Treatment of Stage III B - IV Non-Small Cell Lung Cancer

Chemotherapy, biomarker testing and precision cancer medicines and immunotherapy are used to treat stage IIIB-IV NSCLC.

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 3/2019

Stage IIIB and stage IV non-small cell lung cancers (NSCLC) are considered advanced and may be found in both lungs, in the fluid that surrounds the lungs or heart, or have spread to other parts of the body such as the liver, brain, or bones.

Rarely some patients with advanced NSCLC have cancer that can be treated with surgery or radiation therapy however systemic therapy with precision cancer medicines, immunotherapy or chemotherapy has become the mainstay of treatment for most patients.

Advanced NSCLC has historically not been considered to be curable, however recent advances in genomics leading to the development of precision cancer medicine and immunotherapy have led to improved survival in selected patients well beyond what was expected just a few years ago. Advances in the use of newer precision cancer medicines is rapid and ALL individuals with NSCLC should undergo testing for biomarkers to determine if they can benefit from these newer drugs.1,2,3

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.

Precision Cancer Medicine & Immuno-oncology

Advances in precision cancer medicine that target the genetic makeup of the cancer and immuno-oncology (drugs that use your immune system to help fight cancer) have led to the approval of several new treatments that have improved the outcomes of individuals with NSCLC when compared with traditional chemotherapy.1 These targeted therapies are designed to treat only the cancer cells while minimizing damage to normal, healthy cells. The ability to test a patient’s cancer for unique biomarkers that can identify differences at the genetic level, and to make treatment decisions based on those differences, is the hallmark of precision medicine.1,2,3


Immunotherapy treatment of NSCLC has progressed considerably over the past few decades and has now become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer.

The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction, however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.

Checkpoint inhibitors are one kind of immunotherapy that has clearly improved the treatment of NSCLC. Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells.2Overall two thirds of lung cancer patients have some expression of PD-1, and one third are “high expressers” meaning over 50% of the tested tumor expresses PD-1. Keytruda® (pembrolizumab) and other checkpoint inhibitors appear superior to chemotherapy in patients with advanced NSCLC and clinical studies have demonstrated that patients with higher levels of the PD-L1 ligand tend to achieve greater benefit from treatment with compared to those with lower levels of PD-L1. A diagnostic test to measure the level of PD-L1 is available.1,2,3,4,5,6

Currently available checkpoint inhibitors:

  • Keytruda® (pembrolizumab)
  • Opdivo (nivolumab)
  • Imfinzi (durvalumab)
  • Tecentriq® (atezolizumab)

Other targeted treatments have emerged to match a person’s genetic makeup or a tumor’s genetic profile. As a result, all patients should undergo molecular testing for epidermal growth factor receptor (EGFR), the anaplastic lymphoma kinase (ALK) mutation, and the ROS1 mutation; the results of this testing can guide physicians in determining which therapies are more likely to be effective. In fact, guidelines now recommend molecular testing on a sample of the cancer taken during a biopsy so that the results can be considered before deciding on treatment.3


Lung Cancer Biomarkers

PD-1 & PD-L1: A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. Overall two thirds of lung cancer patients have some expression of PD-1, and one third are “high expressers” meaning over 50% of the tested tumor expresses PD-1.3

Epidermal growth factor receptor (EGFR): The EGFR pathway is a normal biologic pathway found in healthy cells. It is involved in regular cellular division and growth. However, certain mutations within the EGFR gene can lead to an overactive EGFR pathway, leading to the development and/or spread of cancer. These cancers are referred to as EGFR-positive, and there are several FDA-approved medications to block the activity of EGFR and slow cancer growth for EGFR-positive cancers. 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® (erlotinib) plus chemotherapy have delayed time to cancer progression and improved survival compared to those treated with chemotherapy alone.3,7,8

  • Tagrisso (osimertinib)
  • Tarceva (erlotinib)

Anaplastic Lymphoma Kinase (ALK) gene: Approximately 5% of all NSCLC’s have an ALK mutation. The ALK mutation is responsible for initiating and promoting cancer growth. Individuals with ALK+ NSCLC can be treated with precision cancer medicines that target this abnormality. Individuals with ALK+ lung cancer tend to be non-smokers or former light smokers; younger, have a type of NSCLC referred to as adenocarcinoma, and respond worse to standard chemotherapy regimens than patients who do not have the ALK mutation. Alecensa® (alectinib) and Xalkori (crizotinib) target ALK + NSCLC and recent studies have suggested that Alcensa may produce better outcomes.3,9,10

  • Zykadia® (ceritinib)
  • Alecensa (alectinib)
  • Xalkori (crizotinib)
  • Alunbrig (brigatinib)

ROS-1+ Lung Cancer: The ROS-1 mutation is an uncommon mutation found in only 1% of individuals with NSCLC. Research has indicated that the ROS-1 mutation plays a role in the development and progression of some lung cancers, and patient characteristics are similar to those who have ALK+ NSCLC.3

BRAF V600E mutation: The BRAF gene is known to play a part in cell growth, and mutations in BRAF are common in several types of cancer.

  • Tafinlar® (dabrafenib) and Mekinist® (trametinib) administered in combination.10


Chemotherapy is a systemic therapy that 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. Unlike precision cancer medicine chemotherapy doesn’t target specific cancer cells. It may affect normal cells leading to many side effects of 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).11

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.12

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.13

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.14,15

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.15 To learn more about bone metastases and bone health, go to the Bone Information Center.

Managing Brain Metastases

When NSCLC spreads to the brain, it can cause 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 Treatment

The progress that has been made in the treatment of NSCLC has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of NSCLC.

Precision Cancer Medicine: A targeted or precision therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Precision cancer medicines that “target” cancer cells offer the advantage of reduced treatment-related side effects and improved outcomes. Therapies directed at EGFR, ALK, PD-1, PD-L1, and BRAF have already improved the treatment of advanced NSCLC. How best to use these targeted medicines and the identification of new targets is ongoing. ALL NSCLC patients should undergo genomic testing in order to benefit from this area of active research.

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.

Epacadostat is a novel drug that blocks an enzyme called IDO1, which is implicated in the growth and spread of cancer cells. Investigators have theorized that the combination may be more effective than the use of either drug as a single agent.16

Ensartinib (X-396) is a novel ALK inhibitor that is well tolerated and has antitumor activity in patients with ALK positive NSCLC. Ensartinib is being developed for the treatment of solid tumors where ALK is deregulated.Ensartinib 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, all acquired resistance to Xalkori®.17

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®.2,5

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.18

Nintedanib is an angiokinase inhibitor that when combined with Taxotere® improves progression-free and overall survival in patients with NSCLC-adenocarcinoma.19

Next: Surgery for Non Small Cell Lung Cancer

Next: Radiation Therapy for Non Small Cell Lung Cancer

Next: Precision Cancer Medicine for Non Small Cell Lung Cancer


1 Merck’s KEYTRUDA® (pembrolizumab)Demonstrates Superior Progression-Free and Overall Survival Compared to Chemotherapy as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer [news release]. Merck website. Available at: June 16, 2016.

2 Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. New England Journal of Medicine. 2015;372(21):2018-20. Abstract. doi: 10.1056/ NEJMoa1501824.

3 Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. Journal of Clinical Oncology. 2014;32(32):3673-79. Available at: Accessed September 30, 2016.

4 Brahmer J, Reckamp KL, Bass P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. New England Journal of Medicine. 2015;373(2):123-35. Abstract. doi: 10.1056/NEJMoa1504627.

5 Borghaei H, Paz-Arez L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. New England Journal of Medicine. 2015;373(17):1627-39. doi: 10.1056/NEJMoa1507643.

6 Bristol-Myers Squibb Announces Top-Line Results from CheckMate -026, a Phase 3 Study of Opdivo (Nivolumab) in Treatment-Naïve Patients with Advanced Non-small Cell Lung Cancer [news release]. Bristol-Myers Squibb website. Available at:–026-a-Phase-3-Study-of-Opdivo-nivolumab-in-Treatment-Nave-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer/default.aspx. August 5, 2016.

7 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.

8 OSI Pharmaceuticals. FDA Approves Tarceva as a Maintenance Therapy for Advanced Non-small Cell Lung Cancer. Available at: 3. Accessed April 19, 2010.

9 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: 10.1056/NEJMoa1408440

10 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.

11 Chemotherapy for non small cell lung cancer:

12 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:.

13 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.

14 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.

15 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.


17 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)

18 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.

19 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.