Lung cancer remains the leading cause of cancer-related deaths in men and women, accounting for 1 in every 4 deaths caused by cancer in the United States, according to the American Cancer Society. However, recent advances in immunotherapy treatment for lung cancer—especially for the type of lung cancer known as non–small-cell lung cancer (NSCLC)—are giving hope to patients living with this disease.
So far, 3 checkpoint inhibitors have been approved by the FDA for NSCLC since March 2015, and many new immunotherapy drugs are now in development. In addition, researchers are studying the possibility of using other drugs or chemotherapies together with immunotherapy drugs, as well as the combination of 2 immunotherapy drugs together, as potentially the best way to prolong survival and improve outcomes for patients with lung cancer.
“Immunotherapy is a powerful new tool that we are just learning how to best use for treating lung cancer. It is really important that we do the clinical trials that will tell us which immunotherapy agents or combinations are right for individual patients,” says David P. Carbone, MD, PhD, Barbara J. Bonner Chair in Lung Cancer Research, and Director, James Thoracic Center, Ohio State University Comprehensive Cancer Center, Columbus.
Why Is Immunotherapy Successful in Lung Cancer?
Initially, lung cancer was considered a non-immunogenic cancer type, because it had not responded well to immunotherapy that was meant to stimulate the growth of immune cells and control the growth of cancer cells.1 However, with increased understanding of the immune system and its relation to malignant tumors, researchers discovered that tumors were actively inhibiting the immune response at certain “checkpoints,” and inhibitors of these checkpoints had the ability to amplify the body’s immune response to cancer cells. This discovery opened the door to immunotherapy drugs for patients with lung cancer.
Checkpoint inhibitors are therapies that “release the brakes” on the immune system. One caveat is that there needs to be an underlying immune response already in place for checkpoint inhibitors to be effective. According to the National Cancer Institute, tumors with genomic mutations (alterations) are more likely to have that underlying immune response. Certain tumor types—such as lung, melanoma, and bladder—are prone to this type of mutations or changes and are more likely to generate an immune response, making them better candidates for checkpoint inhibitors.
However, just because lung cancer is a good fit for certain types of immunotherapy does not mean that immunotherapy will work for every patient with lung cancer. Checkpoint inhibitors that target the PD-1 and PD-L1 (a protein that binds to the PD-1 checkpoint) have so far been found successful in lung cancer.
Having PD-L1 expression often dictates whether a patient is eligible for treatment with drugs called PD-1 inhibitors. So far, PD-1 inhibitors are effective only in approximately 20% to 30% of patients with NSCLC, according to researchers. So investigators are continuing to study new types of immunotherapy drugs as well as combination drugs for lung cancer.
Immunotherapy Drugs for Lung Cancer
The anti-PD-1 Opdivo (nivolumab) was first approved by the FDA in 2015 for use in patients with advanced or metastatic (spreading) NSCLC, regardless of PD-L1 expression, in patients whose disease continues to progress during or after platinum-based chemotherapy. Opdivo can be used in patients with NSCLC that is associated with specific genetic mutations called EGFR or ALK and whose lung cancer progresses despite the use of appropriate therapies. Opdivo is administered intravenously over 60 minutes, once every 2 weeks.
Opdivo was initially approved for patients with squamous NSCLC. The approval was based on a study showing that patients who received Opdivo lived an average of 3.2 months longer than patients who received only standard chemotherapy. Serious adverse effects were seen only in 7% of patients who received Opdivo compared with 55% of patients who received chemotherapy.2
In October 2015, the FDA approved Opdivo for patients with nonsquamous NSCLC after a study showed that the use of Opdivo increased patient survival to an average of 12.2 months compared with 9.4 months with chemotherapy.
The most common adverse events reported with Opdivo are usually mild and less than that observed with chemotherapy, consisting of fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, muscle weakness, cough, difficulty breathing, constipation, decreased appetite, back pain, joint pain, upper respiratory tract infection, and fever.
Another anti-PD-1 is Keytruda (pembrolizumab), which was also approved by the FDA in 2015 for the treatment of patients with metastatic NSCLC. Keytruda was first approved for patients with NSCLC expressing PD-L1 and an EGFR or ALK mutation whose disease progresses during or after platinum-based chemotherapy, based on a study of 1033 patients who had high PD-L1 expression. Patients who received a low or a high dose of Keytruda survived longer (an average of 10.4 months with low dose and 12.7 months with high dose) than patients who received chemotherapy (8.2 months with chemotherapy). However, patients with high PD-L1 expression survived even longer: those who received the higher dose of Keytruda survived more than twice longer than those receiving chemotherapy.
In 2016, the FDA approved Keytruda as the first immunotherapy drug that can be used as the first treatment for patients with metastatic NSCLC and high PD-L1 expression, but without EGFR or ALK mutation, based on results of a study of 305 patients who had not received any treatment and had a longer period without disease progression than patients who received chemotherapy as the first treatment. Keytruda is administered intravenously over 30 minutes, once every 3 weeks.
The side effects associated with Keytruda are also generally mild and less than with chemotherapy, and include fatigue, pruritus, diarrhea, decreased appetite, rash, fever, cough, difficulty breathing, musculoskeletal pain, constipation, and nausea.
The third anti-PD-L1 immunotherapy drug is Tecentriq (atezolizumab), which was approved by the FDA in 2016 for patients with metastatic NSCLC that continues to progress during or after platinum-containing chemotherapy. Patients with NSCLC and EGFR or ALK mutations can receive Tecentriq if their cancer progresses despite receiving appropriate therapy with other drugs. Tecentriq is administered intravenously over 60 minutes, once every 3 weeks.
The approval of Tecentriq for lung cancer was based on 2 studies that compared this immunotherapy drug with chemotherapy. In both studies, patients with lung cancer who received Tecentriq survived an average of at least 3 months longer than those receiving chemotherapy.
The side effects were again mild; the most common side effects with Tecentriq occurring in more than 20% of patients are fatigue, decreased appetite, cough, difficulty breathing, nausea, musculoskeletal pain, and constipation.
New Treatments on the Horizon
Although only PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of patients with lung cancer so far, other immunotherapy drugs are being studied.
Other Checkpoint Inhibitors
Immunotherapy focusing on other checkpoint inhibitors, known as CTLA-4, are being tested for lung cancer. One of these treatments, Yervoy (ipilimumab), is already approved for patients with metastatic melanoma, and researchers are hopeful that it will be approved for lung cancer. Other clinical trials are testing combinations of 2 or more checkpoint inhibitors to be used together for lung cancer.
Although no monoclonal antibodies have so far been shown to be effective in lung cancer, monoclonal antibodies are another type of immunotherapy drugs that are being tested for lung cancer. According to ClinicalTrials.gov, more than 100 clinical trials that involve monoclonal antibodies are currently recruiting new patients with lung cancer.
Therapeutic vaccines treat cancer by presenting to a patient with cancer specific antigens (molecules that can generate an immune response) that can stimulate immune responses against those antigens in tumors. Some antigens being studied for lung cancer vaccines are MAGE-3 (found in 42% of lung cancers), NY-ESO-1 (found in 30% of lung cancers), and p53 (found in 50% of lung cancers). These are also being investigated in combination with checkpoint inhibitors. Currently, lung cancer vaccines are only available in clinical trials.
Another immunotherapy being studied for lung cancer is known as “adoptive-cell therapy.” This technique involves removing T-cells from the patient and genetically altering those cells to increase their anti-cancer activity.
The T-cells are then given back to the patient, with a goal of improving how the patient’s immune system fights cancer. Several adoptive-cell therapy techniques are currently in clinical trials, including for lung cancer.
Although immunotherapies, especially checkpoint inhibitors, have been breathing new life into lung cancer treatment, there is much work to be done. Researchers believe that the answer can be found in combining various immunotherapies with each other, or combining an immunotherapy with traditional chemotherapy or radiotherapy.
Patients with lung cancer are urged to consider participating in an immunotherapy clinical trial to gain access to new treatments, while also assisting in research that is propelling immunotherapy to the forefront of cancer treatment. Visit ClinicalTrials.gov and search “lung cancer” and “immunotherapy” to find a list of current clinical trials.
We wish to thank David P.Carbone, MD, PhD, for his contribution to this article and his thorough review of the contents. Dr. Carbone is Barbara J. Bonner Chair in Lung Cancer Research, and Director, James Thoracic Center, Ohio State University Comprehensive Cancer Center, Columbus. He is an expert in the molecular genetics of lung tumors, and his research is focused on lung cancer, specifically genetics, immunotherapy, and gene therapy. He serves on LUNGevity Scientific Advisory Board.
- El-Osta H, Shahid K, Mills GM, Peddi P. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment. OncoTargets and Therapy. 2016;9:5101-5116.
- Herzberg B, Campo M, Gainor J. Immune checkpoint inhibitors in non-small cell lung cancer. The Oncologist. 2016;21:1-8.
- Opdivo was approved for squamous NSCLC after a clinical trial showed that patients who received Opdivo lived 3.2 months longer than those receiving only chemotherapy
- Serious adverse effects were seen in only 7% of patients receiving Opdivo compared with 55% of patients receiving chemotherapy
- Opdivo was also approved for patients with nonsquamous NSCLC after results showed that patients receiving Opdivo survived an average of 2.8 months longer than those receiving chemotherapy
- Keytruda is another immunotherapy drug approved for patients with NSCLC; it is the only immunotherapy drug that is approved for use as the first treatment in these patients
- Another immunotherapy drug approved for NSCLC is Tecentriq; in 2 clinical trials, patients who received Tecentriq survived at least 3 months longer than those receiving chemotherapy
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