Targeted Therapies for Lung Cancer: An Overview

Targeted therapies are cancer drugs (usually pills) that target and inhibit specific genetic abnormalities in cancer tumors. Over 200 known genetic abnormalities are suspected to occur in different kinds of cancer tumors. These are not the same genes that indicate whether you’re at risk of getting cancer. These are genetic changes that occurred in a body’s cells at some point and caused those cells to become a cancerous tumor.

For lung cancer patients, at least fifteen abnormal genes can be identified by molecular profiling of lung cancer tumor tissue. Molecular profiling examines tumor tissue for specific proteins made by these abnormal genes. More genetic abnormalities in cancer tumors can be found by full genomic sequencing, but that’s a post for another day.

Two abnormal genes in lung cancer currently have targeted treatments approved by the FDA. Both of them are found mostly in non small cell lung cancer (NSCLC) with the adenocarcinoma cell type:
— EGFR mutations (approximately 10% of NSCLC tumors in USA)
— ALK fusions (3-7% of NSCLC tumors)
In the ALK fusion, the ALK gene isn’t mutated, but is fused with another gene in the DNA strand. However, some sources call every genetic abnormality in cancer tumors a “mutation” for simplicity.

The 2013 NCCN Guidelines for oncologists, which are the gold standard of cancer treatment in the USA, now state all patients diagnosed with NSCLC adenocarcinoma be routinely tested for an EGFR, which is targeted by the drug Tarceva, and ALK, which is targeted by the drug Xalkori.

However, NCCN guidelines are having trouble keeping up with the fast pace of research and drug development for cancers. Xalkori was approved by the FDA for ALK-positive NSCLC in August 2011 under its expedited review program, but it took over a year for the guidelines to direct oncologists to test advance stage NSCLC patients for ALK.

My genetic abnormality (y’all were certain I had one, right?) is a ROS1 rearrangement. Rather than mutating, ROS1 pairs with another gene, but it’s something of a slut and can pair with more than one gene to cause lung cancer. ROS1 was first announced in a medical journal article in January 2012 and doesn’t have an FDA- approved targeted treatment yet. However, Xalkori (which is approved for ALK-positive patients) is working well for ROS1ers in our clinical trial, which began in 2012. Some oncologists are starting to test never smoker NSCLC patients for ROS1.

EGFR, ALK, ROS1 are examples of “driver mutations.” A driver mutation contributes to a tumor’s progression by causing a tumor to ignore the programmed cell death inherent in normal cells, continue growing even when it crowds into other tissues, and spread tumor seeds into the bloodstream and lymphatic system. Darned inconsiderate, if you ask me.

You can see why driver mutations make such attractive targets for new cancer drugs: if you can inhibit or eliminate the driver mutation, you can stop the cancer.

Targeted drugs for several more lung cancer mutations are currently in clinical trials for NSCLC and small cell lung cancer (SCLC).