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 from 2016 to 2017.1 Their cancers did not contain certain gene mutations. About two-thirds of the patients were treated with chemotherapy plus Keytruda and about one-third were treated with chemotherapy alone (which was considered the placebo group). The Keytruda + chemo or the placebo + chemo were administered every 3 weeks for up to 35 cycles. 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 size or decreased in size. At one year, about 34% of patients who received Keytruda were alive without progression compared to about 17% of patients treated with chemotherapy alone. On average, patients who received Keytruda lived about 9 months without progression compared to about 5 months in patients treated with chemotherapy alone.
Although patients whose cancer does not increase in size in the short-term do not necessarily live longer, a five-year follow-up of the phase 3 Keynote189 trial showed that the use of Keytruda in combination with chemotherapy improved long-term survival outcomes as well as and progression-free survival (PFS). The median overall survival was 22 months in the Keytruda plus chemotherapy group compared to 10.6 months for the placebo group.2
A more recent study published in 2023, Keynote-671, evaluated 800 patients with early stages of non-small cell lung cancer regarding the impact of medication before and after surgery.3 Everyone got chemotherapy before surgery, and half of the patients got Keytruda immunotherapy before and after surgery while the other half got a placebo before and after surgery. Just over 62% of those who got Keytruda were cancer-free after 2 years, compared to almost 41% who got the placebo. This statistically significant difference has been reported to be a 42% reduction in the risk of cancer recurrence, progression, or death, which is somewhat misleading since the absolute difference is 21%. After two years of study, 81% of patients who got Keytruda were still alive, compared to 78% of those who got a placebo. This 3% difference was not statistically significant, which means that it might have happened by chance and additional research is needed to see if patients getting Keytruda before and after chemo actually live longer. While the findings after 2 years are important, it will be equally important to eventually evaluate the longer-term benefits.
Nivolumab (Opdivo) plus Ipilimumab (Yervoy)
Almost 2,000 patients with advanced squamous and non-squamous, non-small cell lung cancer were enrolled in the CheckMate 227 trial between 2015 to 2016.4 Their cancers did not contain certain gene mutations. The researchers grouped patients according to “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, about 43% of patients treated with combination immunotherapy plus chemotherapy were alive without progression after one year, 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 for patients treated with chemotherapy alone. However, the 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 they die 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 how long patients live. An added question is whether side effects from the drug are so unpleasant that the patients are not really benefiting.
In 2020, the FDA approved the combination therapy of Nivolumab (Opdivo) plus Ipilimumab (Yervoy) as a first-line treatment for patients with metastatic NSLC if they had tumors referred to as having a Programmed death ligand (PD-LI) of greater than 1% with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK).5 In this study, of the 1190 total patients, 396 were assigned to receive combination therapy, 396 received only nivolumab, and 397 received only chemotherapy. The median overall survival was 17.1 months for patients who took nivolumab plus ipilimumab and 14.9 months for patients with only chemotherapy. Survival rates at 1 year and 2 years were 62.6% and 40.0%, respectively, for combination patients, and 56.2% and 32.8% at 1 year and 2 years, respectively, with chemotherapy-only patients. The rate of overall survival was statistically significantly higher among the patients who received nivolumab plus ipilimumab than those who received chemotherapy.
Atezolizumab (Tecentriq) plus Bevacizumab (Avastin)
About 1,200 patients with advanced non-squamous, non-small cell lung cancer participated in theIMpower 150 trial, a study that was published in 2017. 6 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. Based on the findings from the IMpower150 trial, the FDA approved atezolizumab in combination with bevacizumab and chemotherapy for first-line treatment for patients with metastatic NSCLC in 2018.7 As of 2023, it is still unknown whether 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:
1.Gandhi, L., et al. (2018). Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. New England Journal of Medicine, 378(22), 2078–2092. https://doi.org/10.1056/nejmoa1801005
2.Flaherty, C. (2022, November 4). Keynote-189 analysis supports pembrolizumab/chemo as a frontline standard in metastatic NSCLC. OncLive. https://www.onclive.com/view/keynote-189-analysis-supports-pembrolizumab-chemo-as-a-frontline-standard-in-metastatic-nsclc
3.Wakelee, H., et al. (2023). Perioperative pembrolizumab for early-stage non–small-cell lung cancer. New England Journal of Medicine. https://doi.org/10.1056/nejmoa2302983
4.Hellmann, M. D., et al. (2018). Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. New England Journal of Medicine, 378(22), 2093–2104. https://doi.org/10.1056/nejmoa1801946
5.Center for Drug Evaluation and Research. (n.d.-b). FDA approves nivolumab plus ipilimumab for first-line MNSCLC (PD-L1 tu. U.S. Food and Drug Administration. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1
6.ScienceDaily. (2017, December 7). First line combination therapy improves progression-free survival in advanced lung cancer. ScienceDaily. https://www.sciencedaily.com/releases/2017/12/171207094950.htm
7.Center for Drug Evaluation and Research. (n.d.). FDA approves atezolizumab with chemotherapy and bevacizumab for first-. U.S. Food and Drug Administration. https://www.fda.gov/drugs/fda-approves-atezolizumab-chemotherapy-and-bevacizumab-first-line-treatment-metastatic-non-squamous