by Dr. C.H. Weaver M.D. updated 11/2022
The statistics may be familiar: lung cancer is the leading cause of cancer death among both men and women in the United States. Lung cancer kills more people than breast cancer, prostate cancer, and colorectal cancer combined.
The past few years, however, have brought some exciting new approaches to managing non–small cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer, and it’s become increasingly apparent that specific characteristics of the cancer can have a profound effect on the behavior of the cancer and its response to certain treatments. These characteristics include not only the particular type of cell involved but also the genetic makeup of the cancer.
Traditionally, lung cancers were defined by how they looked under the microscope into two broad categories. Small cell and non-small lung cancer (NSCLC). NSCLC further divided in squamous and non-squamous sub types. Treatment decisions were based solely on these classifications.
Doctors now understand that lung cancers may differ from one another based on what genes have mutations, and “genomic testing” can be performed on a biopsy sample of the cancer and sometimes with a "blood biopsy" to identify the specific genetic abnormality driving the growth of the lung cancer. Once the cancer driving mutation is identified a specific precision cancer medicine or immunotherapy can be developed to attack that specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Since 2015 over 15 new precision cancer medicines have been developed and approved for the treatment of specific lung cancer causing genetic mutations. Today all patients should undergo genomic biomarker testing at the time of diagnosis or lung cancer recurrence in order to determine if they have a treatable mutation or are eligible for participation in a clinical trial evaluating newer precision cancer medicines and immunotherapies.
Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.
Lung Cancer Biomarkers & Medicines to Target Them
Testing an individual’s lung cancer for specific biomarkers and genomic alterations allow doctors to identify cancer driving genetic mutations and offer the most personalized treatment approach utilizing precision medicines. Individuals with lung cancer should undergo genomic testing to determine whether newer precision cancer medicines are a treatment option.2,6,7
- NSCLC: EGFR, MET, ALK, TRK, RET, BRAF, ROS1 mutations can be treated with a specific precision cancer medicine.
- Squamous and non-squamous NSCLC with high levels of PD-L1 can benefit from treatment with immunotherapy.
PD-1 Checkpoint Inhibitors
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 an attack by the body’s immune cells. Checkpoint inhibitor drugs that block the PD-1 pathway 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.
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. A diagnostic test to measure the level of PD-L1 is available and checkpoint inhibitors are a standard treatment in the management of lung because they improve survival.8,9,10
- Keytruda® (pembrolizumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
- Tecentriq® (atezolizumab)
- Libtayo (cemipilimab)
The 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 several FDA-approved medications know as tyrosine kinase inhibitors (TKI) that block the activity of EGFR and slow cancer growth are now available.
EGFR mutations are most common in individuals who never smoked, woman, people of Asian ethnicity, and those with a type of lung cancer known as adenocarcinoma.11,12 There are several FDA approved TKI inhibitors and an expanding number of precision cancer medicines that target specific mutations in EGFRs including EGFR exon insertions and MET exon 14 skipping mutations.
- Tagrisso (Osimertinib)
- Tarceva (Erlotinib)
- Erbitux (Cetuximab)
- Iressa (Gefitinib)
- Gilotrif (Afatinib)
- Vectibix (Panutumamab)
ALK+ Lung Cancer: Approximately 5% of all NSCLC have an identified mutation referred to as the anaplastic lymphoma kinase (ALK) mutation. The ALK mutation is responsible for initiating and promoting cancer growth. Individuals with ALK+ lung cancer tend to be non-smokers or former light smokers; younger, and are a type of NSCLC referred to as adenocarcinoma (based upon the cells affected); and respond worse to standard chemotherapy regimens than patients who do not have the ALK mutation.13,14 There are several FDA approved medications that target ALK and others in development. Overview of ALK Inhibitors here
- Zykadia® (ceritinib)
- Alecensa (alectinib)
- Alunbrig (brigatinib)
- Xalkori (crizotinib)
- Alunbrig (brigatinib)
HER2 + Lung Cancer: Approximately 2-4% of patients with NSCLC over-express human epidermal growth factor-2 (HER-2), which is a protein displayed on the outside of a cell that is involved in cellular growth and replication. Over expression of HER-2 is implicated in the uncontrolled growth of cancer and Enhertu is FDA approved for treatment.33
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.14,20
- Rozlytrek (entrectinib)
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.16
- Zelboraf® (vemurafenib) BRAF V600E kinase inhibitor
- Tafinlar® (dabrafenib) BRAF V600E kinase inhibitor
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
- Mekinist® (trametinib) MEK V600 kinase inhibitor
- Cotellic® (cobimetinib) MEK V600 kinase inhibitor
A combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with a BRAF mutation. The combination of Taflinar plus Mekinist has been evaluated and FDA approved.16
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.17
MET + Lung Cancer: The mesenchymal-epithelial transition (MET) cancer driving mutation occurs in up to 5% of individuals with NSCLC and can be targeted with MET inhibitor medications.
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.18,19
- Vitrakvi (larotrectinib)
- Rozlytrek (entrectinib)
RAS is an oncogene —a gene that encodes proteins that function as switches to turn on various genes for cell growth and division. Mutations in the RAS genes result in permanently “turned on” switches that in turn result in uninhibited cell division, which can lead to cancer. There are three types of RAS oncogenes, designated NRAS, GRAS, and KRAS.
KRAS mutations are detected in approximately 15% to 30% of lung adenocarcinomas and analyses of two clinical trials shows that Keytruda immunotherapy is more effective than chemotherapy for treating NSCLC with KRAS including G12C mutations.31,32 Precision cancer medicines targeting KRAS and G12C where approved in mid 2021.
- Lumakras (sotorasib) irreversibly inhibits KRAS G12C which occurs in roughly 13% of NSCLC’s.
Immunotherapy for Lung Cancer
Precision immunotherapy treatment of NSCLC has also progressed considerably over the past few decades and is now a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. Doctors have been trying for years to find ways to harness an individual’s immune system to fight 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 mechanism that suppress the immune system which allow a cancer to grow.
Researchers are mainly focused on two promising types of immunotherapy. One type creates a new, individualized treatment for each patient by removing some of the person’s immune cells, altering them genetically to kill cancer, and then infusing them back into the bloodstream. This procedure has been pioneered mainly in the treatment of leukemia or lymphoma.
The second type of immunotherapy is a group of drugs that do not have to be tailored to each patient; these are called checkpoint inhibitors. These drugs block a mechanism, called a checkpoint, that cancer uses to shut down the immune system. These drugs have been approved by the US Food and Drug Administration (FDA) to treat several types of cancer, including NSCLC.8,9
Checkpoint inhibitors work on killer T-cells—the white blood cells that are often described as the soldiers of the immune system. T-cells have built-in brakes, or checkpoints, to turn them off and keep them from attacking normal tissue, which could result in autoimmune diseases. One checkpoint stops T-cells from multiplying; another weakens them and shortens their life span.
Several checkpoint inhibitors have already been approved for treatment of patients with more-advanced NSCLC, based on clinical trials showing they were superior to chemotherapy. Keytruda has shown prolonged survival and an increased time to cancer recurrence compared with standard chemotherapy in patients with newly diagnosed advanced NSCLC whose tumors expressed high levels of PD-L1.8
This is in contrast to the checkpoint inhibitor Opdivo, which, in another clinical trial in newly diagnosed patients, did not improve outcomes for PD-L1–positive NSCLC when compared with chemotherapy. This came as a bit of a surprise to many in the oncology community, but the results may be explained by the fact that the Opdivo trial did not require participants’ cancers to have as high a level of PD-L1 expression.9
Researchers suspect that checkpoint inhibitors might work better if they are combined with treatments that kill tumor cells because debris from dead cancer cells may help the immune system recognize its target. The immunotherapy combination of Opdivo + Yervoy for example prolongs survival compared to chemotherapy when used as initial treatment of NSCLC.
Checkpoint inhibitors and immunotherapy are not without side effects. In addition to causing lung inflammation, checkpoint inhibitors can lead to autoimmune disease, including colitis and rheumatoid arthritis, which result from an attack on other tissues by the revved-up immune system.
More-detailed and in-depth results of the recent clinical trials evaluating checkpoint inhibitors is forth coming, and this will provide better guidance regarding their optimal use in the treatment of NSCLC. Importantly, there are also ongoing clinical trials evaluating these and other novel targeted and immunotherapies for the management of NSCLC; patients should discuss the potential role of these trials with their treating physician.
- 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.
- 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: http://jco.ascopubs.org/content/32/32/3673. 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: http://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: 3. 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.
- 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.
- Chemotherapy for non small cell lung cancer:
- Lancet Oncol. 2019 May 20. Epub ahead of print.
- 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 at:.
- 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.
- 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.
- Liu S, et al. Targeting HER2 Aberrations in Non-Small Cell Lung Cancer with Osimertinib. Clin Cancer Res. 2018;24(11):2594-2604.