Targeted molecular therapies for non-small cell lung cancer: Clinical Update

For too long, treatment for advanced non-small cell lung cancer was brutally simple: platinum chemotherapy and a trip to the attorney to get one's affairs in order. Fortunately for patients, it's not quite so straightforward anymore. Effective targeted molecular therapies for non-small cell lung cancer are now available, often taken orally with fewer side effects than traditional cytotoxic chemotherapy. The new treatments are in no way cures, but they can prolong survival and improve quality of life with advanced (stage IIIB and IV) non-small cell lung cancer (NSCLC). Only a minority of non-small cell lung cancers express mutations that make them vulnerable to the best targeted chemotherapy drugs. As additional drugs are developed targeting the known mutations, that proportion is growing -- along with the costs of treating advanced non-small cell lung cancer.

EGFR and ALK in Non-Small Cell Lung Cancer

All patients with advanced NSCLC should have biopsy specimens of their primary tumor or a metastasis tested for the presence of a so-called driver mutation. The most important driver mutations in non-small lung cancer are EGFR and ALK:

• Epidermal growth factor receptor (EGFR) is present in about 15% of non-small cell lung cancers in the U.S. EGFR-positive NSCLC can be treated with the tyrosine kinase inhibitors erlotinib (Tarceva), gefitinib (Iressa) or afatinib (Gilotrif).

• Anaplastic lymphoma kinase (ALK) is only present in about 4% of U.S. non-small cell lung cancers, often in younger, non-smoking patients. NSCLC with ALK mutations can be treated by crizotinib (Xalkori) and ceritinib (Zykadia), also tyrosine kinase inhibitors.

Pulmonologists performing bronchoscopic fine needle aspiration biopsies (EBUS) should collect several passes to obtain adequate tissue specimens for molecular testing. Transthoracic needle biopsy specimens are almost always adequate.

Immunotherapy for Non-Small Cell Lung Cancer

Immunotherapy is also emerging as a powerful tool in some advanced NSCLC. About a quarter of patients with NSCLC have tumors that express high levels of programmed death ligand (PD-L1). This mutation makes them vulnerable to pembrolizumab (Keytruda), a humanized monoclonal antibody against PD-1. In a large randomized trial in patients with advanced NSCLC who had PD-L1 expressed on at least half of tumor cells, pembrolizumab was associated with longer survival and fewer serious side effects than traditional platinum-based chemotherapy. Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF) and prevents its stimulation of blood vessels in the tumor. Bevacizumab improves survival from advanced adenocarcinoma and other nonsquamous NSCLC.

NSCLC with Other Driver Mutations

Many patients with advanced non-small cell lung cancer harbor other driver mutations for which no drug has yet been approved for lung cancer treatment by the FDA. These mutations can be targeted by “off-label” use of drugs approved for treatment of other cancers that express the same mutations. Most often, these off-label treatments are used as second-line therapies for patients not responding to or unable to receive more established lung cancer treatments:

• ROS1: Crizotinib is recommended for some patients instead of traditional chemotherapy.

• RET: RET inhibitors such as cabozantinib or vandetanib (both approved for thyroid cancer) are sometimes used instead of chemotherapy as second line agents.

• MET: Certain MET mutations may respond to a MET inhibitor such as cabozantinib or crizotinib.

• BRAF V600: BRAF inhibitors vemurafenib or dabrafenib (approved as melanoma treatments) may be alternative therapies.

• HER2: Patients with particular mutations might benefit from afatinib or trastuzumab (a breast cancer treatment) added to chemotherapy.

The complexity of new molecular targeted therapies is upsetting the apple cart of established treatment protocols for advanced non-small cell lung cancer — and that’s a good thing. Hundreds of clinical trials are underway to try to identify the best new ways to administer these agents, with or without traditional therapies, and in what order. And that's not counting the new drugs just behind them in the pipeline. All this innovation does seem to be improving health outcomes -- somewhat. In a huge study in France, about half of 18,000 tested lung cancers had a driver mutation, leading to use of a targeted drug instead of traditional chemotherapy in about a quarter of patients. Patients with a driver mutation lived longer (16.5 vs. 12 months) and had better progression-free survival (10 vs. 7 months) than those with no driver mutation. A medical cure for non-small cell lung cancer remains elusive, and health policy experts are right to challenge the enormous costs of off-label use of chemotherapy drugs for advanced cancer to extend life by only months, on average. As more targeted drugs become available, these costs may prove intolerable even in wealthy countries. But the progress itself is undeniable. For many patients with advanced non-small cell lung cancer, short on hope, the long-predicted age of personalized gene-driven medicine is now.