The big news in cancer research last week was the release of clinical trial results showing that patients with advanced non-small-cell lung cancer (NSCLC) who received an immunotherapy drug plus standard chemotherapy as first-line treatment lived “significantly” longer than NSCLC patients who received only chemotherapy.
In the new Phase 3 trial, led by Dr. Leena Gandhi of New York University’s Perlmutter Cancer Center, 69 percent of patients originally assigned to the immunotherapy drug Keytruda®, in combination with chemotherapy, were alive after one year, versus 49 percent of patients who were in a placebo control group.
Experts consider the margin of difference in the two groups’ one-year survival rates particularly noteworthy because patients in the placebo group were allowed to switch to the immunotherapy group if their cancer progressed. Half of the placebo group wound up switching.
The researchers published their study in The New England Journal of Medicine. You may download their article for free at http://www.nejm.org/doi/full/10.1056/NEJMoa1801005.
Keytruda is the brand name for the drug, pembrolizumab, which the large pharmaceutical company, Merck, manufactures. Merck funded the NYU study.
Lung Cancer: Types and Incidence
Lung cancer is the second most common malignancy in the United States, after breast cancer. It has two main types: small-cell carcinoma, also called oat-cell carcinoma, and non-small-cell carcinoma, which are microscopically distinguishable by their appearance.
The vast majority of lung-cancer cases—about 85 percent—are non-small-cell. Small-cell (SCLC) cases are usually, but not always, associated with smoking—on the order of 90 percent. About 85 percent of all lung cancers are caused by smoking.
According to the American Cancer Society, an estimated 234,000 people will be diagnosed in the United States with lung cancer this year, 70,000 of whom will have advanced cancer, and 154,050 will die from it.
“Advanced” lung cancer has metastasized—spread—beyond its original site. Most patients diagnosed with advanced lung cancer receive chemotherapy, typically a platinum-based drug and the drug, pemetrexed, as first-line therapy, but it provides only marginal benefit. Many of these patients don’t survive long enough to try second- or third-line treatments; hence researchers are trying to develop and use more effective approaches earlier.
Immunotherapy & Cancer Genetics
Immunotherapy drugs are designed to use the patient’s immune system, which has been disabled by the cancer, to fight the malignant invaders. They are therapies that work by targeting specific genes or proteins found in cancer cells or in cells related to cancer growth.
Genes tell cells how to make proteins that keep the cell working. Cancer cells are normal cells that have already undergone several genetic mutations. The genetics of a person’s cancer—of the mutations and the gene changes in tumors—are, therefore, key to the type of therapy that should be used to treat him or her.
In contrast, chemotherapy drugs simply kill cancer cells—along with normal cells. They are not therapies targeted to the cancer itself.
Keytruda, Opdivo® (nivolumab, a Bristol Myers Squibb product), and Tecentriq® (atezolizumab, from Genentech) are immunotherapy drugs known as checkpoint inhibitors, a term I will explain below. They belong to a larger category of drugs called monoclonal antibodies. Monoclonal antibodies block a specific target on the outside of cancer cells or in the area around the cancer and are usually given intravenously.
Cancer Gene Mutations, PD-L1 Status
Because immunotherapy drugs have specific targets, the 616 patients enrolled in the NYU randomly-assigned double-blind trial had to meet certain important eligibility criteria. Among other hurdles, they had to have received no previous treatment for their metastatic NSCLC, and their cancer had to be pathologically confirmed to lack EGFR or ALK mutations. The cells in their tumors also had to have a “proportion score for programmed death ligand 1 (PD-L1) of 50% or greater.”
I will try to explain these mutations and PD-L1 status—even though I don’t truly understand what’s happening at the cellular level—because I think late-stage NSCLC patients may be hearing about them. My older sister recently called me with the sad news that a childhood friend of hers has been diagnosed with Stage 4 non-small-cell lung cancer. When I started asking questions about the genetics of her friend’s tumors, my sister said she wasn’t sure, but she had heard some initials mentioned.
Cancer begins when normal cells begin to change, growing uncontrollably and forming cell masses called tumors. In a healthy cell, Epidermal Growth Factor Receptor (EGFR) allows cells to grow and divide. When there are too many receptors, caused by a mutation, as happens in cancer, cancer cells continue to grow and divide uncontrollably.
If a patient has NSCLC with an anaplastic lumphoma kinase (ALK) mutation, the ALK gene starts coding abnormally for an enzyme called tyrosine kinase, of which there are many types. Tyrosine kinases act as chemical messengers to tell cells to divide and multiply. When they are acting abnormally, they drive cancer growth.
My explanation is simplistic. The point to glean from it is that if your NSCLC has one of these mutations, you need to receive an immunotherapy drug that blocks the EGFR protein or tyrosine kinase. Keytruda, Opdivo, and Tecentriq do not do this.
Programmed death (PD)-1 is a “checkpoint” protein on T cells, also called T lymphocytes, in the immune system. Cytotoxic or “killer” T cells search out and destroy cancer cells.
PD-1 normally acts as a kind of “off” switch to keep the T cells from attacking other cells in the body. It does this when it attaches to PD-L1, another protein. When PD-1 and PD-L1 bind, PD-1 basically tells the T cell to leave the other cell alone. Some cancer cells evade T-cell attack because they have large amounts of PD-L1. Checkpoint inhibitors, such as Keytruda, block this binding and, thereby, boost the immune response against cancer cells. They activate T cells.
CTLA-4 is another protein on some T cells that acts as an “off” switch, keeping the immune system in check. The drug Yervoy® (ipilimumab) is a monoclonal antibody that attaches to CTLA-4 and stops it from working, thereby boosting the body’s immune response to cancer. Yervoy has been used to treat melanoma, but, compared to the PD-1 or PD-L1 target drugs, it has very serious side effects.
The bottom line to cancer immunotherapy is that it is personalized medicine. The drugs target specific changes in cancer cells, and those changes differ from patient to patient.
Keytruda, Opdivo, and Tecentriq inhibit PD-1 and its ligand PD-L1. All of these drugs have been approved as second-line therapy for metastatic non-small-cell lung cancer. Keytruda also has replaced chemotherapy as the first-line treatment of choice for patients with a PD-L1 score of 50 percent or higher.
But patients with a tumor proportion score of 50 percent or higher represent a minority of those with NSCLC. The NYU study offers promise that a first-line combination therapy of a PD-1 or PD-L1 inhibitor with standard chemotherapy may maximize a patient’s chance of a positive response and lead to prolonged survival.