Metastatic Non-Small Cell Lung Cancer

NCCN GUIDELINES FOR PATIENTS® 2021 Non-Small Cell Lung Cancer Metastatic

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NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 1 About

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American Lung Association Caring Ambassadors Free ME From Lung Cancer The American Lung Association strongly The Caring Ambassadors Lung Cancer As a lung cancer survivor and Vice President supports efforts to help ensure all patients Program is pleased to endorse these NCCN and CEO of Free ME From Lung Cancer, I facing lung cancer get the highest standard Guidelines for Patients: Lung Cancer. am pleased to endorse this vitally important of treatment and care. Helping patients Patients and their loved ones need reliable resource so that lung cancer patients can understand treatment guidelines is one resources to achieve the best possible have the information needed to make important step in empowering them to get outcomes for their disease. lungcancercap. informed decisions about their treatment. the care they want and need. That is why we org freemefromlungcancer.org are pleased to endorse NCCN’s efforts to provide accessible treatment guidelines and information to patients through the NCCN GO2 Foundation for Lung Guidelines for Patients. lung.org Clifton F. Mountain Foundation for Education Cancer and Research in Lung Cancer Founded by patients and survivors, GO2 American Lung Cancer The Clifton F. Mountain Foundation for Foundation for Lung Cancer, transforms Screening Initiative Education and Research in Lung Cancer survivorship as the world’s leading was created approximately 30 years ago organization dedicated to saving, extending, The American Lung Cancer Screening by Clifton F. Mountain, MD, who developed and improving the lives of those vulnerable, Initiative strongly advocates spreading the International System for the Staging at risk, and diagnosed with lung cancer. We awareness about the importance of lung of Lung Cancer while at M.D. Anderson work to change the reality of living with lung cancer screening for high-risk individuals. Cancer Center in Houston, Texas. The cancer by ending stigma, increasing public It is critical to help patients and healthcare Foundation’s primary function has been to and private research funding, and ensuring providers understand that increasing early educate physicians about application of the access to care. go2foundation.org detection of lung cancer through low- Staging System to lung cancer patients, and dose CT screening has been proven to be to emphasize that early detection of lung one of the easiest ways to combat lung cancer is key to the best outcomes possible. cancer. We are determined to empower Lung Cancer Research The Foundation has created and distributed Foundation high-risk individuals, especially those (worldwide) handbooks for physicians’ from disadvantaged backgrounds, and pockets, as a practical aid to proper staging. As a non-profit organization focused on provide them with accessible screening and The Foundation has a current interest in supporting lung cancer research, the Lung treatment options. Thus, we are proud to educating primary care providers to keep Cancer Research Foundation is proud to collaborate with the NCCN and endorse their lung cancer in their differential diagnoses. endorse the NCCN Guidelines for Patients. Guidelines for Patients. alcsi.org As President, Merel Mountain Nissenberg These guidelines play an important role in participates as the Advocate for the M.D. providing lung cancer patients with up to Anderson Lung Cancer SPORE; serves on date information and empowering them to the Lung Cancer Collaborative Group of the make informed decisions about their care. Early Detection Network of NCI; and is a lcrf.org participant in LungCAN.

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NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 3 NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 4 Metastatic Non-Small Cell Lung Cancer

Contents

6 Lung cancer basics

11 Tests for metastatic lung cancer

20 Treatment of driver mutations

30 Treatment by PD-L1 level

37 Treatment by cell type

46 Making treatment decisions

54 Words to know

58 NCCN Contributors

59 NCCN Cancer Centers

60 Index

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 5 1 Lung cancer basics

7 Types of lung cancer 8 Lung cancer stages 8 Metastatic lung cancer 10 Review

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 6 1 Lung cancer basics Types of lung cancer

Lung cancer starts in the cells of the Lung cancer is a cancer of lung cells. Other lungs. Non-small cell lung cancer is cancers that have spread to the lung are not the more common type of lung cancer. lung cancers. For example, breast cancer that Read this chapter to learn more about has spread to the lungs is still breast cancer. lung cancer, including metastatic lung cancer. Lung carcinomas Almost all lung cancers are carcinomas. Carcinomas are cancers of cells that line the inner or outer surfaces of the body. Lung Types of lung cancer carcinomas form from cells that line the airways of the lungs. The airways of the lungs The lungs are the main organs of the are called the bronchus, bronchioli, and alveoli. respiratory system. They deliver oxygen to Lung carcinomas are divided into 2 groups the blood and remove carbon dioxide from the based on how the cells look. blood. The transfer of these gases in and out of the body is called respiration. † Small cell lung cancer (SCLC)

† Non-small cell lung cancer (NSCLC)

Airways of the lungs

Air moves through your body in a series of airways. It travels down your throat and through the windpipe (trachea). The windpipe splits into 2 airways called bronchi. Inside the lung, each bronchus branches off into the parts of the lung, called lobes. The right lung has 3 lobes, and the left lung has 2 lobes. The bronchi divide into smaller airways called the bronchioli. At the end of the bronchioli are sacs called alveoli. Oxygen is transferred from air into the blood in the alveoli.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 7 1 Lung cancer basics Lung cancercancer stagesstages | Metastatic lung cancer

Non-small cell lung cancer of cancer cells in mucus and no detection of a NSCLC is much more common than SCLC. lung tumor. There are 3 main types of NSCLC. Stage 0 † Adenocarcinoma Stage 0 is rare. Abnormal or cancer cells † Squamous cell carcinoma have formed in the airways but haven’t grown into the lung tissue. Stage 0 is also called † Large cell carcinoma carcinoma in situ. Adenocarcinoma is the most common lung cancer. It often forms from cells that line the Stages 1 through 3 alveoli and make mucus. Squamous cells line Stage 1, stage 2, and stage 3 cancers have the bronchi. Large cell carcinoma forms from grown into lung tissue. Some have spread to any of the large cells that are throughout the nearby disease-fighting tissue called lymph airways. nodes. These cancers have not spread to body parts far from the lung tumor.

Stage 4 Lung cancer stages To be stage 4, lung cancer must have already spread far by the time of diagnosis. Lung The stage of the cancer describes the extent of cancer tends to travel to the brain and adrenal the cancer in the body. Doctors use it for many gland and from one lung to the other lung. things. It is used to assess the outlook of your Most lung cancers are stage 4. cancer called the prognosis. It is used to plan the right treatment. It is also used for research.

For some people, cancer staging is done twice. The staging assigned before any tissue Metastatic lung cancer (biopsy) testing is called the clinical stage. The The spread of cancer is called metastasis. second staging is called the pathologic stage When lung cancer has spread far from the first and is based on tissue tests. Cancer that is lung tumor, it is called metastatic lung cancer. outside of the lungs may not be found until after surgery. After diagnosis, stage 1, stage 2, or stage 3 lung cancer may metastasize to body parts Staging system far from the lung tumor. Stage 4 lung cancer The American Joint Committee on Cancer is metastatic lung cancer at diagnosis. This (AJCC) staging manual is used to stage lung book discusses treatment for metastatic lung cancer. The stages of NSCLC range from cancers. stage 0 to stage 4. Often, the stages are written with Roman numerals—stages 0, I, II, Learn more about stage 1 through 3 lung III, and IV. Occult carcinoma is a rare finding cancers that have not spread far in NCCN Guidelines for Patients: Early and Locally

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 8 1 Lung cancer basics Metastatic lung cancer

Advanced Non-Small Cell Lung Cancer, Symptoms available at NCCN.org/patientguidelines. Symptoms caused by metastatic NSCLC depend on where it is. Some signs and symptoms of metastatic lung cancer are:

† Trouble breathing, chronic cough, and chest pain

† Pain in bone or spine

† Yellowing of the skin or eyes called jaundice

† Constant feeling of a full stomach

† Headaches, dizziness, or seizures

† Weakness or numbness of arms or legs

† Fatigue and unexplained weight loss

Metastatic lung cancer

Lung cancer that has spread far from the main lung tumor is called metastatic lung cancer. All lung cancers that have spread outside the chest are metastatic lung cancers. Within the chest, distant sites include the tissue lining or fluid around a lung or heart. Lung cancer that has spread from one lung to the other lung is also metastatic lung cancer.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 9 1 Lung cancer basics Review

Treatment Review Metastatic lung cancer is not often treated with local treatment. Local treatment includes † The lungs help the body get the air it surgery, radiation therapy, and chemoradiation. needs to live. It may be an option if metastases are limited. † The lungs are made of many small An example is cancer spread to only the brain airways and sacs. or adrenal gland. Local treatments may also be used to reduce (palliate) symptoms caused by † Lung cancer often starts in the cells that a metastasis. line the airways. These cancers are called carcinomas. Most often, systemic therapy is used to treat † Lung cancer more often affects the metastatic lung cancer. Systemic therapy larger cells of the lungs. These cancers affects all cancer in the body. It can treat are called non-small cell lung cancer widespread metastases. Medical oncologists (NSCLC). are cancer doctors trained to use systemic therapy. The focus of this book is systemic † The cancer stage is a rating of the extent therapy for metastatic lung cancer. of the cancer. Stages of lung cancer range from stage 0 to stage 4. At this time, metastatic lung cancer is unlikely † Metastatic lung cancer has spread far to be cured. The aim of treatment is to reduce from where it started. It includes stage 1 symptoms, control the cancer, and extend through 3 lung cancers that have spread life. Newer treatments are better at controlling far after diagnosis. It also includes all the cancer and improving quality of life. Your stage 4 lung cancers. doctor will tailor treatment to you based on tests described in Chapter 2. † Most often, systemic therapy is used to treat metastatic lung cancer. Systemic therapy affects all cancer in the body. Treatment team A team of health care providers is involved in † There are newer treatments for metastatic diagnosing and treating lung cancers. Your lung cancer that better control the cancer primary doctor may be the first to suspect you and improve quality of life. have lung cancer and refer you to specialists. † A team of experts will work together with The diagnostic, treatment, and supportive you to diagnose and treat the cancer as care experts are explained throughout this well as support you. book. These experts are supported by nurses, technicians, and assistants, who are often on the frontline of cancer care. Patient navigators can help you through the maze of cancer care.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 10 2 Tests for metastatic lung cancer

12 Health history and exam 18 Supportive care 14 Blood tests 19 Review 14 Imaging 15 Biopsy vs. surgery 16 Cancer cell tests 17 Biomarker tests 18 Lung function tests

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 11 2 Tests for metastatic lung cancer Health history and exam

Not all metastatic lung cancers are the Health history and exam same. It is important to get the right tests to learn about the cancer and your Your cancer doctors need to have all of your health. Read this chapter to learn what health information. A complete report of your tests and other health care are needed health is called a medical history. Your doctor before treatment. will also perform a physical exam of your body. An exam is done to find signs of disease and decide which treatments may be options. See Guide 1 for a list of tests used for metastatic lung cancer.

Guide 1 Health tests and services for metastatic lung cancer • Medical history • Current or past smoking Health history and exam • Weight loss • Physical exam • Performance status

• CBC with differential Blood tests • Chemistry profile

• Diagnostic CT of the chest and upper abdomen Imaging • FDG PET/CT • Brain MRI

• Biopsy to remove tissue sample Cancer cell tests • Pathology review to assess for cancer and learn cancer cell type • Biomarker testing

• Spirometry Lung function tests • Gas diffusion test • Body plethysmograph

• Smoking treatment Services • Supportive care

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 12 2 Tests for metastatic lung cancer Health history and exam

Medical history Family history Your doctor will ask about any health problems Be prepared to discuss the health problems and treatments during your lifetime. When you of your close blood relatives. Such family meet with your cancer doctors, be ready to talk members include brothers, sisters, parents, about: and grandparents. Some cancers and other health conditions can run in families. † Illnesses

† Injuries Physical exam Cancer can spread to lymph nodes and cause † Health conditions them to swell. Your doctor will gently press † Symptoms on your body to assess their size. There are lymph nodes all over your body. Lung cancer † Medications often spreads to nodes in the chest and neck. Your doctor will ask about symptoms that may During this exam, also expect the following to be related to lung cancer. Such symptoms be checked: include cough, trouble breathing, chest pain, and weight loss. Early stages of lung cancer † Your body temperature may not cause symptoms. Symptoms in late stages depend where the cancer is. † Your blood pressure

† Your pulse and breathing rate Smoking † Your weight You can get lung cancer even if you never smoked. If you have lungs, you can get lung † How your lungs, heart, and gut sound cancer. Your doctors will ask about current and † How your eyes, skin, nose, ears, and past smoking to plan treatment. mouth look

Tell your doctors if you smoke or have smoked † The size of your organs in the past. Smoking is often measured by † Level of pain when you are touched packs per day and the number of years that you have smoked. Performance status If you do smoke, it is important to quit. Based on your history and exam, your doctor Smoking can limit how well cancer treatment will rate your performance status. Performance works. Nicotine addiction is one of the hardest status is your ability to do day-to-day activities. addictions to stop. The stress of having cancer Doctors use it to assess if you can undergo may make it harder to quit. There is help. Ask certain treatments. your health care providers about counseling and drugs to help you quit.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 13 2 Tests for metastatic lung cancer Blood tests

Blood tests assesses if the chemicals in your blood are too low or high. Abnormal levels can be caused by Blood tests measure blood cells, proteins, and spread of cancer or by other health problems. chemicals in the bloodstream. A blood draw removes a sample of blood for testing. It is done with a needle inserted into a vein. You may need to fast from food and most liquids for Imaging hours before the draw. Imaging makes pictures of the insides of your body. It can show cancer in deep tissue, lymph CBC with differential nodes, or distant body parts. A radiologist is a If not done recently, a complete blood count doctor who’s an expert in reading images. This (CBC) with differential is needed. A CBC doctor will convey the test results to your other measures parts of the blood including counts doctors. of white blood cells, red blood cells, and platelets. A differential measures the counts of Your doctors will use imaging results to plan each type of white blood cell and checks the where to biopsy and which treatment is best. balance of the counts. Cancer and other health Scans that were done more than 60 days ago problems can cause low or high blood counts. should not be used to decide your treatment.

Chemistry profile Chemicals in your blood come from your liver, bone, and other organs. A chemistry profile

Imaging

Pictures of the insides of your body can be made with imaging. During the scan, you will lie on a table that will move into the tunnel of the machine. The pictures will be viewed by a doctor who will look for signs of cancer.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 14 2 Tests for metastatic lung cancer Biopsy vs.

Diagnostic CT Biopsy vs. surgery Computed tomography (CT) makes a more detailed image than a plain x-ray. It takes many To diagnose lung cancer, a biopsy or surgery is pictures of your body from different angles used to remove bits of tissue for testing. Often, using x-rays. A computer then combines the tissue from the metastasis is removed rather pictures to make a 3-D image. than from the lung tumor. The tissue must be large enough to run several special lab tests. A diagnostic CT involves a higher dose of radiation and contrast. Contrast is a substance Your doctor may try to diagnose and stage the that is often injected into the bloodstream. It cancer at the same time. The body part that makes the images easier to read. For cancer likely has cancer and is farthest from the lung staging, images of your chest and upper tumor will be sampled and tested. By doing abdomen are needed. this, you’ll have fewer procedures.

Your doctor will use imaging results to select FDG PET/CT the biopsy site. This site is often the adrenal You will also need a PET/CT scan. PET is gland, liver, or bone. The type of biopsy that short for positron emission tomography. A will be done depends on the site. PET/CT scan may detect cancer that was not found by CT alone. † External needle biopsies involve guiding a thin needle through your skin and PET detects cancer with a radioactive sugar into the tumor. These biopsies include and special camera. The radioactive sugar, transthoracic needle aspiration (TTNA), called fluorodeoxyglucose (FDG), will be core needle biopsies, pericardiocentesis, injected into your vein. and thoracentesis.

Cancer quickly uses sugar so it appears † Down-the-throat biopsies involve “hot” in images. Other health problems can guiding tools down your throat into your also cause hot spots, too. Cancer detected windpipe or esophagus. These biopsies by PET/CT often needs to be confirmed with include radial endobronchial ultrasound biopsy or other imaging. (EBUS) bronchoscopy and endoscopic ultrasound (EUS)-guided biopsies.

Brain MRI † Portal surgeries involve making small Magnetic resonance imaging (MRI) uses openings (ports) into your chest. Small a magnetic field and radio waves to make tools are inserted through the ports to pictures. Contrast should be used. If you have remove tissue. These surgeries include or may have metastatic lung cancer, brain MRI thoracoscopy. is very important. It will show if the cancer has † Open surgery involves making a larger spread to your brain. cut through your chest wall to remove tissue. You may have open surgery when other methods won’t work or a larger piece of tissue is needed.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 15 2 Tests for metastatic lung cancer Cancer cell tests

Cancer cell tests Diagnosis Tissue removed during biopsy or surgery is sent to a doctor called a pathologist. Pathologists are experts in tissue and cells It takes a team to decide the best steps to and diagnosing cancer. In a lab, a pathologist diagnose lung cancer. Removing tissue for will look at the tissue with a microscope. If cancer testing is not always easy. Your team lung cancer is found, more tests will be done because not all lung cancers are alike. Lung may include the following experts: cancer differs by cell type and how the cells are abnormal. • Thoracic radiologist • Interventional radiologist Lab results used for diagnosis are included in a pathology report. This report will be sent to • Thoracic surgeon your cancer doctor. Ask for a copy. It is used to • Interventional pulmonologist plan your treatment. Your doctor will review the results with you. Take notes and ask questions. When planning, doctors think about the size and location of tumors, your health history, The pathologist will study the tumor to classify and their experience. They rely on the results the disease. This is called histologic typing. The pathology report will state if the cancer of the physical exam and imaging. started in the lung or elsewhere. If the cancer started in the lung, the report will also list the Test results will determine your treatment type of lung cancer. Cell (histologic) types of plan. Ask questions about and keep copies of lung cancer include: all your test results.

† Adenocarcinoma

† Large-cell lung carcinoma

† Squamous cell carcinoma

† Small cell carcinoma

† Mixed and rare types

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 16 2 Tests for metastatic lung cancer Biomarker tests

Biomarker tests become cancer cells and support cancer growth. Typically, cancer cells do not have Lung cancer differs between people by cell more than one driver mutation. type but also by abnormal cell changes. Changes in cancer cells affect treatment PD-L1 is a protein on the surface of cells. options and are called biomarkers. Because of PD-L1 on cancer cells stops T cells from killing biomarkers, a treatment that helps one person them. The cancer cells survive and make more might not help you. See Guide 2 for a list cancer cells. of biomarkers and which cancers should be tested for them. Most lung cancers do not have a known biomarker for which there is treatment. For lung cancer, there are 2 groups of Treatment options for these cancers are based biomarkers. on the lung cell type. Very few squamous cell carcinomas have a driver mutation. Biomarker † Driver mutations testing may be done if you’ve never smoked or the cancer is a mix of cell types. All lung † PD-L1 cancers should be tested for PD-L1. Driver mutations are also called driver Most often, biomarker testing is performed on oncogenes. They cause normal cells to tissue from the tumor. It is not the same as

Guide 2 Biomarker testing

Adenocarcinoma, large Squamous cell lung cancer cell, and rare lung cancers Driver mutation Sensitizing EGFR mutations ● ● ALK rearrangement ● ● ROS1 rearrangement ● ● BRAF V600E mutation ● ● NTRK gene fusion ● ● MET exon 14 skipping ● ● RET rearrangement ● ● Cell protein PD-L1 ● ● ● Testing is recommended ● Testing if needed

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 17 2 Tests for metastatic lung cancer Lung function tests | Supportive care

genetic testing, which assesses what a person Supportive care inherited from their parents. Supportive care aims to improve your quality of A second biopsy may be needed if the first life. It is also sometimes called palliative care. tissue sample is too small. Sometimes, a Supportive care is important for everyone, sample of blood may be used for biomarker not just people at the end of life. In fact, it has testing. A blood sample is referred to as a been shown to extend and enhance life for “liquid biopsy.” people with metastatic lung cancer.

Broad molecular profiling of all biomarkers is Supportive care can address many needs. It advised. There are other known biomarkers includes care for health problems caused by linked with lung cancer. However, they are rare cancer or cancer treatment. You can get help and related treatments are still being tested in with making treatment decisions. You can get clinical trials. help with coordination of care between health providers.

Your palliative care doctor will work with your Lung function tests oncologists to provide you the best care. Other specialists who may be involved in your care Surgery or radiation therapy may be treatment include: options for some metastatic cancers. First, your doctors will need to know how well your † Respiratory therapists lungs work. There are 3 pulmonary tests that † Rehabilitation specialists may be used to assess your lungs: † Registered dieticians † Spirometry involves blowing into a tube to † Social workers measure how much air and how fast you breathe.

† A gas diffusion test involves breathing in a harmless gas and measuring how much you breathe out. It tells how much oxygen travels from your lungs into your blood.

† Body plethysmograph involves sitting in a small room and breathing into a tube. This test measures how much air your lungs can hold and how much air is left in your lungs after you exhale.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 18 2 Tests for metastatic lung cancer Review

Review † Pulmonary function tests are needed if surgery or radiation therapy will be used † To plan treatment, your doctors need to for treatment. learn about the cancer and your health. † Start supportive care early. It has been † Be ready to tell your doctors about any shown to extend and enhance life for health problems and treatments you’ve people with metastatic lung cancer. had in your lifetime.

† Ask your doctor for help to quit smoking. Quitting may improve treatment results.

† Your doctors will examine your body for signs of disease. The exam will include touching parts of your body to see if anything feels abnormal.

† Your doctors will rate your ability to do day-to-day activities in order to decide your treatment options.

† Your doctors will order blood tests. Blood tests are used to look for signs of cancer.

† Diagnostic CT can help show where the cancer has spread. PET/CT may detect cancer that CT did not. MRI is used to see if the cancer has spread to your brain.

† A biopsy is needed to confirm that there is cancer. Doctors use imaging to decide what tissue should be removed and how best to remove it. Often, samples from the adrenal gland, liver, or bone are removed.

† A pathologist will study your tissue samples with a microscope. If there is cancer, the pathologist will identify the type of cell from which the cancer formed.

† Metastatic lung cancer should be tested for biomarkers to identify what is the best treatment for you. A treatment that helps one person might not help you. Most lung cancers do not have a known biomarker.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 19 3 Treatment of driver mutations

21 Driver mutations 22 Targeted therapy 22 Sensitizing EGFR mutations 24 ALK rearrangement 26 ROS1 rearrangement 26 BRAF V600E mutation 27 MET exon 14 skipping 28 Side effects 29 Review

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 20 3 Treatment of driver mutations Driver mutations

Driver mutations promote the growth of parts. Abnormal changes in genes are called cancer. They are most often found in mutations. adenocarcinomas and mixed cell types of lung cancer. Targeted therapy of A driver mutation causes normal cells to lung cancer stops the effects of driver become cancer cells. It enables the cancer mutations. cells to quickly duplicate, survive, and spread in the body. There are different types of driver mutations. Driver mutations are detected by biomarker testing of cancer cells and not Driver mutations genetic testing, which assesses inherited changes from parent to child. Genetic information tells your cells what to do. In lung cancer, a common driver mutation is a It is located in the nucleus of a cell and stored gene rearrangement. A gene rearrangement in 46 long strands of DNA. A gene is a small is also called a gene fusion. This term refers segment of DNA. DNA strands are carried and to one part of a gene switching places (fusing) protected in 23 chromosomes. with a part from another gene. The gene fusion produces an abnormal protein that promotes Abnormal changes in genetic information cancer growth. often occur in cancer cells. The DNA can be broken, missing, rearranged, or have extra

Genetic information

The nucleus is the control center or “brain” of cells. Within the nucleus is genetic information that tells the cells what to do. The information is stored in DNA. DNA looks like a twisted ladder when uncoiled from a chromosome. Genes are segments of DNA that contain “instructions” for the cell. Abnormal changes in genes that promote cancer growth are called driver mutations.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 21 3 Treatment of driver mutations Targeted therapy | EGFR mutations

Targeted therapy biomarker test results. If a driver mutation is found, you have two options: Targeted therapy is used to treat driver mutations of lung cancer. It treats cancer by † You may stop your current treatment early stopping the specific ways by which cancer and start targeted therapy. cells live, survive, and die. It harms fewer † The other option is to finish your current types of normal cells than chemotherapy, treatment (including the last phase called which destroys any type of fast-growing cell. maintenance treatment), and then start targeted therapy. Kinase inhibitors The most common type of targeted therapy for lung cancer is kinase inhibitors. They are pills that can be taken at home. Sensitizing EGFR mutations

Kinases are a type of cell protein. They are A surface receptor called EGFR can be part of many chemical pathways, some of overactive causing lung cells to quickly grow. which start cell growth. They are often part of Mutations in the gene that controls EGFR a structure called a surface receptor. Surface are common. Sensitizing mutations are the receptors are on the outer membrane of a cell. ones that cause overactive EGFR. First- They start changes within the cell when turned line treatment options for sensitizing EGFR on. mutations are listed in Guide 3.

Kinases change the action of other proteins by attaching phosphates to them. Kinase inhibitors stop cell growth signals by blocking Guide 3 the transfer of phosphates. This lowers the First-line treatment of sensitizing number of new cancer cells being made. EGFR mutations

VEGF antibodies Preferred options Cancer cells need blood to grow, so they • Osimertinib release a protein called VEGF. VEGF triggers endothelial cells to form new blood vessels Other options on tumors. VEGF antibodies stop VEGF, • Erlotinib and the cancer cells die from a lack of blood. • Afatinib You will need to go to a health care center to • Gefitinib receive VEGF antibodies through a slow drip • Dacomitinib (infusion). • Erlotinib and ramucirumab • Erlotinib and bevacizumab Switching to targeted therapy You may have started a treatment different than targeted therapy before getting

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 22 3 Treatment of driver mutations Sensitizing EGFR mutations

First-line treatment After first-line treatment Erlotinib (Tarceva®) and gefitinib (Iressa®) were Within a few years on first-line treatment, lung the first EGFR inhibitors used to treat lung cancer starts to grow again in most people. cancer. The second group of EGFR inhibitors You may get a biopsy: to be developed were afatinib (Gilotrif®) and dacomitinib (Vizimpro®). The newest EGFR † If the cancer grows while on erlotinib, inhibitor is osimertinib (Tagrisso®). afatinib, gefitinib, or dacomitinib, testing for a T790M mutation is advised. The All EGFR inhibitors have been found to work T790M mutation in the EGFR gene often well in well-designed clinical trials. Osimertinib occurs after taking these drugs. It stops is preferred because it stops cancer growth for the cancer drugs from working. A liquid a longer period of time. If your first treatment biopsy should be tried before a tumor was immunotherapy, a short delay in starting biopsy is done. osimertinib may be needed to prevent health † To rule out transformation to small cell problems. lung cancer, you may get a biopsy. Erlotinib is sometimes combined with a Treatment options depend on how the cancer VEGF antibody. VEGF antibodies include worsens. Your doctor will check for symptoms bevacizumab (Avastin®) and ramucirumab and if the cancer has spread to more places. (Cyramza®). It is not safe to receive Options are listed in Guide 4. bevacizumab if you are coughing up blood (hemoptysis).

Guide 4 Options after first-line treatment for sensitizingEGFR mutations

Local treatment of limited tumors may be helpful for some people

Stay on first-line treatment if it has some benefit • Stay on erlotinib, afatinib, gefitinib, or osimertinib unless the cancer is widespread • Stay on dacomitinib unless the cancer is in the brain or widespread

Switch to a different targeted therapy • Switch to osimertinib if the lung cancer cells have a T790M mutation • Switch to afatinib with cetuximab if cancer worsens while taking osimertinib

Start treatment for cell type as listed in Chapter 5

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 23 3 Treatment of driver mutations ALK rearrangement

If the cancer is not widespread, your doctor ALK rearrangement may recommend local treatment. It is used to treat cancer in a specific place like the brain A surface receptor called ALK can be or adrenal gland. In addition, EGFR inhibitors overactive causing lung cells to quickly will be used to control cancer growth. The type grow. The cause of ALK overactivity is a of local treatment received differs between rearrangement of the ALK gene. First-line people: treatment options for ALK rearrangements are listed in Guide 5. † Stereotactic radiosurgery (SRS) for brain tumors There are 5 ALK inhibitors used to treat lung cancer. Crizotinib (Xalkori®) was the first ALK † Surgery inhibitor used to treat lung cancer. The second † Stereotactic ablative radiotherapy (SABR) group of ALK inhibitors to be developed were ceritinib (Zykadia®), alectinib (Alecensa®), and † Image-guided thermal ablation therapy if brigatinib (Alunbrig®). The newest ALK inhibitor radiation therapy is not safe is lorlatinib (Lorbrena®). Despite the cancer worsening, first-line treatment may be slowing down cancer After first-line treatment growth. If this treatment is stopped, the cancer Within a few years of starting first-line may worsen quicker. Staying on first-line treatment, lung cancer starts to grow again treatment may be an option if the cancer isn’t in most people. Treatment options depend widespread. Your doctor may not keep you on on how the cancer worsens. Your doctor will dacomitinib if the cancer has spread to your brain. There is no research on dacomitinib for brain metastases. Guide 5 First-line treatment of ALK If first-line treatment stops working, switching rearrangement to a different targeted therapy may be an option. Your doctor may switch your treatment Preferred options to osimertinib if the lung cancer cells have a • Alectinib T790M mutation. • Brigatinib • Lorlatinib Your doctor may switch treatment to afatinib and cetuximab if you were taking osimertinib. Cetuximab stops growth signals from EGFR by Other options attaching to EGFR on the outside of cells. It is • Ceritinib received by infusion. Sometimes useful If targeted therapy is not likely to help, your • Crizotinib doctor may recommend other treatment. Treatment used for cell type may be an option. See Chapter 5.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 24 3 Treatment of driver mutations ALK rearrangement check for symptoms and order tests to see may worsen quicker. Staying on first-line if the cancer has spread to more places. treatment may be an option if the cancer isn’t Treatment options are listed in Guide 6. widespread. Crizotinib doesn’t work if the cancer has spread to your brain. The other If the cancer is not widespread, your doctor ALK inhibitors work better in the brain. may recommend local treatment. Local treatment is used to treat cancer in a specific If first-line treatment stops working, your place like the brain or adrenal gland. In treatment may be switched to a newer ALK addition, ALK inhibitors will be used to control inhibitor. Treatment may be switched to cancer growth. The type of local treatment lorlatinib if you’re on alectinib, brigatinib, or received differs between people: ceritinib. If on crizotinib, treatment may be switched to alectinib, brigatinib, ceritinib, or † SRS for brain tumors lorlatinib.

† surgery If ALK inhibitors are not likely to help, your † SABR doctor may advise other treatment. Treatment used for cell type may be an option. See † image-guided thermal ablation therapy if Chapter 5. radiation therapy is not safe

Despite the cancer worsening, first-line treatment may be slowing down cancer growth. If this treatment is stopped, the cancer

Guide 6 Options after first-line treatment ofALK rearrangement

Local treatment of limited tumors may be helpful for some people

Stay on first-line treatment if it has some benefit • Stay on alectinib, brigatinib, ceritinib, or lorlatinib unless the cancer is widespread • Stay on crizotinib unless the cancer is in the brain or widespread

Switch to a newer ALK inhibitor • Switch to lorlatinib if on alectinib, brigatinib, or ceritinib • Switch to alectinib, brigatinib, ceritinib, or lorlatinib if on crizotinib

Start treatment for cell type as listed in Chapter 5

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 25 3 Treatment of driver mutations ROS1 rearrangement | BRAF V600E

ROS1 rearrangement BRAF V600E mutation

A surface receptor called ROS can be A signaling protein inside of cells called BRAF overactive causing lung cells to quickly can be overactive causing lung cells to quickly grow. The cause of the overactivity is a gene grow. It is overactive due to a BRAF V600E rearrangement. Treatment options for ROS1 mutation. Treatment options for BRAF V600E rearrangements are listed in Guide 7. mutation are listed in Guide 8.

Entrectinib (Rozlytrek®) and crizotinib (Xalkori®) Preferred treatment is dabrafenib plus are preferred options. Entrectinib may work trametinib. Dabrafenib (Tafinlar®) stops growth better for lung cancer in the brain. The other signals from BRAF. MEK is a protein within the option is ceritinib (Zykadia®). same signaling pathway as BRAF. Trametinib (Mekinist®) stops growth signals from MEK. In time, the cancer will worsen after first-line treatment. Lorlatinib (Lorbrena®) may be an If dabrafenib plus trametinib makes you too option after first-line treatment. Entrectinib may sick, you may receive vemurafenib (Zelboraf®). be an option after crizotinib if the cancer has Vemurafenib also stops growth signals from spread to the spinal cord or brain. Treatment BRAF. If not received before, treatment used used for cell type may be an option. See for cell type may be an option. See Chapter 5. Chapter 5. In time, the cancer will worsen after first-line treatment. After targeted therapy, treatment used for cell type may be used to treat lung cancer. If not used before, dabrafenib plus Guide 7 trametinib may be started if the cancer Treatment of ROS1 rearrangement worsens on first-line treatment.

Preferred options • Entrectinib First-line • Crizotinib Guide 8 treatment Treatment of BRAF V600E mutation Other options • Ceritinib Preferred options • Dabrafenib plus trametinib • Lorlatinib Options after • Entrectinib first-line Sometimes useful treatment • Treatment for cell type as • Vemurafenib listed in Chapter 5 • Treatment for cell type as listed in Chapter 5

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 26 3 Treatment of driver mutations NTRK gene fusion | MET exon 14 skipping

NTRK gene fusion MET exon 14 skipping

Lung cells have a family of 3 surface receptors Some lung cancers have too much of a called TRK. NTRK genes contain instructions surface receptor called MET. Too much MET for making TRK. Some lung cancers have too causes fast cell growth. The cause of excess much TRK, which causes fast cell growth. The MET is a deleted (skipped) part of the MET cause of excess TRK is a joining (fusion) of gene called exon 14. Treatment options for NTRK with another gene. Treatment options MET exon 14 skipping are listed in Guide 10. for NTRK gene fusion are listed in Guide 9. MET inhibitors are preferred for first-line TRK inhibitors are preferred for first-line treatment. These treatments include capmatinib treatment of people with an NTRK mutation. (Tabrecta™) and tepotinib (Tepmetko®). These treatments include larotrectinib Crizotinib (Xalkori®) is useful for some people. It (Vitrakvi®) and entrectinib (Rozlytrek®). These inhibits MET and other kinases. If not received treatments have not been compared in before, treatment used for cell type may be research, but entrectinib may work better for an option. Treatment regimens are listed in lung cancer in the brain. If not received before, Chapter 5. treatment used for cell type may be an option. See Chapter 5. In time, the cancer will worsen after first-line treatment. After targeted therapy, treatment In time, the cancer will worsen after first-line for cell type may be used to treat lung cancer. treatment. After targeted therapy, treatment If not used before, targeted therapy may be used for cell type may be used to treat lung started if the cancer worsens on first-line cancer. If not used before, a TRK inhibitor may treatment. be started if the cancer worsens on first-line treatment.

Guide 9 Guide 10 Treatment of NTRK gene fusion Treatment of MET exon 14 skipping

Preferred options Preferred options • Larotrectinib • Capmatinib • Entrectinib • Tepotinib

Sometimes useful Sometimes useful • Crizotinib • Treatment for cell type as listed in Chapter 5 • Treatment for cell type as listed in Chapter 5

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 27 3 Treatment of driver mutations SideRET rearrangementeffects | Side effects

RET rearrangement Side effects

A surface receptor called RET can be All cancer treatments can cause unwanted overactive causing lung cells to quickly health issues. Such health issues are called grow. The cause of the overactivity is a gene side effects. Some side effects may be harmful rearrangement. Treatment options for RET to your health. Others may just be unpleasant. rearrangements are listed in Guide 11. Side effects depend on many factors. These RET inhibitors are preferred for first- factors include the treatment type, length or line treatment. These treatments include dose of treatment, and the person. selpercatinib (Retevmo™) and pralsetinib (Gavreto™). Cabozantinib (Cometriq®, Many effects of treatment quickly resolve after Cabometyx®) and vandetanib (Caprelsa®) treatment ends. Long-term effects start during are useful for some people. They inhibit RET treatment and persist after treatment is done. and other kinases but don’t work as well as Less often, effects start long after treatment preferred treatments. If not received before, has ended. treatment used for cell type is another option. See Chapter 5. Ask your treatment team for a complete list of side effects of your treatments. Also, tell In time, the cancer will worsen after first-line your treatment team about any new or worse treatment. After targeted therapy, treatment symptoms you get. There may be ways to help used for cell type may be an option. If not used you feel better. There are also ways to prevent before, targeted therapy may be started if the some side effects. cancer worsens on first-line treatment. NCCN has a patient guide on late and long- term effects of cancer and treatment. Such effects include fatigue, poor sleep, and heart disease. Guide 11 Treatment of RET rearrangement Read about common effects in Preferred options NCCN Guidelines • Selpercatinib for Patients: • Pralsetinib Survivorship Sometimes useful Care for Cancer- • Cabozantinib Related Late • Vandetanib and Long-Term Effects, available Other at NCCN.org/ • Treatment for cell type as listed in Chapter 5 patientguidelines.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 28 3 Treatment of driver mutations Review

Review

† A driver mutation causes normal cells to become cancer cells. It enables the cancer cells to quickly duplicate, survive, and spread in the body.

† Targeted therapy is used to treat driver mutations of lung cancer. Kinase inhibitors are the most common type of targeted therapy of lung cancer.

† Some people start treatment before We want your getting the results of biomarker testing. feedback! You could stay on your current treatment then take targeted therapy. A second Our goal is to provide helpful option is to switch from your current and easy-to-understand treatment to targeted therapy. information on cancer. † For each type of driver mutation there is at least one preferred targeted therapy Take our survey to let us and often other regimens. know what we got right and † When targeted therapy is not likely to what we could do better: help, you may start treatment for cell type. NCCN.org/patients/feedback † Ask your treatment team for a complete list of side effects of your treatments. Also, tell your treatment team about any new or worse symptoms you get.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 29 4 Treatment by PD-L1 level

31 Immune checkpoints 31 Immunotherapy 32 Treatment options 35 Side effects 36 Review

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 30 4 Treatment by PD-L1 level Immune checkpoints | Immunotherapy

Some people have lung cancer cells CTLA-4 and PD-1 are two types of brake that evade death by T cells. Read this pedals on T cells. chapter to learn more about this survival skill of cancer cells. Immunotherapy In people with lung cancer, the brake pedals restores the killing ability of T cells. on T cells may be overused. CTLA-4 is activated when attached to B7 on immune cells called dendritic cells. PD-1 is activated when attached to PD-L1 on lung cancer cells. Immune checkpoints With the brakes on, T cells are not able to kill cancer cells. The body’s defense against disease is called the immune system. T cells are a key part of this system. T cells that kill infected and cancer cells are called cytotoxic or killer T cells. Immunotherapy Immunotherapy is a treatment that uses The immune system has “brakes” that prevent the immune system to kill cancer cells. or slow down an immune response. The Immune checkpoint inhibitors are a type of brakes are called immune checkpoints. They immunotherapy. They work by releasing the protect the body’s healthy cells. Proteins called brake pedals on T cells.

Immunotherapy

Some lung cancers consist of cells that have PD-L1 on their surface. PD-L1 can attach to PD-1 on T cells and stop T cells from killing cancer cells. Immunotherapy stops PD-L1 from attaching. As a result, T cells are able to attack PD-1 inhibitor cancer cells. There are two types of immunotherapy. PD-1 inhibitors attach to T cells. PD-L1 inhibitors attach to cancer cells. PD-L1 inhibitor

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 31 4 Treatment by PD-L1 level Treatment options

There are 5 checkpoint inhibitors used to treat take it. For some people, immunotherapy may metastatic lung cancer: impair their immune system. Tell your doctor if you have an autoimmune disease, such as † Pembrolizumab (Keytruda®) Crohn’s disease, ulcerative colitis, or lupus. Bring a list of your medications to your health † Nivolumab (Opdivo®) care appointments. † Cemiplimab (Libtayo®)

† Atezolizumab (Tecentriq®)

† Ipilimumab (Yervoy®) Treatment options

These checkpoint inhibitors block proteins Immunotherapy options are partly based to keep the immune checkpoint turned off. on PD-L1. A pathologist will assess the Pembrolizumab, nivolumab, and cemiplimab percentage of cancer cells with PD-L1. A are PD-1 inhibitors. They attach to PD-1 on sample of a lung tumor is needed for testing. T cells and block PD-L1. Atezolizumab is a PD-L1 inhibitor. It attaches to PD-L1 on † High PD-L1 means that at least half of the cancer cells so PD-L1 can’t attach to T cells. cancer cells have PD-L1 (50% or more) Ipilimumab is a CTLA-4 inhibitor. It attaches to † Low PD-L1 means that less than half of CTLA-4 on T cells and blocks attachment to cancer cells have PD-L1 (1% to 49%) B7. † No PD-L1 means that fewer than 1 out of Checkpoint inhibitors are slowly injected into a 100 cells have PD-L1 (less than 1%) vein (infusion). It may take 30 or 60 minutes to get the full dose. Infusions are received every For lung cancer with PD-L1, see Guide 12 for few weeks. The number of weeks between a list of treatment options for adenocarcinoma, treatments depends on the inhibitor used. large cell, and rare lung cancer. Treatment Often, people get infusions until they stop options for squamous cell lung cancer are working and the cancer worsens. listed in Guide 13. Treatment of lung cancer with no PD-L1 is discussed in Chapter 5. Not all lung cancers should be treated with immunotherapy. Immunotherapy should First-line treatment not be the first treatment if the cancer cells Used alone, PD-1 inhibitors have good results have cancer-promoting (driver) mutations. for lung cancer with high PD-L1. Combining Cancers with driver mutations should first be PD-1 or PD-L1 inhibitors with chemotherapy treated with targeted therapy as described also has good results. It is standard treatment in Chapter 3. First-line targeted therapy has when PD-L1 is high or low. better results and causes less serious health problems. Platinum-doublet chemotherapy is used with checkpoint inhibitors. It consists of cisplatin Immunotherapy may also not be given if it may or carboplatin—drugs made with platinum— be unsafe. Some people may be too sick to and another type of chemotherapy. Choice of

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 32 4 Treatment by PD-L1 level Treatment options

Guide 12 First-line treatment options by PD-L1 level Adenocarcinoma, large cell, and rare types of lung cancer Preferred regimens Low PD-L1 High PD-L1 Pembrolizumab ● Atezolizumab ● Cemiplimab ● Pembrolizumab, carboplatin, and pemetrexed ● ● Pembrolizumab, cisplatin, and pemetrexed ● ● Other regimens Nivolumab, ipilimumab, carboplatin, and pemetrexed ● ● Nivolumab, ipilimumab, cisplatin, and pemetrexed ● ● Atezolizumab, carboplatin, paclitaxel, and bevacizumab ● ● Atezolizumab, carboplatin, and albumin-bound paclitaxel ● ● Sometimes useful Nivolumab with ipilimumab ● ● Pembrolizumab ●

Guide 13 First-line treatment options by PD-L1 level Squamous cell lung cancer Preferred regimens Low PD-L1 High PD-L1 Pembrolizumab ● Atezolizumab ● Cemiplimab ● Pembrolizumab, carboplatin, and paclitaxel ● ● Pembrolizumab, carboplatin, and albumin-bound paclitaxel ● ● Other regimens Nivolumab, ipilimumab, carboplatin, and paclitaxel ● ● Sometimes useful Nivolumab with ipilimumab ● ● Pembrolizumab ●

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 33 4 Treatment by PD-L1 level Treatment options

chemotherapy partly depends on the type of Maintenance treatment cancer cell. Platinum-doublet chemotherapy If treatment results are good, you may shift can cause health problems called side effects. to maintenance treatment, which includes You must be healthy enough to get this some of your first-line treatments. This is chemotherapy. called continuation maintenance. The goal of maintenance treatment is to prolong the Two checkpoint inhibitors, nivolumab and time until the cancer worsens. Options for ipilimumab, are used together to treat lung maintenance treatment are listed in Guide 14. cancer. They are given with platinum-doublet chemotherapy. Within a few years on first-line treatment, lung cancer starts to grow again in most people. Atezolizumab with platinum-doublet Options after first-line treatment are listed in chemotherapy is an option for non-squamous Chapter 5. cell cancers. Bevacizumab is a part of one atezolizumab regimen. It is a targeted therapy called a VEGF antibody. It stops the growth of blood vessels on tumors. Without blood, cancer cells die.

Guide 14 Maintenance treatment options by PD-L1 level

Adenocarcinoma, large cell, and rare lung cancers Low PD-L1 High PD-L1 Pembrolizumab ● ● Nivolumab and ipilimumab ● ● Atezolizumab ● ● Pembrolizumab and pemetrexed ● ● Atezolizumab and bevacizumab ● ● Cemiplimab ● Squamous cell lung cancer Pembrolizumab ● ● Nivolumab and ipilimumab ● ● Atezolizumab ● Cemiplimab ●

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 34 4 Treatment by PD-L1 level Side effects

Side effects

Immunotherapy can cause your immune cells to attack healthy cells in your body. This results in health problems called side effects. Learning to manage side effects is Immune-related side effects range from mild to well worth the effort! life-threatening. They can occur during or after treatment. Some side effects may worsen over the course of treatment, with each treatment – Jon dose. Most side effects can be managed if “ Lung cancer survivor found and treated early.

NCCN has a two-part book series on immunotherapy side effects. One book focuses on side effects of immune checkpoint inhibitors. It includes care options for many side effects, such as:

† Rash, itching, or blisters

† Fatigue

† Diarrhea

† Low or high hormone levels

† Lung inflammation

† Joint and muscle pain

† Heart inflammation

† Dry eyes

Read about managing side effects in NCCN Guidelines for Patients: Immunotherapy Side Effects, Immune Checkpoint Inhibitors, available at NCCN.org/patientguidelines.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 35 4 Treatment by PD-L1 level Review

Review

† The body’s defense against disease is called the immune system. T cells are part of this system. They kill cancer cells.

† Immune checkpoints keep immune responses in check. PD-1 and CTLA-4 are two types of immune checkpoints on T cells. † In people with lung cancer, PD-1 and Let us know what CTLA-4 are often activated and stop T cells from killing cancer cells. you think!

† Immune checkpoint inhibitors are a type of Please take a moment to immunotherapy. They prevent PD-1 and CTLA-4 from being activated. complete an online survey about the NCCN Guidelines † Immunotherapy options for lung cancer for Patients. are based on the level of PD-L1. PD-L1 is a protein on lung cancer cells that turns on PD-1. When PD-1 is activated, T cells do NCCN.org/patients/response not kill cancer cells.

† When PD-L1 is high, immunotherapy by itself can be used for treatment. Immunotherapy combined with chemotherapy is also standard treatment for low and high PD-L1.

† If treatment results are good, you may stay on some of them to increase the time until the cancer worsens. This is called maintenance treatment.

† Immunotherapy can cause your immune cells to attack healthy cells in the body. The immune-related health problems range from mild to life-threatening. Most of these health problems can be managed if found and treated early.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 36 5 Treatment by cell type

38 Cell type 39 Performance status 40 Systemic therapy 44 Clinical trials 45 Review

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 37 5 Treatment by cell type Cell type

Lung cancer differs between people There are 3 main types of lung cancer. They based on the type of cell affected. are named after the normal cell from which the Read this chapter to learn the best cancer formed: treatment options based on cell type. Treatment can be further improved † Lung adenocarcinoma with clinical trials. † Large cell carcinoma

† Squamous cell carcinoma Cell type Rare types of lung cancer are sometimes described as “not otherwise specified (NOS).” Most lung cancers do not have a known biomarker for which there is treatment. When there is no biomarker, treatment is based on other factors, such as:

† Type of cancer cell

† Performance status

† Health conditions and medications

Types of non-small cell lung cancer

There are 3 main types of lung cancer. Adenocarcinoma is the most common type. It is a cancer of mucus-making cells. Large cell carcinoma starts in large cells of the lung. Squamous cell carcinoma starts in squamous cells.

Credit: https://commons.wikimedia.org/wiki/ File:Mucinous_lung_adenocarcinoma_--_high_ mag.jpg

https://commons.wikimedia.org/wiki/File:Large_ cell_carcinoma_of_the_lung_.jpg

https://commons.wikimedia.org/wiki/File:Lung_ squamous_carcinoma_--_high_mag.jpg

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 38 5 Treatment by cell type Performance status

Performance status that is in many places and in hard-to-reach places. It is given in cycles of treatment days Performance status is your ability to do day- followed by days of rest. The cycles vary in to-day activities. Disease can limit what you length depending on which drugs are used. can do. Your doctors will use your performance status to decide what treatments are options A performance score of 3 or 4 suggests that for you. cancer drugs will be too harmful. NCCN experts advise receiving supportive care if The Eastern Cooperative Oncology Group the cancer does not have a driver mutation. (ECOG) Performance Status is a common Treatment of driver mutations is discussed in scoring system. It consists of five scores Chapter 3. ranging from 0 to 4. Lower scores represent a better ability to do self-care. See Guide 15 for Supportive care aims to improve your quality of treatment based on performance scores. life. It is sometimes called palliative care. One of its aims is to treat the symptoms caused Performance scores of 0 to 2 mean that by the cancer. Talk with your doctor about you are fairly healthy. NCCN experts advise supportive care to get the best care plan for receiving systemic therapy. Systemic therapy you. is a term for cancer drugs that travel in the bloodstream to the cancer. It can treat cancer

Guide 15 Performance status and treatment

Score Abilities Treatment

0 You are fully active. Systemic therapy

You are able to do self-care activities but unable to 1 Systemic therapy do hard physical work.

You are able to do self-care activities and spend 2 most of waking time out of bed. You are unable to do Systemic therapy any work.

You are unable to do self-care activities and any Supportive care if there is 3 work. You spend most of waking time in bed. no driver mutation

Supportive care if there is 4 You are fully disabled. no driver mutation

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 39 5 Treatment by cell type Systemic therapy

Systemic therapy treatment. Another option is gemcitabine with either docetaxel or vinorelbine. The classic treatment of widespread metastatic lung cancer is chemotherapy. Chemotherapy Bevacizumab is a part of some systemic is a term for drugs that kill rapidly dividing regimens. It is a targeted therapy called a cells. Newer treatments are sometimes used VEGF antibody. It stops the growth of blood with chemotherapy to improve control of the vessels on tumors. Without blood, cancer cells cancer. Treatment options for lung cancer die. without biomarkers are listed in Guide 16 and Guide 17. Sometimes, regimens with 2 chemotherapy drugs are not options. Instead, a single-agent chemotherapy may be given. There are First-line treatments several drugs that may be used: For performance scores of 0 or 1, chemotherapy with immunotherapy is standard † Albumin-bound paclitaxel treatment. The type of immunotherapy used is called immune checkpoint inhibitors. † Docetaxel Checkpoint inhibitors are used to treat lung † Gemcitabine cancer with PD-L1 as discussed in Chapter 4. They also extend life when lung cancer does † Paclitaxel not have PD-L1. There are 4 inhibitors used to † Pemetrexed (only for non-squamous cell treat lung cancer based on cell type: types)

† Pembrolizumab (Keytruda®) Side effects † Nivolumab (Opdivo®) All cancer treatments cause health problems † Atezolizumab (Tecentriq®) called side effects. Side effects from chemotherapy are caused by the death of † Ipilimumab (Yervoy®) fast-growing normal cells. Immune checkpoint inhibitors can cause your immune cells to Platinum-doublet chemotherapy is used with attack healthy cells in your body. checkpoint inhibitors for treatment. It consists of cisplatin or carboplatin—drugs made with Ask your treatment team for a complete list platinum—and another type of chemotherapy. of side effects of your treatments. Also, tell Choice of chemotherapy partly depends on the your treatment team about any new or worse type of cancer cell. symptoms you get. There may be ways to help you feel better. There are also ways to prevent Some people are not able to receive immune some side effects. checkpoint inhibitors. Checkpoint inhibitors may not be an option because of an autoimmune Read about immune-related side effects in disease, certain medicines, or higher NCCN Guidelines for Patients: Immunotherapy performance scores. In these cases, platinum- Side Effects, Immune Checkpoint Inhibitors. doublet chemotherapy is most often used for Fatigue, pain, and other side effects are

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 40 5 Treatment by cell type Systemic therapy

Guide 16 First-line systemic therapy by performance status (PS) Adenocarcinoma, large cell, and rare types of lung cancer Chemotherapy with immunotherapy PS 0 or 1 PS 2 (Carboplatin or cisplatin), pemetrexed, and pembrolizumab (preferred) ● Carboplatin, paclitaxel, bevacizumab, and atezolizumab ● Carboplatin, albumin-bound paclitaxel, and atezolizumab ● Nivolumab and ipilimumab ● (Carboplatin or cisplatin), pemetrexed, nivolumab, and ipilimumab ● Chemotherapy without immunotherapy Carboplatin, paclitaxel, and bevacizumab ● (Carboplatin or cisplatin), pemetrexed, and bevacizumab ● Cisplatin and another chemotherapy ● Carboplatin and another chemotherapy ● ● Gemcitabine and (docetaxel or vinorelbine) ● ● Single-agent chemotherapy ●

Guide 17 First-line systemic therapy by performance status (PS) Squamous cell lung cancer Chemotherapy with immunotherapy PS 0 or 1 PS 2 Carboplatin, paclitaxel, and pembrolizumab (preferred) ● Carboplatin, albumin-bound paclitaxel, and pembrolizumab (preferred) ● Nivolumab and ipilimumab ● Carboplatin, paclitaxel, nivolumab, and ipilimumab ● Chemotherapy without immunotherapy Cisplatin and another chemotherapy ● Carboplatin and another chemotherapy ● ● Gemcitabine and (docetaxel or vinorelbine) ● ● Single-agent chemotherapy ●

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 41 5 Treatment by cell type Systemic therapy

addressed in NCCN Guidelines for Patients: The goal of maintenance treatment is to Survivorship Care for Cancer-Related Late and increase the time until the cancer worsens. Long-Term Effects. Both patient guides are You may stay on maintenance treatment for available at NCCN.org/patientguidelines. 2 years if your first-line treatment included immunotherapy. If immunotherapy was part of second-line treatment, stay on maintenance treatment until the cancer worsens.

Options after first-line treatment In time, lung cancer often starts to grow again after first-line treatment. Preferred treatments include immune checkpoint inhibitors if not received before. If the cancer worsened while taking a checkpoint inhibitor, switching to another checkpoint inhibitor is not advised. Options after first-line treatment are listed in Guide 19.

Other options include docetaxel with Monitoring and maintenance ramucirumab. Ramucirumab is a targeted Systemic therapy is given in cyles of treatment therapy called a VEGF antibody. Single-agent days followed by days of rest. After 2 cycles, chemotherapy is another option. your doctor will assess the results. The extent of the cancer can be seen on computed Your doctor will monitor treatment results. tomography (CT) scans. Contrast may be You will get a CT scan every 6 to 12 weeks. used. CT will be repeated after another 2 to 4 Contrast may be used. cycles. In general, systemic therapy is given for 4 cycles. If treatment isn’t making you too sick, a total of 6 cycles may be completed.

If results are good at the end of treatment, you may stay on at least one of the medicines. This is called continuation maintenance. Another option is changing to a medicine that you didn’t take as a first-line treatment. This is called switch maintenance. Options for maintenance treatment are listed in Guide 18.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 42 5 Treatment by cell type Systemic therapy

Guide 18 Maintenance treatment by lung cell type

Continuation maintenance • Bevacizumab • Pemetrexed • Bevacizumab and pemetrexed • Pembrolizumab and pemetrexed Adenocarcinoma, large cell, and • Atezolizumab and bevacizumab rare types of lung cancer • Atezolizumab • Nivolumab and ipilimumab • Gemcitabine Switch maintenance • Docetaxel

Continuation maintenance • Nivolumab and ipilimumab • Gemcitabine Squamous cell lung cancer • Pembrolizumab Switch maintenance • Pemetrexed

Guide 19 Options after you’ve had chemotherapy with or without immunotherapy

• Nivolumab Preferred options • Pembrolizumab • Atezolizumab

• Docetaxel • Gemcitabine Other options • Ramucirumab and docetaxel • Pemetrexed (non-squamous only)

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 43 5 Treatment by cell type Clinical trials

Clinical trials Who can enroll? Every clinical trial has rules for joining, called Despite advances in treatment, more research eligibility criteria. The rules may be about age, is needed. There still is no cure for metastatic cancer type and stage, treatment history, or lung cancer. Improving treatment is made general health. These requirements ensure possible with clinical trials. that participants are alike in specific ways and that the trial is as safe as possible for the A clinical trial is a type of medical research participants. study. After being developed and tested in a laboratory, potential new ways of fighting Informed consent cancer need to be studied in people. If found Clinical trials are managed by a group of to be safe and effective in a clinical trial, a experts called a research team. The research drug, device, or treatment approach may team will review the study with you in detail, be approved by the U.S. Food and Drug including its purpose and the risks and Administration (FDA). benefits of joining. All of this information is also provided in an informed consent form. Read Everyone with cancer should carefully consider the form carefully and ask questions before all of the treatment options available for their signing it. Take time to discuss with family, cancer type, including standard treatments and friends, or others you trust. Keep in mind that clinical trials. Talk to your doctor about whether you can leave and seek treatment outside of a clinical trial may make sense for you. the clinical trial at any time.

Phases Start the conversation Most cancer clinical trials focus on treatment. Don’t wait for your doctor to bring up clinical Treatment trials are done in phases. trials. Start the conversation and learn about all of your treatment options. If you find a study † Phase I trials study the dose and safety that you may be eligible for, ask your treatment of an investigational drug or treatment team if you meet the requirements. Try not to approach. be discouraged if you cannot join. New clinical † Phase II trials study how well the drug or trials are always becoming available. approach works against a specific type of cancer. Frequently asked questions † Phase III trials test the drug or approach There are many myths and misconceptions against a standard treatment. If the surrounding clinical trials. The possible results are good, it may be approved by benefits and risks are not well understood by the FDA. many with cancer.

† Phase IV trials study the long-term What if I get the placebo? safety and benefit of an FDA-approved A placebo is an inactive version of a real treatment. medicine. Placebos are almost never used alone in cancer clinical trials. All participants

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 44 5 Treatment by cell type Review receive cancer treatment. You may receive a Review commonly used treatment, the investigational drug(s), or both. † Treatment for lung cancer without biomarkers is partly based on the cell Do I have to pay to be in a clinical trial? type. Rarely. It depends on the study, your health † Performance status is your ability to do insurance, and the state in which you live. Your day-to-day activities. Doctors use this treatment team and the research team can status to decide which treatments are help determine if you are responsible for any safe options. costs. † Systemic therapy consists of cancer drugs. It is recommended for a performance score of 0 through 2. Supportive care is recommended for scores 3 and 4.

† Chemotherapy with immunotherapy is standard treatment for fairly healthy people. Other options are chemotherapy Finding a clinical trial by itself or chemotherapy with bevacizumab. The cancer drugs selected for treatment are based on the cell type. In the United States † Learn about the side effects of your NCCN Cancer Centers treatments. Let your treatment team know NCCN.org/cancercenters about any new or worsening symptoms. † Your doctor will monitor the results of The National Cancer Institute (NCI) treatment. You may receive between 4 cancer.gov/about-cancer/treatment/clinical-trials/ and 6 cycles of treatment. search † Maintenance treatment slows down the Worldwide growth of the cancer. It consists of one or more drugs from your first treatment. The U.S. National Library of Medicine (NLM) clinicaltrials.gov/ † The next treatment options for lung cancer are immunotherapy if not received before, chemotherapy with ramucirumab, Need help finding a clinical trial? and single-agent chemotherapy. NCI’s Cancer Information Service (CIS) 1.800.4.CANCER (1.800.422.6237) † Clinical trials are a type of research. cancer.gov/contact New ways of fighting cancer are studied among people in clinical trials. A clinical trial may be an option in addition to standard treatment.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 45 6 Making treatment decisions

47 It’s your choice 47 Questions to ask your doctors 52 Resources

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 46 6 Making treatment decisions It’s your choice

It’s important to be comfortable with when considering options and making the cancer treatment you choose. This treatment decisions. choice starts with having an open and honest conversation with your doctors. Second opinion It is normal to want to start treatment as soon as possible. While cancer can’t be ignored, It’s your choice there is time to have another doctor review your test results and suggest a treatment plan. This is called getting a second opinion, and it’s In shared decision-making, you and your a normal part of cancer care. Even doctors get doctors share information, discuss the options, second opinions! and agree on a treatment plan. It starts with an open and honest conversation between you Things you can do to prepare: and your doctor.

† Check with your insurance company Treatment decisions are very personal. What about its rules on second opinions. There is important to you may not be important to may be out-of-pocket costs to see doctors someone else. Some things that may play a who are not part of your insurance plan. role in your decision-making: † Make plans to have copies of all your † What you want and how that might differ records sent to the doctor you will see for from what others want your second opinion.

† Your religious and spiritual beliefs Support groups † Your feelings about certain treatments like Many people diagnosed with cancer find surgery or chemotherapy support groups to be helpful. Support groups † Your feelings about pain or side effects often include people at different stages such as nausea and vomiting of treatment. Some people may be newly diagnosed, while others may be finished with † Cost of treatment, travel to treatment treatment. If your hospital or community doesn’t centers, and time away from work have support groups for people with cancer, † Quality of life and length of life check out the websites listed on page 52.

† How active you are and the activities that are important to you Questions to ask your doctors Think about what you want from treatment. Possible questions to ask your doctors are Discuss openly the risks and benefits of listed on the following pages. Feel free to use specific treatments and procedures. Weigh these questions or come up with your own. Be options and share concerns with your doctor. clear about your goals for treatment and find If you take the time to build a relationship with out what to expect from treatment. your doctor, it will help you feel supported

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 47 6 Making treatment decisions Questions to ask your doctors

Questions to ask about testing and staging

1. What tests will I have? Is biomarker testing needed?

2. Do I need a biopsy? What kind of biopsy do I need? Will enough tissue be removed for biomarker testing? What are the risks?

3. How do I prepare for testing?

4. What if I am pregnant?

5. Where do I go to get tested? How long will the tests take and will any test hurt?

6. Should I bring someone with me? Should I bring a list of my medications?

7. How soon will I know the results and who will explain them to me?

8. Would you give me a copy of the pathology report and other test results?

9. What type of lung cancer do I have? What is the stage? Has the cancer spread far?

10. Can this cancer be cured? If not, how well can treatment stop the cancer from growing?

11. Who will talk with me about the next steps? When?

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 48 6 Making treatment decisions Questions to ask your doctors

Questions to ask about treatment options

1. What are my treatment options? Are you suggesting options other than what NCCN recommends? If yes, why?

2. Do your suggested options include clinical trials? Please explain why.

3. What will happen if I do nothing?

4. How do my age, overall health, and other factors affect my options? What if I am pregnant or planning to get pregnant?

5. Does any option offer a cure or long-term cancer control? Are my chances any better for one option than another? Less time-consuming? Less expensive?

6. How do you know if treatment is working? How will I know if treatment is working?

7. What are my options if treatment stops working?

8. What are the possible complications? What are the short- and long-term side effects of treatment?

9. What can be done to prevent or relieve the side effects of treatment?

10. What supportive care services are available to me during and after treatment?

11. Can I stop treatment at any time? What will happen if I stop treatment?

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 49 6 Making treatment decisions Questions to ask your doctors

Questions to ask about clinical trials

1. Are there clinical trials for my type of cancer?

2. What are the treatments used in the clinical trial?

3. What does the treatment do?

4. Has the treatment been used before? Has it been used for other types of cancer?

5. What are the risks and benefits of this treatment?

6. What side effects should I expect? How will the side effects be controlled?

7. How long will I be in the clinical trial?

8. Will I be able to get other treatment if this doesn’t work?

9. How will you know the treatment is working?

10. Will the clinical trial cost me anything? If so, how much?

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 50 6 Making treatment decisions Questions to ask your doctors

Questions to ask about getting treated

1. Will I have to go to the hospital or elsewhere? How often? How long is each visit?

2. What do I need to think about if I will travel for treatment?

3. Do I have a choice of when to begin treatment? Can I choose the days and times of treatment?

4. How do I prepare for treatment? Do I have to stop taking any of my medicines? Are there foods I will have to avoid?

5. Should I bring someone with me when I get treated?

6. Will the treatment hurt?

7. What should I do if a side effect gets bad when my cancer center is closed?

8. How much will the treatment cost me? What does my insurance cover?

9. Will I miss work or school? Will I be able to drive?

10. Is home care after treatment needed? If yes, what type?

11. How soon will I be able to manage my own health?

12. When will I be able to return to my normal activities?

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 51 6 Making treatment decisions Resources

Resources National Coalition for Cancer Survivorship canceradvocacy.org/toolbox American Cancer Society cancer.org/cancer/lung-cancer.html NCCN Patient Resources NCCN.org/patients American Lung Association lung.org

American Lung Cancer Screening Initiative alcsi.org

Caring Ambassadors Program, Inc. lungcancercap.org share with us. Free ME from Lung Cancer freeMEfromLungCancer.org

GO2 Foundation for Lung Cancer go2foundation.org Take our survey And help make the Lung Cancer Alliance NCCN Guidelines for Patients lungcanceralliance.org better for everyone!

NCCN.org/patients/comments Lung Cancer Research Foundation lcrf.org

LUNGevity Foundation LUNGevity.org

National Cancer Institute (NCI) cancer.gov/types/lung

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 52 Ü Words to know

bronchioli Words to know Small airways within the lungs. bronchus adenocarcinoma One of the two main airways that extends into A cancer of cells that line organs and make the lungs. fluids or hormones. cancer stage adrenal gland A rating of the outlook of a cancer based on its A small organ on top of each kidney that growth and spread. makes hormones. carcinoma AJCC A cancer of cells that line the inner or outer American Joint Committee on Cancer surfaces of the body. alveoli chemoradiation The tiny sacs in the lungs where gases are A cancer treatment with both cell-killing drugs transferred in and out of the blood. and high-energy rays. anaplastic lymphoma kinase (ALK) chemistry profile A type of protein on the edge of a cell that A lab test of the amount of 8 chemicals in a sends signals for cell growth. sample of blood. Also called metabolic panel. biomarker chemotherapy Any molecule in your body that can be Cancer drugs that stop the cell life cycle so measured to assess your health. cells don’t increase in number. biomarker testing clinical stage Tests of any molecule in your body that can be The rating of the extent of cancer before measured to assess your health. Also called treatment is started. molecular testing. clinical trial biopsy A type of research that assesses how well A procedure that removes fluid or tissue health tests or treatments work in people. samples to be tested for a disease. complete blood count (CBC) board certified A lab test that measures the parts of the blood. A status for doctors who finished training in a computed tomography (CT) specialized field of medicine. A test that uses x-rays from many angles to body plethysmograph make a picture of the insides of the body. A test of how much air is in your lungs after continuation maintenance inhaling or exhaling. A treatment phase using one or more first-line bronchi drugs to prolong good treatment results. The two airways extending from the windpipe contrast into the lungs. A dye put into your body to make clearer pictures during imaging.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 54 Words to know core needle biopsy lymph node A procedure that removes tissue samples with A small, bean-shaped, disease-fighting a hollow needle. Also called core biopsy. structure. diagnosis magnetic resonance imaging (MRI) An identification of an illness based on tests. A test that uses radio waves and powerful magnets to make pictures of the insides of the DNA body. deoxyribonucleic acid maintenance treatment ECOG A treatment phase that is given to prolong Eastern Cooperative Oncology Group good treatment results. endobronchial ultrasound–guided medical history transbronchial needle aspiration (EBUS- A report of all your health events and TBNA) medications. A procedure that removes lung tissue with a needle on an imaging device guided down the metastasis windpipe. The spread of cancer from the first tumor to a new site. epidermal growth factor receptor (EGFR) A protein on the edge of a cell that sends mutation signals to the cell to grow. Abnormal changes in coded instructions within cells (genes). FDG fluorodeoxyglucose NCCN National Comprehensive Cancer Network gas diffusion A test that uses harmless gas to measure how non-small cell lung cancer (NSCLC) much you can breathe out. A cancer that starts in lung cells that are not small. gene Coded instructions in cells for making new NOS cells and controlling how cells behave. Not otherwise specified gene rearrangement pathologic stage A coded instruction within a cell that is made A rating of the extent of cancer based on tests from parts of other coded instructions. given after treatment. immunotherapy pathologist A treatment with drugs that help the body find A doctor who’s an expert in testing cells and and destroy cancer cells. tissue to find disease. large-cell lung carcinoma performance status A cancer of lung cells that lack features to A rating of one’s ability to do daily activities. classify as another type of lung cancer. pericardiocentesis lobe A procedure that removes fluid from around A clearly seen division in an organ. the heart with a needle.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 55 Words to know

physical exam side effect A review of the body by a health expert for An unhealthy or unpleasant physical or signs of disease. emotional response to treatment. platinum-doublet chemotherapy small cell lung cancer (SCLC) A treatment with two cell-killing drugs, one of A cancer of small, round lung cells. which contains the chemical platinum. spirometry positron emission tomography (PET) A test that uses a tube to measure how fast A test that uses radioactive material to see the you breathe. shape and function of body parts. squamous cell carcinoma positron emission tomography/computed A type of cancer of thin and flat cells that line tomography (PET/CT) the surface of organs. A test that uses two picture-making methods to stereotactic radiosurgery (SRS) show the shape and function of tissue. Treatment of a brain tumor with high-dose prognosis radiation within one or a few sessions. The likely course and outcome of a disease supportive care based on tests. Health care that includes symptom relief but pulmonary function tests not cancer treatment. Also sometimes called A set of breathing tests to test the strength of palliative care. the lungs. surgery radiation oncologist An operation to remove or repair a part of the A doctor who’s an expert in treating cancer body. with radiation. switch maintenance radiation therapy A treatment phase with a new drug that is A treatment that uses intense energy to kill given to prolong good treatment results. cancer cells. targeted therapy respiratory system A drug treatment that impedes the growth The group of organs that transfers gases in process specific to cancer cells. and out of the body. thoracic radiologist ROS1 A doctor who’s an expert in reading imaging A type of protein on the edge of a cell that tests of the chest. sends signals for cell growth. thoracoscopy stereotactic ablative radiotherapy (SABR) A procedure to do work in the chest with a Treatment with high-dose radiation within one device passed through a small cut in the skin. or a few sessions. Also called stereotactic Also called VATS. body radiation therapy (SBRT). trachea The airway between the throat and airway into the lungs. Also called the windpipe.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 56 Words to know transthoracic needle aspiration (TTNA) A procedure that removes tissue samples with a thin needle guided through the ribs. ultrasound A test that uses sound waves to take pictures of the inside of the body. vascular endothelial growth factor (VEGF) A molecule that triggers the growth of blood vessels.

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 57 NCCN Contributors

NCCN Contributors

This patient guide is based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer, Version 4.2021. It was adapted, reviewed, and published with help from the following people:

Dorothy A. Shead, MS Laura J. Hanisch, PsyD John Murphy Senior Director Medical Writer/Patient Information Specialist Medical Writer Patient Information Operations Stephanie Helbling, MPH, CHES® Erin Vidic, MA Rachael Clarke Medical Writer Medical Writer Senior Medical Copyeditor Susan Kidney Kim Williams Tanya Fischer, MEd, MSLIS Graphic Design Specialist Creative Services Manager Medical Writer

The NCCN Guidelines® for Non-Small Cell Lung Cancer, Version 4.2021 were developed by the following NCCN Panel Members: David S. Ettinger, MD/Chair Matthew A. Gubens, MD, MS Jose M. Pacheco, MD The Sidney Kimmel Comprehensive UCSF Helen Diller Family University of Colorado Cancer Center Cancer Center at Johns Hopkins Comprehensive Cancer Center *Sandip P. Patel, MD Douglas E. Wood, MD/Vice Chair Aparna Hegde, MD UC San Diego Moores Cancer Center Fred Hutchinson Cancer Research Center/ O’Neal Comprehensive Seattle Cancer Care Alliance Cancer Center at UAB Gregory J. Riely, MD, PhD Memorial Sloan Kettering Cancer Center Dara L. Aisner, MD, PhD Mark Hennon, MD University of Colorado Cancer Center Roswell Park Comprehensive Cancer Center Steven E. Schild, MD Mayo Clinic Cancer Center Wallace Akerley, MD Rudy P. Lackner, MD Huntsman Cancer Institute Fred & Pamela Buffett Cancer Center *Theresa A. Shapiro, MD, PhD at the University of Utah The Sidney Kimmel Comprehensive Michael Lanuti, MD Cancer Center at Johns Hopkins Jessica R. Bauman, MD Massachusetts General Hospital Fox Chase Cancer Center Cancer Center Aditi P. Singh, MD Abramson Cancer Center at the Ankit Bharat, MD Ticiana A. Leal, MD University of Pennsylvania Robert H. Lurie Comprehensive Cancer University of Wisconsin Center of Northwestern University Carbone Cancer Center James Stevenson, MD Case Comprehensive Cancer Center/ Debora S. Bruno, MD, MS Jules Lin, MD University Hospitals Seidman Cancer Case Comprehensive Cancer Center/ University of Michigan Rogel Cancer Center Center and Cleveland Clinic Taussig University Hospitals Seidman Cancer Cancer Institute Center and Cleveland Clinic Taussig Billy W. Loo, Jr., MD, PhD Cancer Institute Stanford Cancer Institute Alda Tam, MD The University of Texas Joe Y. Chang, MD, PhD Christine M. Lovly, MD, PhD MD Anderson Cancer Center The University of Texas Vanderbilt-Ingram Cancer Center MD Anderson Cancer Center Tawee Tanvetyanon, MD, MPH Renato G. Martins, MD, MPH Moffitt Cancer Center Lucian R. Chirieac, MD Fred Hutchinson Cancer Research Center/ Dana-Farber/Brigham and Women’s Seattle Cancer Care Alliance Jane Yanagawa, MD Cancer Center UCLA Jonsson Erminia Massarelli, MD Comprehensive Cancer Center Thomas A. D’Amico, MD City of Hope National Medical Center Duke Cancer Institute Stephen C. Yang, MD Daniel Morgensztern, MD The Sidney Kimmel Comprehensive Thomas J. Dilling, MD, MS Siteman Cancer Center at Barnes- Cancer Center at Johns Hopkins Moffitt Cancer Center Jewish Hospital and Washington University School of Medicine Jonathan Dowell, MD UT Southwestern Simmons Thomas Ng, MD NCCN Staff Comprehensive Cancer Center The University of Tennessee Health Science Center Kristina Gregory, RN, MSN, OCN Scott Gettinger, MD Vice President, Clinical Information Programs Yale Cancer Center/Smilow Cancer Hospital *Gregory A. Otterson, MD The Ohio State University Comprehensive Travis E. Grotz, MD Cancer Center - James Cancer Hospital Miranda Hughes, PhD Mayo Clinic Cancer Center and Solove Research Institute Oncology Scientist,/Seniior Medical Writer

* Reviewed this patient guide. For disclosures, visit NCCN.org/about/disclosure.aspx. NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 58 NCCN Cancer Centers

NCCN Cancer Centers

Abramson Cancer Center The Sidney Kimmel Comprehensive Stanford Cancer Institute at the University of Pennsylvania Cancer Center at Johns Hopkins Stanford, California Philadelphia, Pennsylvania Baltimore, Maryland 877.668.7535 • cancer.stanford.edu 800.789.7366 • pennmedicine.org/cancer 410.955.8964 www.hopkinskimmelcancercenter.org UC Davis Fred & Pamela Buffett Cancer Center Comprehensive Cancer Center Omaha, Nebraska Robert H. Lurie Comprehensive Sacramento, California 402.559.5600 • unmc.edu/cancercenter Cancer Center of Northwestern 916.734.5959 | 800.770.9261 University health.ucdavis.edu/cancer Case Comprehensive Cancer Center/ Chicago, Illinois University Hospitals Seidman Cancer 866.587.4322 • cancer.northwestern.edu UC San Diego Moores Cancer Center Center and Cleveland Clinic Taussig La Jolla, California Cancer Institute Mayo Clinic Cancer Center 858.822.6100 • cancer.ucsd.edu Cleveland, Ohio Phoenix/Scottsdale, Arizona 800.641.2422 • UH Seidman Cancer Center Jacksonville, Florida UCLA Jonsson uhhospitals.org/services/cancer-services Rochester, Minnesota Comprehensive Cancer Center 866.223.8100 • CC Taussig Cancer Institute 480.301.8000 • Arizona Los Angeles, California my.clevelandclinic.org/departments/cancer 904.953.0853 • Florida 310.825.5268 • cancer.ucla.edu 216.844.8797 • Case CCC 507.538.3270 • Minnesota case.edu/cancer mayoclinic.org/cancercenter UCSF Helen Diller Family Comprehensive Cancer Center City of Hope National Medical Center Memorial Sloan Kettering San Francisco, California Los Angeles, California Cancer Center 800.689.8273 • cancer.ucsf.edu 800.826.4673 • cityofhope.org New York, New York 800.525.2225 • mskcc.org University of Colorado Cancer Center Dana-Farber/Brigham and Aurora, Colorado Women’s Cancer Center | Moffitt Cancer Center 720.848.0300 • coloradocancercenter.org Massachusetts General Hospital Tampa, Florida Cancer Center 888.663.3488 • moffitt.org University of Michigan Boston, Massachusetts Rogel Cancer Center 617.732.5500 The Ohio State University Ann Arbor, Michigan youhaveus.org Comprehensive Cancer Center - 800.865.1125 • rogelcancercenter.org 617.726.5130 James Cancer Hospital and massgeneral.org/cancer-center Solove Research Institute The University of Texas Columbus, Ohio MD Anderson Cancer Center Duke Cancer Institute 800.293.5066 • cancer.osu.edu Houston, Texas Durham, North Carolina 844.269.5922 • mdanderson.org 888.275.3853 • dukecancerinstitute.org O’Neal Comprehensive Cancer Center at UAB University of Wisconsin Fox Chase Cancer Center Birmingham, Alabama Carbone Cancer Center Philadelphia, Pennsylvania 800.822.0933 • uab.edu/onealcancercenter Madison, Wisconsin 888.369.2427 • foxchase.org 608.265.1700 • uwhealth.org/cancer Roswell Park Comprehensive Huntsman Cancer Institute Cancer Center UT Southwestern Simmons at the University of Utah Buffalo, New York Comprehensive Cancer Center Salt Lake City, Utah 877.275.7724 • roswellpark.org Dallas, Texas 800.824.2073 214.648.3111 • utsouthwestern.edu/simmons huntsmancancer.org Siteman Cancer Center at Barnes- Jewish Hospital and Washington Vanderbilt-Ingram Cancer Center Fred Hutchinson Cancer University School of Medicine Nashville, Tennessee Research Center/Seattle St. Louis, Missouri 877.936.8422 • vicc.org Cancer Care Alliance 800.600.3606 • siteman.wustl.edu Seattle, Washington Yale Cancer Center/ 206.606.7222 • seattlecca.org St. Jude Children’s Research Hospital/ Smilow Cancer Hospital 206.667.5000 • fredhutch.org The University of Tennessee New Haven, Connecticut Health Science Center 855.4.SMILOW • yalecancercenter.org Memphis, Tennessee 866.278.5833 • stjude.org 901.448.5500 • uthsc.edu

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 59 Index Index

ablation 24–25 blood test 12, 14 biomarker testing 12 biopsy 12, 15, 23 cancer stage 8 chemoradiation 10 chemotherapy 32–34, 40–42 clinical trial 44–45 driver mutation 21 imaging 12, 14–15, 42 immunotherapy 31–35, 40–42 lung function test 12, 18 medical history 12–13 NCCN Cancer Centers 59 NCCN Contributors 58 pathology report 16 performance status 12–13, 39 physical exam 12–13 radiation therapy 10, 24–25 second opinion 47 side effect 28, 35, 40 smoking 12–13 surgery 10, 24–25 supportive care 12, 18 targeted therapy 22–28

NCCN Guidelines for Patients®: Metastatic Non-Small Cell Lung Cancer, 2021 60 Ü NCCN GUIDELINES FOR PATIENTS® Non-Small Cell Lung Cancer Metastatic

2021

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