Immunotherapy for Treatment of Advanced Non-Small Cell Lung Cancer

Danielle Shapiro, MD, MPH, Cancer Prevention and Treatment Fund

Immunotherapy could become the new standard of care for initial treatment of advanced lung cancer. Unfortunately, most lung cancer patients have advanced lung cancer when they are diagnosed, meaning the cancer has already spread to other areas of the body, including the brain and liver. Groundbreaking research shows that when added to chemotherapy, immunotherapy could help patients with advanced lung cancers live longer. Cancer experts presented this new research at the 2018 annual American Association for Cancer Research meeting.

This research gives hope, but it is still in the early stages of understanding what treatments work for which patients. As with a lot of new cancer drugs, we don’t yet know how these treatments may affect patients’ quality of life, and whether or not those who live for a longer period of time also have a better quality of life.

When deciding which treatments are best for you or your family member, consider the benefits of these treatments along with their side effects and costs, and not just what is best for advanced lung cancer patients on average.

What is Immunotherapy?

Immunotherapy boosts the body’s ability to kill cancer cells. It also helps the body repair damage caused by chemotherapy treatments, which are often very toxic. A certain class of immunotherapies, called “immune checkpoint inhibitors,” block the protein PDL-1. Cancer cells that make the PDL-1 are able to escape the body’s defenses, which increases the cancer’s ability to grow and spread.

Many of these immunotherapies have been approved as a second or third options to treat advanced lung cancers, only after other treatments have not worked. The results of key clinical studies described below may convince doctors to try these treatments earlier on.

Findings from Clinical Trials

Keytruda (Pembrolizumab)

More than 600 patients with advanced non-squamous, non-small cell lung cancer were studied in the Keynote-189 clinical trial.1 Their cancers did not contain certain gene mutations. About two-thirds of the patients were treated with chemotherapy plus immunotherapy and about one-third were treated with chemotherapy alone. After one year, about 69% of patients treated with immunotherapy plus chemotherapy were alive compared to about 49% of patients treated with chemotherapy alone. On average, patients who were treated with standard chemotherapy lived about 11.3 months. We don’t yet know what the average was for patients who received immunotherapy plus chemotherapy.

Immunotherapy also delayed progression of cancers (also known as “progression free survival”). That is, compared to standard chemotherapy, patients treated with immunotherapy lived for a longer period of time where their cancer either stayed the same or decreased in size. At one year, about 34% of patients who received immunotherapy were alive without progression compared to about 17% of patients treated with chemotherapy alone. On average, patients who received immunotherapy lived about 9 months without progression compared to about 5 months in patients treated with chemotherapy alone.

Nivolumab (Opdivo) plus Ipilimumab (Yervoy)

Almost 2,000 patients with advanced squamous and non-squamous, non-small cell lung cancer were studied in the CheckMate 227 trial.2 Their cancers did not contain certain gene mutations. The researchers used a new experimental grouping system called “tumor mutational burden,” or TMB. Studies show that cancers with a higher TMB are more likely to respond to immunotherapy.

In patients with a high TMB, at one year, about 43% of patients treated with combination immunotherapy plus chemotherapy were alive without progression compared to about 13% of patients treated with chemotherapy alone.

On average, patients with a high TMB who received combination immunotherapy lived about 7.2 months without progression compared to about 5.5 months in patients treated with chemotherapy alone.

However, research does not yet tell us if the patients taking these drugs lived longer. “Overall survival” measures how long a patient lives regardless of whether he/she dies from lung cancer or something else. That’s especially important with cancer treatment, because the treatment itself can be so toxic that it kills some patients. Since the difference in progression-free survival is less than 2 months, there may be no difference in terms of living longer. An added question is whether side effects from the drug are so unpleasant that the patients are not really benefiting.

Atezolizumab (Tecentriq) plus Bevacizumab (Avastin)

About 1,200 patients with advanced non-squamous, non-small cell lung cancer were studied in the IMpower 150 trial.3 The majority of cancers did not contain certain gene mutations, but some did. IMpower 150 studied the benefit of immunotherapy plus bevacizumab. Bevacizumab (Avastin) is a “VEGF inhibitor,” which means it blocks cancer cells from making new blood vessels. Bevacizumab plus chemotherapy is approved by the U.S. FDA for treating advanced non-squamous, non-small cell lung cancer.

At one year, about 37% of patients treated with combination bevacizumab and immunotherapy plus chemotherapy were alive without progression compared to about 18% of patients treated with bevacizumab plus chemotherapy.

On average, patients who received combination immunotherapy and bevacizumab plus chemotherapy lived about 8.3 months without progression compared to about 6.8 months in patients treated with bevacizumab plus chemotherapy. Surprisingly, patients whose lung cancer had certain gene mutations had a similar benefit. Previously, scientists believed that immunotherapy provided no benefit for patients whose lung cancers carried certain gene mutations.

However, research does not yet tell us if the patients taking these drugs lived longer. Since the difference in progression-free survival is only 1.5 months, there may be no difference in terms of living longer. An added question is whether side effects from the drug are so unpleasant that the patients are not really benefiting.

Treatment Side Effects

On average, side effects of immunotherapy were similar to chemotherapy alone. Common side effects include nausea, vomiting, diarrhea, and rash. Serious side effects include a weakened immune system and inflammation of the lungs, liver and the kidneys. In a few cases, patients with inflammation of the lungs died.

The Bottom Line

Immunotherapy has been used for advanced lung cancer when other options have not worked. This new research shows that some of these therapies may be beneficial if used sooner after diagnosis. When deciding which treatments are best for you or your family member, consider the benefits of these treatments along with their side effects and costs, and not just what is best for advanced lung cancer patients on average. Ask the tough questions about evidence of living longer (not just whether you would die of lung cancer) and about quality of life when you talk with your doctor about which treatment options may be right for you.

All articles are reviewed and approved by Diana Zuckerman, PhD, and other senior staff.

References:

Gandhi, Leena et al. Pembrolizumb plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. New England Journal of Medicine. 2018. https://doi.org/10.1056/NEJMoa1801005

Hellmann, Matthew D. et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. New England Journal of Medicine. 2018. https://doi.org/10.1056/NEJMoa1801946

First Line Combination Therapy Improves Progression-Free Survival in Advanced Lung Cancer. European Society for Medical Oncology. 2017. http://www.esmo.org/Latest-News/First-Line-Combination-Therapy-Improves-Progression-Free-Survival-In-Advanced-Lung-Cancer