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Targeted Therapy for Lung Cancer

Targeted therapy may be the wave of the future, and the “one treatment fits all” mentality may soon be a thing of the past. In order to have access to these targeted therapies, however, it is necessary for tumors be tested for any mutations that would indicate the type of therapy most appropriate in a particular case. Depending on which particular mutation the tumor may harbor, the patient’s treatment can be matched with what will potentially offer the best response rates in that specific case. Unfortunately, not all doctors and oncologists are aware that tumor testing exists, or that targeted therapies are available. If your doctor is not familiar with these options, it is highly advisable to seek a second opinion from a lung cancer specialist well versed on the subject.

To have a tumor tested, there needs to be enough available tissue. This tissue may be obtained through surgery, VATS (video-assisted thoracoscopic surgery), CT guided core needle biopsy, etc. Tumor samples obtained in these ways should provide enough material for analysis. Tissue obtained through fine need aspiration may not prove adequate. Simply put, the larger the sample, the more likelihood of confirming the presence of a mutation. Many academic centers, as well as certified laboratories, offer tumor testing services. Additionally, fourteen medical facilities in the U.S. are participating in a federally funded study called the Lung Cancer Consortium Protocol, offering advanced lung cancer patients a free screening of their tumors for genetic mutations, some of which may be targets for treatment with existing or experimental therapies. Tumors will be tested at no cost to the participant, and if applicable, medical professionals will notify them of clinical trials that specifically target the mutation found in their tumors. A database will also be compiled so that as new therapies are developed, patients can be contacted and linked to new trials.

Lung Cancer mutations pie chart courtesy of Lung Cancer Foundation of America

Courtesy of Lung Cancer Foundation of America

While a number of different mutations have been identified in lung cancer to date, effective targeted therapies have not yet been developed for all of them. At the present time, the three mutations most commonly tested for are the EGFR, ALK and KRAS genes. Since a positive result for one of these mutations generally means that the tumor will test negative for the others, treatment can be focused where the best results may be obtained. Following is a chart showing the breakdown of currently identified non-small cell lung cancer mutations.

Non-small cell lung cancer is the most common form of lung cancer with adenocarcinomas being the most common sub-type. 20% to 30% of tumors of adenocarcinoma histology have the EGFR mutation. These mutations predominate in female never-smokers. Currently, the two drugs of choice for targeted therapy of this mutation have been Tarceva (erlotinib) with a response rate of 82%, and Iressa (gefitinib), with a response rate of 72%. Both of these drugs are classified as tyrosine kinase inhibitors, and work by slowing or blocking the activity of a specific protein called Epidermal Growth Factor Receptor 1 (HER1/EGFR) which allows cancer cells to multiply. They are not chemotherapy drugs, and are taken in pill form as prescribed by the doctor. While studies have shown these drugs to be successful in helping patients with the EGFR mutation to live longer, they appear to be somewhat limited by the ultimate development of resistance; approximately 50% eventually show the emergence of a second mutation. Second generation EGFR inhibitors are in development, but efficacy has been limited due to toxicity.

Approximately 2% to 7% of non-small cell lung cancers are ALK (anaplastic lymphoma kinase) mutations. Patients with ALK rearrangements are generally younger than most non-small cell lung cancer patients, and are often never to light smokers. Recently, researchers have determined that a new drug, crizotinib, shows efficacy in patients with this mutation. Crizotinib targets the “driver kinase”, blocking its activity and preventing the tumor from growing. Data obtained from clinical trials has shown that in patients who had received prior treatments that either failed or worked only for a brief period of time, crizotinib offered a 72% chance the tumor would shrink or remain stable for at least six months. As with the EGFR inhibitors, however, tumors tend to adapt to target therapies, and eventually render them ineffective. The Food and Drug Administrationapproved crizotinib - which will be sold under the name Xalkori - for advanced stage non-small cell lung cancer which has been determined to be ALK (anaplastic lymphoma kinase) positive.

KRAS mutations are common in non-small cell lung cancer, and since a high percentage of those having this mutation have a smoking history, it has been hypothesized that there is a direct relationship to tobacco exposure. That said, not all studies are in complete agreement, and while it appears that some mutations in KRAS are associated with cigarette smoking, KRAS mutations also occur in never-smokers (less than 100 cigarettes per lifetime). Because of the commonality of this mutation, it has attracted considerable attention for targeted therapy. Unfortunately, however, RAS inhibitors have proven clinically ineffective despite being tested in a large number of clinical trials. Research is being conducted on an ongoing basis.

Two other lung cancer mutations that occur with less frequency than EGFR and ALK, are the HER2 and BRAF mutations. Since some success has already been noted in other cancers (breast and melanoma) where these mutations occur, it would seem likely that similar success could be obtained with therapies targeting the same mutations in lung cancer.

HER2 is part of the same family of tyrosine kinase receptors as EGFR. In lung cancer, mutations in HER2 occur in only 2% to 3% of non-small cell lung cancers, and like EGFR and ALK, typically are seen in the adenocarcinoma sub-type, and more frequently in women and never-smokers. Unfortunately, because of the relatively low percentage of patients with this particular mutation, routine tumor testing and the availability of clinical trials has been limited. At present, patients who are identified as HER2-mutant are treated with first-line chemotherapy, with HER2 specific trials designated as second-line or greater therapy. Although some patients have been able to obtain the drugs used to target HER2, (i.e., Herceptin and Tykerb) on an off-label basis, both drugs are expensive and there is difficulty in gaining approval for payment of treatments. The Lung Cancer Mutation Consortium is offering tumor testing for HER2 mutations with the goal of getting all participating medical institutions (currently fourteen) to join together to promote and complete clinical trials of this uncommon mutation.

Another target in non-small cell lung cancer is the BRAF mutation. While BRAF mutations are among the most common in cancers in general, they only represent 1% to 3% in lung cancer. They are most commonly found in adenocarcinomas and in former or current smokers. Currently the most promising studies of BRAF have been those associated with the treatment of melanoma, a potentially deadly form of skin cancer that has been notoriously difficult to treat. In contrast to BRAF mutations in melanoma, there appear to be many different BRAF mutations in lung cancer, making testing more complicated. Scientists are also unsure at this point which of these different mutations might respond best to targeted therapy. The Lung Cancer Mutation Consortium is testing for multiple BRAF mutations, with direction to clinical trials being offered through the Consortium.

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