung cancer who had these EGFR mutations.

Introducing new lung cancer treatments to the market

Before either gefitinib or erlotinib became fully approved as first-line treatment for patients with EGFR mutations, many additional clinical trials were necessary. This took time. In May 2013, erlotinib was finally approved by the FDA as initial treatment for these patients, along with an accompanying assay (test) to use on tumor tissue to determine whether EGFR mutations were present.

In contrast, gefitinib was pulled from the U.S. market in 2005, although it continued to be used elsewhere in the world. Due to FDA requirements for full (as opposed to accelerated) approval, trials of gefitinib as compared to traditional chemotherapy didn’t show significant improved patient benefit. Remember, these trials in the 2000s included all patients with recurrent non-small cell lung cancer, not only those with EGFR mutations. Gefitinib did not come back to the U.S. and receive full first-line approval for those living with EGFR-positive lung cancer until July 2015.

The future of lung cancer treatment

In the past decade, many other biomarkers and precision medications have been developed, such as those for ALK, ROS1, MET, RET, PDL1, etc. Current guidelines call for testing patients with lung cancer using a panel of biomarkers to direct therapy. It is no longer assumed that all types of lung cancer should be treated the same way. All of this development started with the accidental discovery of the potential for gefitinib to inhibit EGFR in lung cancer!

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