by Dr. C.H. Weaver M.D. updated 6/2022
Stage IIIB and 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 will have cancer that can be treated with surgery or radiation therapy however systemic therapy with precision cancer medicines, immunotherapy or chemotherapy is 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 and immunotherapy is rapid and ALL individuals with NSCLC should undergo genomic testing for biomarkers to determine if they can benefit from these newer drugs. Testing can be done on tissue or from blood.1-4
General Treatment Guidelines
- A liquid biopsy should be performed upon initial evaluation of NSCLC because it may better help identify treatable mutations than tissue biopsy alone.
- Initial treatment of NSCLC in individuals with an identified genomic cancer driving mutation that can be targeted with a precision cancer medicine.
- Individuals with high levels of PD-1 or PD-L1 are treated with checkpoint inhibitor immunotherapy with or without chemotherapy.
- Individuals with low levels of PD-1 or PD-L1 are treated with chemotherapy plus checkpoint inhibitor immunotherapy.4
- Starting checkpoint inhibitor immunotherapy before knowing whether a cancer is positive for EGFR is dangerous - EGFR + patients who receive a checkpoint inhibitor can develop immune mediated lung inflammation (pneumonitis) which is associated with significant mortality.
Precision Cancer Medicines & Immuno-oncology
Precision immunotherapy treatment of NSCLC has progressed considerably over the past few decades and treatment with a "checkpoint inhibitor" has now become a standard initial treatment for patients without a "driver" mutation that can be targeted.
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 improved the treatment of NSCLC and become the initial standard treatment for individuals without an identifiable mutation. 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. Checkpoint inhibitors 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.2
Overall two thirds of lung cancer patients have some expression of PD-L1, and one third are “high expressers” meaning over 50% of the tested tumor expresses PD-1. A diagnostic test to measure the level of PD-L1 is available.1-8
NSCLC Treatment in Individuals with High PD-L1 and No Driver Mutation
Keytruda® (pembrolizumab) and other checkpoint inhibitors have been demonstrated to be superior to chemotherapy treatment when used as single agents in patients with advanced NSCLC and higher levels of the PD-L1 ligand. Five year survival rates of 23% have been achieved with Keytruda used as a single agent.1 The average patients experiences a response to Keytruda in about 2 months.
The combination of a checkpoint inhibitor + chemotherapy also prolongs survival compared to treatment with chemotherapy alone. Keytruda in combination with Alimta (pemetrexed) and cisplatin or carboplatin chemotherapy improves the response rate from 19% to 48%, delays cancer progression, and prolongs survival compared to treatment with chemotherapy alone.2
Currently available checkpoint inhibitors:
- Keytruda® (pembrolizumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
- Tecentriq® (atezolizumab)
NSCLC Treatment in Individuals with Low PD-L1 and No Driver Mutation
Chemotherapy drugs are a systemic therapy that kills rapidly dividing cells, a hallmark of cancer. Chemotherapy has been the main treatment for advanced NSCLC for many years. Unlike precision cancer medicines 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).17
The combination of chemotherapy and a checkpoint inhibitor is the standard initial treatment for NSCLC with low PD-L1 and no driver mutations that can be targeted because the combination improves survival compared to treatment with chemotherapy alone.17-20 Keytruda and Tecentriq when combined with chemotherapy have been shown to prolong survival compared to treatment with chemotherapy alone.
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.21
Targeting Specific "Driver" Mutations
Testing for EGFR, ALK, ROS1, BRAF, MET, RET, TRK, KRAS and other "driver" mutations is essential because precision cancer medicines have been developed to target each of these mutations.4
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. EGFR-targeted drugs that have been shown to benefit selected patients with NSCLC belong to a class of drugs known as tyrosine kinase inhibitors (TKIs). The drugs enter the cell and interfere with EGFR from within. There are several TKI's approved for the treatment of EGFR positive NSCLC and more in development.
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. Recent studies have suggested that Alcensa (alectinib) may produce better outcomes.3,9,11,13
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 and can be targeted with Xalkori.10
BRAF & MEK Kinase Inhibitors: The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Lung cancers may carry the BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Another mutation known as V600K may also be present. BRAF and MEK inhibitors are precision cancer medicines that block the activity of the V600E and V600K mutations respectively.11
- Zelboraf® (vemurafenib) BRAF V600E kinase inhibitor
- Tafinlar® (dabrafenib) BRAF V600E kinase inhibitor
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- Mekinist® (trametinib) MEK V600 kinase inhibitor
- Cotellic® (cobimetinib) MEK V600 kinase inhibitor
RET + Lung Cancer: Genetic alternations in the RET ( rearranged during transfection) receptor tyrosine kinase are present in 1-2% of NSCLC's and drive their development and growth.14
TRK + Lung Cancer: Tropomyosin receptor kinases (TRK) fusions are rare chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. (15,16)
- Vitrakvi (larotrectinib)
KRAS: KRAS mutations are detected in approximately 15% to 30% of lung adenocarcinomas and analyses of clinical trials shows that immunotherapy alone or combined with chemotherapy is more effective than chemotherapy for treating NSCLC with KRAS including G12C mutations. Precision cancer medicines targeting KRAS and G12C specifically are also now available.31,32,35
Treatment of Older Individuals
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
A study presented at the 2021 World Conference on Lung Cancer suggests age does not negatively impact survival benefit from Checkpoint Inhibitors with stage IV NSCLC. Researchers analyzed 86,173 patients with stage IV NSCLC--24,136 patients were age 75 and older and 62,037 patients were under age 75 and confirmed the survival benefit from ICIs for patients 75 years of age and older and that chronological age does not appear to impact the survival benefit of ICIs in stage IV NSCLC.34
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® and Tarceva® (erlotinib). For patients who are candidates for maintenance therapy, the approach has been shown to delay cancer progression and improve overall survival.9,23 Learn more...
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 Xgeva® (denosumab) can be used to reduce the risk of complications from bone metastases.
Xgeva® has been directly compared to Zometa® for the treatment of bone metastases in 702 individuals with NSCLC and 109 with small-cell lung cancer (SCLC). Xgeva® was found to be associated with a decrease in SREs and improved overall survival when directly compared with Zometa.24
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, surgery or medication. Some but not all systemic therapies cross the "blood-brain" barrier and can shrink the cancer. About 30% of NSCLC's that express PD-1 respond to Keytruda treatment.33
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.
Identification of Driver Mutations: Researchers have already identified several genetic mutations that "drive" the growth of lung cancer. Specific medications have been developed to target the EGFR, ALK, ROS1, BRAF, MET, RET, TRK "driver" mutations. Researchers continue to look for new mutations that can be targeted and several targeted therapies are being evaluated in clinical trials to determine their effectiveness.
Refining the use of Checkpoint Inhibitors: There is ongoing research to determine how best to use checkpoint inhibitors for the treatment of NSCLC. Checkpoint inhibitors may work better in some PD-L1 positive cancers that others. For example the tumor mutational burden (TMB) is a measurement of the mutations carried by tumor cells and a higher TMB is associated with greater response to treatment.30
The Lung-MAP Trial for Squamous Cell Carcinoma
In Lung-MAP (Lung-MAP.org), 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.
- Reck M, et al "Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non -- small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater" J Clin Oncol 2019; DOI: 10.1200/JCO.18.00149.
- 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.
- Merck’s KEYTRUDA(R) (pembrolizumab) Significantly Improved Overall Survival and Progression-Free Survival as First-Line Treatment in Combination with Pemetrexed and Platinum Chemotherapy for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (KEYNOTE-189)
- 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 here. Accessed September 30, 2016.
- 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.
- 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.
- 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: investor.bms.com/investors/news-and-events/press-releases/press-release-details/2016/Bristol-Myers-Squibb-Announces-Top-Line-Results-from-CheckMate–026-a-Phase-3-Study-of-Opdivo-nivolumab-in-Treatment-Nave-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer/default.aspx. August 5, 2016.
- 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.
- OSI Pharmaceuticals. FDA Approves Tarceva as a Maintenance Therapy for Advanced Non-small Cell Lung Cancer. Available at: investor.osip.com/releasedetail.cfm?ReleaseID=460783. Accessed April 19, 2010.
- United States Food and Drug Administration (FDA). FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. Available at: . Accessed March 11, 2016.
- FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation
- 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
- 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.
- Gainor JF, et al. Abstract 9008. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
- Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children
- Entrectinib Granted Priority Review by FDA for NTRK+ Tumors and ROS1+ NSCLC
- Chemotherapy for non small cell lung cancer
- Lancet Oncol. 2019 May 20. Epub ahead of print.
- FDA Approves Merck’s KEYTRUDA® (pembrolizumab) as First-Line Combination Therapy with Pemetrexed and Carboplatin for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC), Irrespective of PD-L1 Expression
- Abstract LBA1_PR ‘Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150)‘ will be presented by Martin Reck during the Proffered Paper session ‘Combining immune checkpoint inhibitors and VEGF targeted therapies in cancer treatment’ on Thursday, 7 December, 18:15 to 19:15 (CET) in Room A. Annals of Oncology, Volume 28, 2017 Supplement 11.
- Second Phase III Study of Avastin Plus Chemotherapy Shows Improved Progression-Free Survival in First-Line Non-Squamous, Non-Small Cell Lung Cancer. Available here.
- 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.
- 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.
- 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.
- 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)
- 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.
- 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.
- Ramalingam S. Abstract CT078. Presented at American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
- LBA4 - Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in KEYNOTE-042.
- Gadgeel S, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC.
- Lancet Oncol. 2020 May;21:655-663).
Nakajima EC, Ren Y, Vallejo JJ, et al. Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis. Presented at ASCO 2022; June 3-7, 2022. Abstract 9001.