Advancements in technology have improved the quality, cost and turnaround time for assessing genetic mutations in tumor tissue. This has helped to translate precision medicine into standard clinical practice.  Testing for genetic alterations is now a standard part of the work-up for a patient with newly diagnosed advanced lung cancer.  Additionally, since getting a sample of tumor tissue is not always possible, blood can be analyzed for tumor DNA and also provides a mechanism for assessing the genetic make-up of a tumor.  This is especially helpful in lung cancer where getting tumor tissue may be challenging.  We know that cancers grow by increasing “go” signaling, called oncogenes, and decreasing “stop” signals like tumor suppressor genes.  Genetic changes in an oncogene, like epidermal growth factor receptor (EGFR), can cause a tumor to keep growing.  It has been known for many years that activating mutations in EGFR can predict response to drugs that inhibit EGFR, including erlotinib (Tarceva®), gefitinib (Iressa®), afatinib (Gilotrif®) and osimertinib (Tagrisso®).  We also know that other targetable mutations can occur in non-small cell lung cancer (NSCLC) and cause “go” signals through other genes besides EGFR.  These include BRAF activating mutations, MET exon skipping, RET fusions, ERBB2 mutations and others.  These mutations are considered “rare” but with more than 224,000 new cases of lung cancer expected to be diagnosed in 2016, even “rare” mutations can affect several thousands of patients every year.  For example, MET exon 14 mutations are seen in about 3-4% of non-small cell lung cancers but this translates to around 7000 patients each year.¹ 

Below is a brief review of 3 less common alterations as they relate to NSCLC and the evidence supporting drugs directed to these targets.

1. BRAF activating mutations: BRAF is an oncogene that is most commonly associated with melanoma and activating mutations are seen in about 50% of cutaneous melanomas. Activating mutations in BRAF are seen in up to 7% of NSCLC and typically occur in current or former smokers.  Inhibitors of BRAF, and a protein downstream of BRAF called MEK, have been initially developed in melanoma but are being assessed in other cancer types like NSCLC.  There are 2 BRAF inhibitors approved (dabrafenib (Tafinlar®)and vemurafenib (Zelboraf®) and 2 MEK inhibitors approved (trametinib (Mekinist®) and cobimetinib (Cotellic®).  These drugs are most effective when a BRAF inhibitor is used in combination with a MEK inhibitor. Dabrafenib plus trametinib is the most commonly studied combination in NSCLC.  A phase 2 trial of 59 patients with previously treated NSCLC that was found to have a BRAF activating mutation were treated with this combination of drugs.  An objective response was seen in 63% of patients with 2 patients having a complete response and 34 patients having a partial response in tumor shrinkage.  The median duration of response to the drugs was 9 months.² 

2. MET exon 14 skipping mutations: MET is an oncogene that can promote cancer growth when it’s consistently turned on.  MET is a receptor for a protein called HGF.  When HGF binds to MET, it turns on MET which causes “go” signals to cancer cells to grow.  The body can regulate these signals by destroying MET when it does not need it to be turned on.  This specific MET alteration prevents MET from being destroyed and keeps it turned on, continuing to send “grow” signals to the cancer cells.  This MET alteration is seen in about 3-4% of NSCLC and is more common in a subtype of NSCLC called “pulmonary sarcomatoid carcinoma”.  Additionally, patients with this MET alteration are usually older (median age of 72 years of age), female, and former or current smokers.³  There are several drugs that can inhibit MET with crizotinib (Xalkori®) being the most commonly investigated in NSCLC.  Crizotinib is a drug that inhibits several different targets in lung cancer and is most commonly used for patients whose cancers have genetic alterations of ROS1 or ALK.  In a small case series of 5 patients with NSCLC who were previously treated with other drugs, 4 patients received crizotinib with 3 of these patients have a partial response and progression free survival of 3.6 months or more (2 patients were still responding after 3.1 and 4.6 months, each).⁴ 

3. RET activating fusions: RET is an oncogene that can become activated by “fusing” with another gene. This happens when the chromosome where RET is located breaks into 2 pieces and reassembles upside-down.  These alterations are called “fusions” and they are reported by listing both genes, such as KIF53-RET.  This means that the RET gene has been fused to part of the KIF53 gene.  This causes the RET gene to be turned on and signal to cancer cells to grow.  RET fusions are seen in about 1-2% of NSCLC and are more common in younger patients who are never-smokers.  There are several drugs that can inhibit RET with cabozantinib (Cometriq®) and vandetanib (Caprelsa®) being the ones looked at the most in NSCLC.  These drugs are both approved for a type of thyroid cancer. A phase 2 trial of 26 patients with NSCLC who had RET-fusions and who had received prior treatment were given cabozantinib.  A partial response was seen in 28% of patients.  Of these patients, 75% of them had at least a 30% decrease in tumor size within the first 4 weeks of receiving the drug.  The median duration of treatment was 7 months with 4 patients receiving the drug for longer than one year.⁵  Vandetanib was also assessed in a phase 2 trial of 18 patients with NSCLC who had RET-fusions and who had received prior treatment.  Confirmed tumor responses were seen in 53% of patients and the progression free survival was 4.7 months.⁶  

These genetic markers are all mentioned in treatment guidelines for NSCLC, however an ongoing question focuses on when to use targeted therapy that has been tested in a smaller group of patients compared with standard chemotherapy or immunotherapy that has been tested in larger numbers of patients.  All of the trials discussed above were small and performed in patients who received prior therapy.  Ongoing studies are trying to help answer this question.  The best answer for each patient depends not only on the genetic tumor results but also other aspects of each patient’s disease and personal characteristics, making discussion with the medical team essential for personalizing therapy.    

References:

1. Thomas A, et al. Refining the treatment of NSCLC according to histologic and molecular subtypes. Nat Rev Clin Oncol. 2015;12(9):511-526.
2. Planchard D, et al. Dabrafenib plus trametinib in patients with previously treated BRAF V600E-mutatnt metastatic NSCLC: an open-label, multicenter phase 2 trial. Lancet Oncol. 2016;17(7):984-993.
3. Awad, MM, et al. MET exon 14 mutations in NSCLC are associated with advanced age and stage-dependent MET genomic amplification and c-MET overexpression.  J Clin Oncol. 2016;34(7):721-730.
4. Paik, PK, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discovery.  2015,5(8):842-849.
5. Drilon, A, et al. Cabozantinib in patients with advanced RET-rearranged NSCLC: an open-label, single-center, phase 2 single-arm trial. Lancet Oncol. 2016;17:1653-60.
6. Yoh K, et al. Vandetanib in patients with previously treated RET-rearranged advanced NSCLC (LURET): an open-label multicenter phase 2 trial.  (Lancet Respir Med. 2017;5(1):42-50).