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Understanding Immunotherapy And Side Effects In Advanced Lung Cancer

Treatment for lung cancer has changed significantly with immunotherapy, an expert said during the CURE® Educated Patient® Lung Cancer Summit.

An expert explained that the side effects associated with immunotherapy is different than chemotherapy in lung cancer.

For patients with advanced-stage non-small cell lung cancer (NSCLC), it's important to understand how immunotherapy works and the known side effects. An expert explained all of these key aspects during CURE®'s Educated Patient® Lung Cancer Summit.

"Treatment for advanced lung cancer has really evolved in the last two decades. Twenty years or so, the treatment used to be only chemotherapy," explained Dr. Jyoti Malhotra, director of thoracic medical oncology at the City of Hope Orange County, at the summit. "Today, [immunotherapy] is the treatment for advanced NSCLC when a patient is diagnosed."

How Immunotherapy Works in Lung Cancer

Before patients receive any treatment for NSCLC, Malhotra noted that it's important for the tumor to undergo proper testing.

"Patients should have testing done on the tumor for any molecular or genomic alterations. If identified, treatment with targeted therapy is the best approach," she said. "In patients whose tumor do not have a target identified, the approach then depends on PD-L1 expression measured in the tumor."

PD-L1 is a type of protein that maintains the body's immune responses, according to the National Cancer Institute. However, it may be found in abnormally high amounts on certain types of cancer cells. PD-L1 prevents T cells (immune cells) from killing cancer cells when it binds to PD-1, a type of protein found on T cells. Immune checkpoint inhibitors, a type of immunotherapy, bind to PD-L1 and block its binding from PD-1 to allow it to destroy the cancer cells.

"PD-L1 expression is a biomarker which predicts the response to immunotherapy," Malhotra added. "If [the PD-L1 expression] is high, patients can receive treatment with immunotherapy with a PD-1 or PD-L1 inhibitor. If it's low, then the recommended approach is a combination of chemotherapy and immunotherapy."

READ MORE: Imfinzi Plus Ceralsertib Addresses 'Major Unmet Need' in Lung Cancer

Improved Responses to Immunotherapy

In the initial trials that compared immunotherapy drugs to chemotherapy, Malhotra noted that patients demonstrated "durable responses" and continued to for years.

"So, the next step was to think if somehow immunotherapy can be combined with chemotherapy and moved into the first line setting or treatment for patients who are newly diagnosed," she said.

The phase 3 KEYNOTE-189 trial, Malhotra further explained, was the study that evaluated this approach. Patients with NSCLC who were untreated and recently received their diagnoses were divided into two groups in the trial. The first group received the immunotherapy drug, Keytruda, plus chemotherapy, said Malhotra. In the second group, patients were treated with placebo (inactive drug) plus chemotherapy.

"The results showed a large improvement in the survival of more than 11 months when the combination of chemotherapy and immunotherapy was used," Malhotra emphasized. "This became the new standard of care where all patients today — if they do not have a targetable mutation and are newly diagnosed — go and receive chemoimmunotherapy."

Of note, patients who had higher PD-L1 expressions experienced a greater benefit after receiving chemoimmunotherapy, Malhotra said. Still, patients — regardless of PD-L1 expression levels — benefited from chemoimmunotherapy, she explained.

Similarly, Malhotra said that chemoimmunotherapy is standard of care for patients with small cell lung cancer (SCLC) after results from the Impower133 and CASPIAN trials.

Side Effects and Safety With Immunotherapy

Patients may also have fewer side effects when treated with immunotherapy, Malhotra noted.

"The toxicities that we see with immunotherapy are a little bit different from chemotherapy because the mechanism of action of immunotherapy is different," she explained. "It does not cause acute or accumulative toxicities like we see with chemotherapy. The side effects from immunotherapy really happen because of an activated immune system."

It's important to note that having an activated immune system may "act against normal tissue," Malhotra said, and could also cause nonspecific inflammation in organs. Side effects related to inflammation may include pneumonitis (inflammation in the lung tissue), which often comes with symptoms such as coughing or shortness of breath.

Malhotra also explained that side effects associated with an activated immune system may not be observed immediately and start to emerge around two to three months after starting treatment.

"Another thing to remember is that the immunotherapy drugs do stay in the body for quite some time," she advised. "And even after that treatment has been stopped, the side effects from immunotherapy can manifest later or persist even after discontinuing the drug and therefore, it is important to keep that in mind."

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Stage 4 Lung Cancer

Lung cancer is a type of cancer that grows in your lung tissue. Stages of cancer span from 0-4, with stage 4 being the most advanced stage of lung cancer. Lung cancer is often diagnosed in the later stages because symptoms may be difficult to detect before stage 3 or 4. There are two main types of lung cancer—small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

Small cell lung cancer (SCLC) makes up about 10-15% of all lung cancer cases, and non-small cell lung cancer (NSCLC) makes up about 80-85% of lung cancer cases. SCLC tends to spread more rapidly beyond the lungs to other parts of the body. 

Lung cancer is the leading cause of cancer-related death in the United States. However, more research is being done every day to advance treatment and detect lung cancer sooner. Your healthcare team will create a treatment plan based on how advanced your cancer is. Treatment options for stage 4 lung cancer include chemotherapy, radiation therapy, and immunotherapy. 

An oncologist (a doctor who specializes in the diagnosis and treatment of cancer) will perform several tests to determine what stage, or how advanced, your cancer is. Knowing the stage of cancer helps them develop an effective treatment plan. The American Joint Committee on Cancer (AJCC) developed the TNM staging system to determine how advanced cancer is. The system is broken down into three factors: T for tumor: Measures the size and location of a cancerous tumor N for nodes: Determines if cancer cells have spread to the lymph nodes (a group of glands part of the immune system) M for metastasis: Assesses if cancer cells have spread (metastasized) beyond the lungs to other areas of the body The less advanced stages of lung cancer are stages 0-3. Stage 4 lung cancer means the cancer has spread to other parts of the body. There are two types of stage 4 lung cancer: stage 4A and stage 4B. Stage 4A usually means the cancer has spread to the chest, both lungs, the lining around your lungs (pleura), and the lining around your heart (pericardium). Stage 4B means the cancer has spread to one or more tumors outside of your chest or to other lymph nodes and organs. Both non-small cell lung cancer and small-cell lung cancer use the same staging system, though the system is generally not as important in SCLC. Instead, the cancer might be considered to be in a limited stage (cancer is only on one side of your chest) or an extensive stage (cancer has spread to other parts of your body). Stage 4 lung cancer develops when cancer cells from the lung spread to other parts of the body. The cancer cells can move in several ways, including growing into nearby tissue and passing through lymph node or blood vessel walls. Lung cancer is most commonly caused by smoking tobacco. Smoking is linked to 80% of lung cancer deaths in the U.S. Smoking cigars or menthol cigarettes and using chewing tobacco can also cause lung cancer. It is rare to be diagnosed with lung cancer if you have never smoked, but it's possible. Exposure to secondhand smoke, air pollution, and diesel exhaust can also cause lung cancer. Risk Factors There are several environmental and lifestyle risk factors for lung cancer. Depending on the environment you live or work in, you may be able to alter some of the following risk factors: Secondhand smoke: Being physically close to someone who is smoking increases your risk of lung cancer over time. Radon exposure: Radon is a radioactive gas found in soil and rocks. Consider conducting a radon test in your home to check for exposure. Asbestos exposure: People who work in mines, textile plants, and shipyards are at increased risk for asbestos exposure. Asbestos is a chemical commonly used to create commercial and industrial products.  Exposure to chemicals: Inhaling chemicals such as arsenic, beryllium, or diesel exhaust in work environments increases your risk of lung cancer. Beta-carotene supplements: People with a history of heavy smoking may have an increased risk of lung cancer if they take beta-carotene (a compound that gives plants their color) supplements. Radiation therapy: If you have received radiation therapy for another type of cancer, it may raise your risk of lung cancer.  Air pollution: People who live in cities with more air pollution with more exposure to things like diesel exhaust from cars are more likely to develop lung cancer.  Family history: If one of your family members has been diagnosed with lung cancer, your risk is higher.  With stage 4 lung cancer, you can experience the symptoms of lung cancer that people with less advanced stages might experience, as well as symptoms in other parts of your body based on where the cancer has spread. Common symptoms of lung cancer include: A bad cough Hoarse voice Chest pain The presence of blood when you cough Loss of appetite Unintended weight loss Shortness of breath Wheezing  Tiredness or weakness Chronic (long-term or repeated) respiratory infections like bronchitis and pneumonia Because stage 4 lung cancer affects other parts of the body, you may also experience: Bone pain, such as in your back or hips Yellowing of the skin and eyes (jaundice), if the cancer has spread to the liver Swollen lymph nodes in the neck or above the collarbone Headache, weakness or numbness in your arm or leg, dizziness, balance issues, seizures, and other nervous system changes if the cancer has spread to the brain Lung cancer can also cause syndromes as it spreads. For instance, cancer that spreads to nerves in the face can lead to Horner syndrome, which causes eyelid drooping. Other conditions that may occur include superior vena cava syndrome (cancerous tumors that grow in the upper right lung) and paraneoplastic syndrome (a group of syndromes that can affect organs that lung cancer cells have not yet spread to). Several tests help diagnose stage 4 lung cancer. When you develop symptoms of lung cancer, your healthcare provider will likely start by performing a physical exam and asking about your medical history. They will ask questions about the symptoms you are experiencing and any risk factors, such as smoking history. Diagnostic tests for lung cancer include: Blood tests: A complete blood count (CBC) can measure blood cells and tumor markers. Sputum markers: A test of saliva and phlegm can detect tumor markers. Lung biopsy: A small sample of lung tissue is taken and sent to a lab to be tested for cancer cells. Bronchoscopy: A healthcare provider inserts a tubed camera into the lungs to look for signs of cancer. Chest X-ray: Images of the lungs and chest cavity can identify abnormalities like tumors. Magnetic resonance imaging (MRI) scan: This test uses strong magnets to take X-ray pictures of the lungs at several angles. Computed tomography (CT) scan: This radiation test can locate the lung tumor and determine its size. People with a history of heavy smoking may benefit from regular lung cancer screenings with a low-dose CT scan. Positron emission tomography (PET) scan: This nuclear scan locates cancer cells throughout your body and determines how far lung cancer has spread. Several treatment options are available, but stage 4 lung cancer can be hard to cure. Your healthcare provider will discuss the ultimate goal of treatment, which may be to help prolong your life or to let you live more comfortably in the time you have left. The treatment plan will depend on how much your cancer has spread and which areas of the body are affected. Stage 4 NSCLC: Treatment may include a combination of surgery, chemotherapy, radiation therapy, targeted therapy, immunotherapy, photodynamic therapy, and laser therapy. Stage 4A: If the cancer has spread to just one other location, you might have surgery and radiation on the secondary location before treating the cancer in the lung. Stage 4B: If the cancer is more widespread, your treatment may begin with genetic testing. Tumors that test positive for certain gene mutations may have to receive targeted therapy (treatment that uses drugs to target specific molecules). Stage 4B NSCLC: If you have high levels of the PD-L1 protein, your healthcare provider may recommend immunotherapy. Immunotherapy drugs boost the immune response to cancer cells, which can attack the PD-L1 protein in cancerous tumors. Targeted therapy and immunotherapy may be given with chemotherapy (cancer cell-killing drugs are injected into your vein). Treatment for stage 4 SCLC typically does not include surgery or radiation, as they are usually ineffective. Chemotherapy and immunotherapy may improve your symptoms and prolong your life. If your symptoms are breathing-related, radiation may help improve your symptoms. Palliative Care With stage 4 lung cancer, it is not uncommon for the cancer to return even after a period of remission (symptoms of your cancer go away). Palliative care is a type of treatment that focuses on extending and improving your quality of life. The goal of palliative care is not to cure cancer but to ease the burden of symptoms from treatment. Palliative care is different from hospice or end-of-life care. This is supportive care that aims to improve symptoms and reduce pain or discomfort. Palliative care varies from person to person, depending on the toll the cancer takes on your body. Your healthcare provider may prescribe pain medications and anti-nausea medications to reduce symptoms related to the cancer and cancer treatments. If one of your symptoms is difficulty breathing, you may be given airway support and oxygen to open your airways and improve breathing. Experiencing cancer often affects your mental health. A solid support system is important throughout the treatment process. For this reason, your healthcare team may add emotional support and counseling to your palliative care. Most cases of stage 4 lung cancer are not curable. Your prognosis (how the cancer will behave in your body over time) depends on several factors: The type of lung cancer you are living with How the cancer is spreading Your age Your overall health before being diagnosed How your body responds to treatment When predicting outcomes, your healthcare team will consider the five-year survival rate. This estimates the percentage of people who will survive five years after diagnosis. The five-year survival rate is 9% for NSCLC and 3% for SCLC. Preventing all lung cancer cases may not be possible, but you can take steps to lower your risk. Although it can be challenging, quitting smoking can reduce your chances of developing lung cancer later in life. The risk of lung cancer can decrease 30-60% after 10 years of quitting smoking. For long-term smokers, it is also important to not take beta-carotene supplements. Check with your healthcare provider right away if you are experiencing common symptoms of lung cancer. Being diagnosed with stage 4 lung cancer can be a scary experience. A big part of living with stage 4 lung cancer is the palliative care you receive as you go through the treatment process. This can vary depending on multiple factors, including the type of lung cancer you are living with, your age, and how your cancer is progressing. Treatment for stage 4 lung cancer can be mentally taxing. Reach out to your healthcare provider or a loved one for emotional and mental health support if it is not already a part of your treatment plan. Although not many people with stage 4 lung cancer live for long, there are treatments available to extend your life.

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