Lung cancer is one of the toughest cancers to treat, affecting nearly 229,000 people and killing nearly 136,000 in 2020. With tough treatment come some truly debilitating side effects, such as nerve damage, loss of appetite, severe nausea and vomiting, diarrhea or constipation, hair loss and mouth sores.
Lung cancer treatment often includes surgery, radiation and a combination of different types of chemotherapy drugs, such as cisplatin and carboplatin, that attack not just cancer cells, but other, healthy cells — such as those in the bone marrow (where new blood cells are made), the lining of the mouth and intestines, and the hair follicles. These drugs also cause blood counts to fluctuate and platelets to plummet, leading to an increased risk of infection, bruising or bleeding, and severe fatigue.
Until recently these treatments were the only weapons in cancer doctors’ arsenals. However, the promising frontier of targeted lung cancer treatment may provide fresh hope for advanced disease. “Ultimately what we need to do to improve cancer treatment is create drugs that just target the ‘abnormal machinery’ in the body,” says Jeremiah Martin, MD, a thoracic surgeon at Southern Ohio Medical Center in Portsmouth. Targeted therapies usually cause less harm to normal cells than chemotherapy or radiation therapy do.
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Targeted Lung Cancer Treatment
Essentially, targeted treatment is just what it sounds like — zeroing in on the cancer and bypassing healthy tissue. Not all lung cancers can be treated this way yet; currently targeted therapy is used to treat advanced cancers. Typically administered intravenously or via pill, this form of treatment is matched to a cancer’s specific gene mutations, proteins, or other substances that contribute to cancer growth. The aim of targeted treatment is to block the growth and spread of cancer cells by:
- blocking or turning off chemical signals that tell cancer cells to grow and divide
- changing proteins inside cancer cells causing them to die
- interfering with the development of blood vessels to feed cancer cells
- carrying toxins to cancer cells to kill them
The key to targeted cancer treatment is biomarkers (also called molecular markers). Biomarkers can include abnormalities in tumor DNA, specific proteins or molecules in the tumor, or substances in the body that contribute to cancer growth. Proteins or molecules in the tumor, or DNA abnormalities are biomarkers that give doctors a more detailed picture of the lung-cancer tumor. Another target is vascular endothelial growth factor (VEGF). VEGF is a substance in the body that stimulates angiogenesis, new blood vessel formation, which is important to cancer because tumors need a blood supply in order to grow.
Biomarkers are found on the surface of the cells, or in the genes that program cells. Doctors may perform tests to determine if a biomarker is present in the tumor or in the body, and thus a more targeted approach can be used to attack it. There are many different types of targeted therapy that may be used alone or in combination with chemotherapy.
Immunotherapy is a treatment that helps the body’s immune system to recognize and destroy cancer cells. Immunotherapy can be used as a targeted therapy or to boost the immune system generally. Immunotherapy drugs called checkpoint inhibitors are used to treat the two main types of lung cancer, small cell (SCLC) and non-small cell lung cancer (NSCLC). About 85% of lung cancers are NSCLC. Checkpoint inhibitors are given by IV infusion. They target and block “checkpoint” proteins located on immune cells. Checkpoints act like switches to turn an immune response on or off. Cancer cells can manipulate these checkpoints to avoid attack by the immune system.
Some checkpoint inhibitors target a protein produced by cancer cells called PD-L1. PD-L1 binds to a receptor protein on T cells (a type of immune cell) called PD-1. When PD-L1 connects to PD-1, the connection prevents the immune system from killing the cancer cell. Checkpoint inhibitors work to disrupt this connection by targeting either the PD-L1 protein or the PD-1 receptor protein. Once this connection is broken, T cells are able to recognize and respond to cancer cells. By blocking checkpoint proteins, checkpoint inhibitors allow the immune response to kill cancer cells.
Checkpoint inhibitors used to boost the immune response against cancer cells include:
- Opdivo (nivolumab)
- Keytruda (pembrolizumab)
- Tecentriq (atezolizumab)
- Imfinzi (durvalumab)
Drugs called angiogenesis inhibitors are targeted treatments that block the growth of blood vessels supporting tumor growth, rather than directly blocking the growth of tumor cells. Some angiogenesis inhibitors accomplish this by binding to VEGF, interfering with its ability to stimulate the formation of blood vessels that feed tumors. Angiogenesis inhibitors approved for NSCLC include:
- Avastin (bevacizumab)
- Cyramza (ramucirumab)
Research is underway to determine if Avastin, as well as other angiogenesis inhibitors for other cancers, may be helpful for treatment of small cell lung cancer. Also, Avastin is under study for pulmonary edema in patients with severe COVID-19 who have acute lung injury and acute respiratory distress syndrome. Research has revealed that patients with COVID have higher levels of VEGF compared to healthy people, and that VEGF is a potential therapeutic target.
Epidermal growth factor receptor (EGFR) inhibitors are a type of targeted therapy aimed at EGFR, a protein on the surface of cells that helps them grow and divide. If cancer cells have too much EGFR on their surface they grow faster. EGFR inhibitors block EGFR, interfering with its signals telling cancer cells to grow. Some EGFR inhibitors can be used to treat advanced NSCLCs that have mutations in the EGFR gene. Mutations in EGFR genes are more likely to occur in women, Asians, light smokers and non-smokers. EGFR inhibitors used in NSCLC with gene mutations include:
- Tarceva (erlotinib)
- Gilotrif (afatinib)
- Iressa (gefitinib)
- Tagrisso (osimertinib)
- Vizimpro (dacomitinib)
About 5% of NSCLCs have an error in a gene called ALK (anaplastic lymphoma kinase), and the brain is a common place for this type of cancer cell to spread. ALK is another biomarker for testing in lung cancer. The ALK mutation is most often seen in non-smokers (or light smokers) who have the adenocarcinoma subtype of NSCLC. An ALK gene mutation produces an abnormal protein that causes cells to grow and divide. Drugs called ALK inhibitors target this abnormal ALK protein. A 2018 analysis of 21 studies found that the ALK inhibitors Zykadia, Alecensa and Alunbrig may be helpful in treating NSCLC cancer that has spread to the brain.
Often ALK inhibitors stop working after a year or two. Doctors then try other drugs or combinations of drugs. ALK inhibitors include:
- Xalkori (crizotinib)
- Zykadia (ceritinib)
- Alecensa (alectinib)
- Alunbrig (brigatinib)
- Lorbren (lorlatinib)
“EGFR inhibitors are the first drugs that have really been shown to work, for patients with the ALK or EGFR mutations,” says Dr. Stevens, MD, PhD, chair and professor of radiation oncology at Oakland University William Beaumont School of Medicine in Rochester, Michigan. In addition to treatments aimed at tumors with changes in EGFR and ALK genes, there are targeted therapies for tumors showing abnormalities in ROS1, BRAF V600E, MET, RET and NTRK genes.
How Well Does Targeted Therapy Work?
A 2020 study by the National Cancer Institute (NCI) found that death rates from NSCLC, the most common type of lung cancer, have fallen sharply in recent years, correlating with the approval of several targeted therapies. The decline in deaths was also associated with longer survival. The researchers determined that deaths from NSCLC in men decreased 3.2% per year from 2006 to 2016. Over this time two-year survival improved from 26% in 2001 to 35% in 2014. Similar improvements in death and survival rates were seen in women. This was the first study to show that death rates were declining faster than incidence rates for NSCLC.
“The survival benefit for patients with non-small cell lung cancer treated with targeted therapies has been demonstrated in clinical trials, but this study highlights the impact of these treatments at the population level,” said Nadia Howlader, PhD, of NCI’s Division of Cancer Control and Population Sciences, in an NCI press release. Howlader, who led the study, added “We can now see the impact of advances in lung cancer treatment on survival.”
Multiple studies from the Lung Cancer Mutation Consortium, an association of more than 20 cancer centers focused on understanding genetic changes that underlie lung cancers, have shown that identifying and targeting cancer-causing changes in certain genes leads to longer survival. One study published in 2018 in Clinical Cancer Research enrolled over a thousand patients with advanced lung cancer who had at least one of 14 cancer-related genes. Patients with mutations in certain genes who were treated with targeted therapy lived 1.5 years longer than those who did not receive targeted therapy. Importantly, with certain gene alterations and targeted treatment, people who smoked experienced survival benefits similar to those who never smoked.
“Patients might only be getting an extra year, but it’s an extra year not spent in hospital.” — Jeremiah Martin, MD
It’s not surprising that genetic testing of tumors is proving more effective than other treatments we’ve seen to date. “Cancer is a disease of a patient’s genes,” says Dr. Stevens.“Sometimes that disease is inherited, and sometimes those cells acquire mutations over time, via environmental changes like smoking, or just randomly. The way these drugs work is to have the ability to target those particular abnormalities that are present in the cancer and turn them off — without impacting the healthy cells.”
The End of Lung Cancer?
But that still doesn’t mean targeted therapy represents a cure — far from it. What it can do is slow the growth of cancers, giving some lung cancer patients the promise of living longer with cancer But longevity isn’t everything. What’s also improved with these treatments is quality of life. “Patients might only be getting an extra year, but it’s an extra year not spent in hospital,” says Martin. Perhaps most importantly from a patient perspective, side effects of typical chemo are greatly reduced with targeted therapies, because they are far less toxic to the body as a whole, says Stevens.
Treatment Side Effects
Side effects with targeted treatments are significantly less likely, and less severe, than with traditional chemotherapy. “There’s no single golden bullet yet but these targeted therapies offer a way to kill/slow down cancer cells with much less side effects,” said Dr. Martin.
That said, targeted therapy can still cause significant side effects, which vary depending on the treatment and from person to person. Side effects include:
- Nausea and vomiting
- Diarrhea or constipation
- Mouth sores
- Shortness of breath or trouble breathing
- Cough
- Feeling tired all the time (fatigue)
- Vision problems including blurred vision, double vision or increased floaters
- Headache
- Muscle pain
- Allergic reactions (while getting an IV drug)
- Increased risks of certain infections
- Second cancers
- Skin changes such as rash, increased sensitivity to sunburn and blistering, dry skin, itching, sores around fingernails and toenails
- Swelling of hands, feet, ankles, arms, legs, face
- Hair loss or thin, dry, brittle hair
- High blood pressure
- Low white blood cell counts leading to infections
- Bleeding or clotting problems, including bleeding from the stomach and intestines
- Clots leading to heart attack or stroke
- Heart damage, especially when targeted treatment is used with chemotherapy
- Autoimmune reactions leading to damage in the intestines, liver, eyes, nerves, lungs thyroid and other organs
Some of these side effects can be severe, even life threatening, such as autoimmune reactions or bleeding from the stomach and intestines. Not every person gets every side effect, and some people get few or none. Patients should ask their doctor about potential side effects, and report all side effects as soon as possible in case they indicate a serious problem. In Dec 2020, a study of Danish patient registries showed that checkpoint inhibitors were associated with heart damage in almost 10% of patients.
Lung cancer research is moving at a rapid pace — since 2018 there have been more than 20 lung cancer treatment approvals — and there continue to be drug approvals for patients whose tumors grow after being on first-line therapy. If your lung cancer does not test positive for a biomarker with an approved targeted therapy, immunotherapy with or without traditional chemotherapy, surgery or radiation may be recommended. For many patients enrolling in a clinical trial seeking out treatments for other markers may be considered.
