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Stage IV Non-Small Cell Lung Cancer


Stage IV non-small cell lung cancer (NSCLC) is found in both lungs, in the fluid that surrounds the lungs or heart, or has spread to other parts of the body such as the liver, brain, or bones.

Although some patients with Stage IV NSCLC have cancer that has spread to only a single other site that can be treated with surgery or radiation therapy, systemic therapy with chemotherapy or targeted therapy is the mainstay of treatment for most patients with Stage IV NSCLC. Targeted therapies (which may be used in combination with chemotherapy) are also playing an increasing role in the treatment of selected patients with NSCLC.

Stage IV NSCLC is usually not considered curable, but newer treatments are prolonging survival and reducing cancer symptoms well beyond what was expected just a few years ago.

About this NSCLC Treatment Information

The following is a general overview of treatment for stage IV NSCLC. Cancer treatment may consist of chemotherapy, targeted therapy, or a combination of these treatment techniques. Combining two or more of these treatment techniques has become an important approach for prolonging survival and increasing a patient’s chance for cure.

Circumstances unique to each patient’s situation influence which treatment or treatments are utilized. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

Chemotherapy for Stage IV NSCLC

Chemotherapy uses drugs that kill rapidly dividing cells, a hallmark of cancer. Cancer chemotherapy may consist of single drugs or combinations of drugs. It can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill.

Chemotherapy is different from surgery or radiation therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread; it thus can kill or eliminate cancers cells at sites great distances from the original cancer. As a result, chemotherapy is considered a systemic treatment.

Patients with advanced NSCLC are treated with chemotherapy to alleviate the symptoms of their disease and prolong their duration of survival. Most treatments involve a combination (regimen) of two chemotherapy drugs. The most commonly used regimens include either cisplatin or carboplatin; combined with one of several other drugs approved for the treatment of NSCLC; Alimta® (pemetrexed), Taxol® (paclitaxel), Taxotere® (docetaxel), Gemzar® (gemcitabine), Camptosar® (irinotecan), or Navelbine® (vinorelbine).1

Targeted Therapy for Stage IV NSCLC

A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes. Targeted therapies are playing an increasing role in the treatment of NSCLC.

Avastin® (bevacizumab): Avastin®is a type of targeted therapy that slows or stops the growth of blood vessels that deliver blood to the cancer, effectively starving the cancer of the oxygen and nutrients it requires to survive and grow. Avastin®, in combination with the chemotherapy drugs paclitaxel and carboplatin, is FDA-approved for the treatment of advanced, non-squamous NSCLC.2

EGFR: Mutations in the epidermal growth factor receptor (EGFR) gene may affect how NSCLC responds to certain drugs. EGFR contributes to the growth of several types of cancer, and drugs that block the activity of EGFR can slow cancer growth. One EGFR-targeted drug that has been shown to benefit selected patients with NSCLC is Tarceva® (erlotinib). Tarceva® is currently approved for the treatment of advanced NSCLC and as maintenance therapy after chemotherapy.3,4

EGFR mutations are most common in people of Asian ethnicity, women, never-smokers, and those with a type of lung cancer known as adenocarcinoma.  Researchers have reported that EFGR positive individuals treated with Tarceva® plus chemotherapy have delayed time to cancer progression and improved survival compared to those treated with chemotherapy alone.4

Xalkori™ (crizotinib): Up to 7% of NSCLC’s have an abnormal version of the ALK gene that contributes to the growth and development of cancer.  Xalkori™ is an oral medication that blocks certain proteins, including the protein produced by this abnormal gene. For advanced NSCLC that test positive for the ALK gene mutation, Xalkori™ has produced very promising rates of response and appears to have some activity treating cancer that has spread to the brain.5,6 A recent clinical trial involving 343 NSCLC patients with overactive ALK reported the results of individuals treated with Xalkori™ or a standard chemotherapy regimen using pemetrexed, and either carboplatin or cisplatin.  On average, individuals treated with Xalkori™, experienced control of their cancer for almost 11 months compared to only 7 months for those receiving the chemotherapy treatment regimen.  Xalkori™ treated patients also experienced a greater reduction in symptoms related to their cancer and improved quality of life.

Maintenance Therapy

Maintenance therapy refers to treatment that is given after initial treatment but before cancer progression. It is a relatively new approach to lung cancer treatment. Drugs that have been approved for maintenance therapy in selected patients include Alimta® (pemetrexed) and Tarceva®. For patients who are candidates for maintenance therapy, the approach has been shown to delay cancer progression and improve overall survival.7, 8

Treatment of Elderly Patients

Many NSCLC cases occur in people over the age of 70, but there is limited information about how best to treat older patients. As a result of the limited information and concern that elderly patients will not be able to tolerate aggressive treatment, older patients may be treated with single-agent chemotherapy rather than the combination chemotherapy that is commonly used in younger patients. Studies have suggested, however, that although combination chemotherapy increases side effects, it also improves survival among elderly patients.9

Managing Bone Complications

NSCLC cells commonly spread to the bone, causing bone metastases. Bone metastases may cause pain, bone loss, increased risk of fractures, and a life-threatening condition characterized by a high level of calcium in the blood, called hypercalcemia.

Preventing or delaying these skeletal-related events (SREs) can preserve quality of life and reduce healthcare costs. Bisphosphonate drugs such as Zometa® (zoledronic acid) and a newer type of bone drug, Xgeva® (denosumab) can be used to reduce the risk of complications from bone metastases.  Xgeva® is a drug that targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Xgeva® is approved for the prevention of bone complications such as fracture in patients with bone metastases from solid (not blood-related) cancers.

Xgeva® has been directly compared to Zometa® for the treatment of bone metastases in 702 with NSCLC and 109 with small-cell lung cancer (SCLC).  Xgeva® is associated with a decrease in SREs and improved overall survival when directly compared with Zometa.10

Managing Brain Metastases

When NSCLC spreads to the brain, it can symptoms such as headaches and seizures. Depending on the number, size, and location of the tumors in the brain, treatment may involve radiation therapy and/or surgery to remove the tumor.

Managing Pleural Effusion

In some patients with advanced NSCLC, fluid collects in the space around the lungs. This is called pleural effusion. The fluid can compress the lung and make it difficult to breath. If a patient is experiencing symptoms due to pleural effusion, the fluid may be drained using a catheter.

Strategies to Improve Non Small Cell Lung Cancer Treatment

The development of more effective treatment for advanced NCSLC requires that new and innovative therapies be evaluated with cancer patients. Future progress in the treatment of NSCLC will result from the continued evaluation of new treatments in clinical trials.

Patients may gain access to better treatments by participating in a clinical trial. Participation in a clinical trial also contributes to the cancer community’s understanding of optimal cancer care and may lead to better standard treatments. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician.

Areas of active investigation aimed at improving the treatment of lung cancer include some of the following:

New Drugs in Development: More-targeted and more-individualized treatments for NSCLC has recently became a reality. Results from studies evaluating ALK-inhibitors continued to show promise and initial studies exploring immunomodulatory approaches using anti-PD-1 antibodies demonstrated high response rates and slowed cancer progression in previously untreated stage IV NSCLC. The optimal approach to using these and other novel drugs has not been established and researchers continue to evaluate different ways of combining these drugs with each other and with other therapies in order to further improve outcomes.

The Lung-MAP Trial for Squamous Cell Carcinoma
In Lung-MAP (, researchers with several public institutions, including the National Cancer Institute (NCI), are working with pharmaceutical companies to study treatment for advanced squamous cell lung cancer. Though only a fraction (about a quarter) of all lung cancer diagnoses as squamous cell, it’s an important area of research, as there are few treatment options for these patients.

Lung-MAP will evaluate several investigational treatments and match patients with the therapy most likely to benefit them. Participants will undergo genomic profiling—a type of testing that provides information about all the genes in an organism, including variation, gene expression, and the way genes interact with each other and the environment. The drugs studied in Lung-MAP are designed to target genomic alterations involved in the growth of cancer, and researchers will use genomic profiling to match patients with the therapy designed to target the particular genomic alterations that their cancer expresses.

This more comprehensive approach marks a change in the typical clinical trial model for targeted therapies, in which separate studies for the same disease focus on particular genomic abnormalities and treatments. Potential participants are tested for that genomic biomarker (a molecule that is a sign of a normal or abnormal process or of a condition or disease), and only individuals who test positive are enrolled in the study. As a result, many patients are left out of each trial and—with multiple, separate trials—overall progress in treatment development is made less efficient.

In Lung-MAP, however, everyone who’s tested will be eligible for a therapy. And several treatments for advanced squamous cell lung cancer will be evaluated under one protocol in an effort to accelerate safe drug development.

X-396 iis a novel ALK inhibitor that is well tolerated and has antitumor activity in patients with ALK positive NSCLC. X-396 is being developed for the treatment of solid tumors where ALK is deregulated. X-396 has been validated in potency and selectivity assays indicating that it is more selective and up to 10 times more potent than competitive ALK inhibitors.

The interim results of one study have demonstrated that among 11 ALK positive patients evaluable for response 6 patients had a partial response (55%) and 2 had stable disease (18%). Of the three patients with progressive disease, and acquired resistance to Xalkori® anti-cancer activity was also observed.11

EGFR: Mutations in the epidermal growth factor receptor (EGFR) gene may affect how NSCLC responds to certain drugs. EGFR contributes to the growth of several types of cancer, and drugs that block the activity of EGFR can slow cancer growth. One EGFR targeted drug that is currently approved for the treatment of advanced NSCLC and as maintenance therapy after chemotherapy is Tarceva®.3, 4

Erbitux® (cetuximab) is another targeted therapy that has produced promising results in selected patients with NSCLC.12

Ganetespib is an investigational drug that targets a protein known as heat shock protein (Hsp) 90. Hsp90 is necessary for the function of several other proteins that are known to play an important role in lung cancer. In a Phase II clinical trial, second-line treatment with a combination of chemotherapy and the investigational drug ganetespib improved overall survival among patients with advanced lung adenocarcinoma.13

Cyramza™ (ramucirumab) is a targeted therapy that inhibits the growth of new blood vessels in tumors and, therefore, slows tumor growth. When combined with Taxotere®, Cyramza™ has been shown to extend overall survival and delay time to cancer progression14

Nintedanib is an angiokinase inhibitor that when combined with Taxotere® improves progression-free and overall survival in patients with NSCLC-adenocarcinoma.15


1 Chemotherapy for non small cell lung cancer:

2 Second Phase III Study of Avastin Plus Chemotherapy Shows Improved Progression-Free Survival in First-Line Non-Squamous, Non-Small Cell Lung Cancer. Available at:

3 Zhou C, Wu Y-L, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet Oncology. Early online publication July 22, 2011.

4 Cappuzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multi-center, randomized, placebo-controlled phase 3 study. The Lancet Oncology. Published early online May 20, 2010.

5 Solomon, B., et al. (2014). First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer New England Journal of Medicine, 371 (23), 2167-2177 DOI

6 Kwak EL, Bang Y-J, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. New England Journal of Medicine. 2010;363:1693-1703.

7 Ciuleanu T, Brodowicz T, Zielinski C et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-40

8 Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncology. 2010;11:521-529.

9 Quoix E, Zalcman G, Oster J-P et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. The Lancet. Early online publication August 9, 2011.

10 Scagliotti GV, Hirsh V, Siena S, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: Subgroup analysis from a randomized phase 3 study. Journal of Thoracic Oncology. 2012; 7(12): 1823-1829.

11 Horn L, Infante J, Blumenshcein G, et al. A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors. J Clin Oncol 32:5s, 2014 (suppl; abstr 8030^)

12 Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525-1531.

13 Ramalingam SS, Goss GD, Andric ZG et al. A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). Presented at the 49th Annual Meeting of the American Society of Clinical Oncology. May 31-June 4, 2013; Chicago, IL. Abstract CRA8007.

14 Perol M, et al. REVEL: A randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the second-line treatment of stage IV non-small cell lung cancer following disease progression after one prior platinum-based therapy. ASCO 2014; Abstract LBA8006.

15 Reck M, Kaiser R, Mellemgaard A, et al: Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The Lancet Oncology. 2014; 15(2): 143-155.

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