Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. After an NSCLC diagnosis, you and your health care team will discuss your treatment options. The initial treatments recommended for a condition are called first-line treatments. Treatments recommended if first-line therapies don’t work or stop working are second- or third-line treatments. This article will review the most common first-line treatments for NSCLC and the options your health care provider may recommend if they don’t work.

Selecting Your NSCLC Treatment Plan

Before you start NSCLC treatment, your health care team will run several tests to learn more about your cancer. These tests can help reveal factors that may influence your treatment, including:

• Your NSCLC subtype — including adenocarcinoma, squamous cell carcinoma, or large cell carcinoma
• The stage of your cancer
• If your cancer has metastasized (spread) and where
• What genetic mutations (changes) are in your cancer cells (called biomarkers)
• Your lung function

Your age, overall health, and personal preferences will also have an impact on the first-line therapy that’s right for you.

Surgery

Surgery to remove the tumor is usually a first-line therapy for people with early-stage NSCLC. If you have stage 0 or stage 1 NSCLC, surgery may be the only treatment you need. However, surgery may be considered even in some cases of stage 2 and early stage 3A NSCLC, depending on where the tumor is and your overall lung health. (Stages of cancer are sometimes also rendered with Roman numerals, e.g., “stage III” instead of “stage 3.)

NSCLC surgery involves removing part or all of a lung. How much lung tissue is removed depends on the location of your tumor and how large it is. If your lungs are healthy enough, your health care team may recommend removing more lung tissue to increase the chance of curing your cancer.

If you have stage 1B, 2, 3, or 4 NSCLC, you may receive other treatments before or after surgery to reduce the risk of recurrence (cancer coming back). Treatments you get before surgery are referred to as neoadjuvant treatments. You may receive neoadjuvant treatments to help shrink your tumor before surgery. Treatments given after surgery are called adjuvant treatments. Your health care team may recommend adjuvant treatments based on what they find during surgery.

Neoadjuvant and adjuvant therapies may include:

• Chemotherapy (chemo)
• Radiation therapy
• Immunotherapy
• Targeted therapies
• A combination of the above treatments

Chemotherapy

Chemotherapy is a treatment that helps kill tumor cells. Most types of chemo for NSCLC are given intravenously (directly into your vein). Sometimes, chemotherapy is combined with other treatments, such as radiation therapy or immunotherapy.

Chemotherapy treatment is given in cycles. After each cycle, you’re given time to rest and recover from the drugs. Cycles typically last three to four weeks, and each drug will have a different schedule. For example, you may receive the drug only on the first day of the cycle, and other medications may be given on multiple days or once every week. Other drugs may be given on days 1 and 8 or days 1, 8, or 15 of a cycle.

Early and locally advanced NSCLC is commonly treated with four to six cycles (of three to four weeks each) of chemotherapy. Chemotherapy can also be combined with other drugs to make the treatment more effective.

Several different types of chemotherapy are used in NSCLC, including:

• Platinum-based chemotherapies, including cisplatin and carboplatin
• Etoposide (Toposar)
• Gemcitabine (Gemzar)
• Paclitaxel
• Pemetrexed (Alimta)
• Taxotere, docivyx (Docetaxel)
• Vinorelbine (Navelbine)

If you have early-stage NSCLC, you may receive a combination of two chemo drugs. Usually, one of the drugs will be a platinum-based chemotherapy. You may only get one chemo drug if your health care team is concerned you may not tolerate two drugs. For most people with advanced NSCLC, platinum-based chemotherapies are first-line chemotherapy.

Radiation Therapy

Radiation therapy helps to kill cancer cells and shrink tumors using high-energy X-rays or particles. Health care professionals may recommend radiation therapy as a first-line therapy for some people with stage 3A and most patients with stage 3B NSCLC. It’s usually combined with other chemo and sometimes followed by immunotherapy or surgery. Radiation therapy may also be a second-line treatment if you can’t have surgery or don’t want surgery.

There are three main types of radiation therapy used for NSCLC:

• External beam radiation therapy — A machine focuses radiation from outside of your body toward the cancer.
• Brachytherapy — Also called internal radiation therapy, this type of radiation therapy places a radioactive substance directly onto the tumor.
• Proton therapy — This type uses particles called protons instead of X-rays, which may help reduce harm to nearby healthy tissue. Proton therapy may be used when protecting vital structures near the tumor is important.

Targeted Therapy

Targeted therapies are used to treat NSCLC with a particular genetic mutation or to stop new blood vessels from forming around the tumor (known as angiogenesis). Targeted therapies are most often used in people with advanced-stage NSCLC.

There are several types of targeted therapies for NSCLC, including:

• Vascular endothelial growth factor (VEGF) inhibitors — Such as bevacizumab (Avastin, Alymsys, Mvasi, Vegzelma, Zirabev) and ramucirumab (Cyramza)
• KRAS inhibitors — Such as sotorasib (Lumakras) and Adagrasib (Krazati)
• Epidermal growth factor receptor (EGFR) inhibitors — Such as afatinib (Gilotrif), erlotinib, dacomitinib (Vizimpro), gefitinib (Iressa), osimertinib (Tagrisso), and lazertinib (Lazcluze)
• ALK inhibitors — Such as alectinib (Alecensa), lorlatinib (Lorbrena), and ceritinib (Zykadia), Brigatinib (Alunbrig), and crizotinib (Xalkori)
• ROS1 inhibitors — Such as entrectinib (Rozlytrek), crizotinib (Xalkori), ceritinib (Zykadia), and repotrectinib (Augtyro)
• BRAF inhibitors — Such as dabrafenib (Tafinlar), encorafenib (Braftovi), and vemurafenib (Zelboraf)
• RET inhibitors — Such as selpercatinib (Retevmo) and pralsetinib (Gavreto)
• MET inhibitors — Such as capmatinib (Tabrecta) and tepotinib (Tepmetko)
• HER2-directed drugs — Such as fam-trastuzumab deruxtecan-nxki (Enhertu) and ado-trastuzumab emtansine (Kadcyla)
• TRK inhibitors — Such as larotrectinib (Vitrakvi) or entrectinib (Rozlytrek), repotrectinib (Augtyro)

Targeted therapies can be considered first-line treatment if you have a certain genetic mutation. For example, if you have a mutation in the ROS1 gene, entrectinib may be used as first-line therapy. Selpercatinib and pralsetinib may be considered first-line therapy in people with NSCLC that has metastasized with an RET mutation. Capmatinib and tepotinib are first-line treatment options for people with metastatic NSCLC and an MET gene mutation. If you have metastatic NSCLC with a mutation in the TRK gene, larotrectinib or entrectinib may be a first-line treatment option for you.

Immunotherapy

Immunotherapy drugs help activate your immune system to target and kill tumor cells. Immunotherapies are often used in neoadjuvant or adjuvant treatment regimens, as well as on patients with metastatic disease They can be used on their own or combined with chemotherapy.

A common treatment approach for NSCLC is immunotherapy with drugs called immune checkpoint inhibitors. These drugs work by blocking certain proteins in cancer cells that usually help the cancer hide from the immune system. By blocking these proteins, checkpoint inhibitors boost your immune system’s response against the tumor.

Two main types of immune checkpoint inhibitors used in NSCLC are PD-1 and PD-L1 inhibitors. PD-1/PD-L1 inhibitors work by blocking either PD-1 or PD-1L proteins. Examples include:

• Atezolizumab (Tecentriq)
• Cemiplimab (Libtayo)
• Durvalumab (Imfinzi)
• Nivolumab (Opdivo)
• Pembrolizumab (Keytruda)

CTLA-4 inhibitors are another type of immune checkpoint inhibitor that works by blocking the CTLA-4 protein. These medications aren’t used alone. They’re combined with a PD-1 inhibitor, with or without chemotherapy This regimen may be considered first-line therapy for some people with advanced-stage NSCLC. Examples include:

• Ipilimumab (Yervoy)
• Tremelimumab-actl (Imjudo)

Treatment Options When NSCLC Progresses or Comes Back

If you start NSCLC treatment with a first-line treatment option and your disease progresses or comes back, your health care team may discuss second- or third-line treatment options with you. The best choice for you depends on if and where the cancer has spread, how big the tumor is, and your treatment goals. Your prognosis (outlook) may vary depending on these factors and your response to treatment. Some people experience stretches of stability and enjoy a better quality of life.

Talk to your health care team about all of the treatment options available to you so you can make an informed decision about your care.

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