New Libtayo Approval Comes After Promising Study
- A type of immunotherapy, Libtayo, in combination with chemotherapy is now approved by the FDA as a first treatment for patients with certain types of advanced non-small cell lung cancer (NSCLC).
- Patients may be eligible if they cannot get surgery or chemo/radiation and don’t have mutations of the ROS1, EGFR, or ALK genes. Those with PD-L1 expression are also eligible.
- The chemo and immunotherapy combination was found to improve overall survival for patients who, in the past, did not have many treatment options.
- This treatment was also shown to increase the time patients can live without worsening of their disease.
Immunotherapy drugs recruit patients' immune systems to fight cancer. A combination of immunotherapy plus chemotherapy helps launch a multi-pronged attack on cancers and achieve better outcomes than could be produced by either treatment alone. This is especially important for advanced lung cancer patients who may not be eligible for curative treatments.Read More
Lung cancer is one of the most deadly cancers in the United States. Around 236,740 new cases of the disease will be diagnosed in 2022. Around 130,180 patients are expected to die from it this year, making it the leading cause of cancer-related death in the US. Lung cancer is split into non-small cell lung cancer (NSCLC) and small-cell lung cancer, with NSCLC being much more common.
A diagnosis of either can be devastating for the patients, especially since most of them are diagnosed when their cancer is locally advanced (stage III; extensive disease confined to the lung, stage III) or metastatic (stage IV; when the disease has spread outside the lungs to other organs). These patients are most often ineligible for surgeries or traditional chemotherapy and/or radiation. Additionally, they may lack targetable mutations, which are changes within their tumor genes that can be specifically targeted by potent modern drugs. Targetable mutations for lung tumors include variations within the EGFR, ALK, and ROS1 genes.
However, the Libtayo and chemotherapy combination offers hope that at least a few of these patients may live for almost 9 months longer than they have in the past.
Dr. Sankar elaborates, “Combination of Libtayo with chemotherapy is now another option for patients with locally advanced or metastatic [NSCLC] without EGFR, ALK or ROS1 mutations. [It] is approved regardless of tumor PD-L1 expression, which is a biomarker used to assess response to immunotherapy. Furthermore, it is an option for patients with locally advanced NSCLC… who are not candidates for definitive treatment with surgery or concurrent chemotherapy in combination with radiation.”
The FDA approval comes at the heels of a study, which treated advanced-stage lung cancer patients with Libtayo and traditional platinum-based chemotherapy and reported promising results.
The study, known as the EMPOWER-Lung 3 trial, was a phase III clinical trial. A phase III clinical trial is the most rigorous test for any treatment or drug, and only those that show significant benefits to patients go on to receive FDA approval.
The EMPOWER-Lung 3 study enrolled 466 patients with advanced or metastatic lung cancers, which include stage III and IV NSCLC. These tumors could be either squamous or non-squamous, which are the two main distinctions for NSCLC based on its appearance under the microscope. These patients were ineligible for standard treatments, such as surgery or chemoradiation. Additionally, they did not have targetable mutations, such as variations within the EGFR, ALK, and ROS1 genes.
For patients without these mutations, the mainstay of treatment is a class of drugs called PD-1 and PD-L1 inhibitors. Libtayo is exactly that. It had demonstrated its effectiveness in a prior clinical trial, which led to its approval as a standalone treatment for advanced NSCLC with PD-L1 expression greater than 50%. In the current trial, Libtayo was combined with traditional chemotherapy as a first-line treatment for advanced lung cancer patients without any requirement for a PD-L1 expression level. In fact, 67% of the patients in this trial had PD-L1 expression of less than 50%.
The patients were randomly split into two groups. One received the chemotherapy and immunotherapy combination, while the other received chemotherapy paired with a placebo. A placebo is an inactive substance that does not have any therapeutic effects. These patients effectively received chemotherapy alone.
Those who received the combination treatment lived for almost 9 months longer than those who received only chemotherapy. “The addition of Cemiplimab demonstrated benefit in tumor response rate (43.3% versus 22.7%) and median overall survival [OS] (21.9 months versus 13.0 months),” says Dr. Schneider. OS is the length of time patients are alive after their initial diagnosis of cancer, per the NIH. The results represent a 29% decrease in the risk of death with the combination treatment.
The study also investigated progression-free survival (PFS), which represents the time a patient is alive without a worsening of their disease. For the combination group, the PFS was 8 months. For the chemotherapy and placebo group, it was just 5 months. This represents a 44% decrease in the risk of disease worsening with the chemotherapy and immunotherapy cocktail.
Dr. Sankar elaborates, “Patients who received chemotherapy with [Libtayo] lived longer, had a longer interval of time before their cancer grew or spread, and a higher rate of tumor shrinkage as compared to patients who received chemotherapy with placebo. Furthermore, the degree of response correlated with PD-L1 levels, which is a biomarker for immunotherapy response.”
How Do the Drugs Work?
Libtayo is an immunotherapy. This means that it interacts with patients' immune systems to fight off cancer.
Dr. Schneider explains, “Cemiplimab is a monoclonal antibody that blocks the PD-1 immune checkpoint typically seen on normal patient lymphocytes that may recognize and eradicate cancer. Blocking PD-1 helps the lymphocytes avoid a decoy mechanism of the cancer that allows it to evade the immune system. Combining this therapy with chemotherapy allows a patient to have "two shots" at an effective therapy at once.”
Dr. Sankar echoes this explanation, saying that “[Libtayo] is a type of immunotherapy called a checkpoint inhibitor. It works by blocking a protein called PD-1 present on T cells. T cells are the immune cells, which kill abnormal cells including cancer cells…. by blocking PD-1, [Libtayo] enhances the function of T cells and revs up the immune system to kill cancer cells.”
Programmed death receptor 1 (PD-1) is necessary for normal immune function. However, this molecule can be hijacked by the cancer cells to evade detection and destruction. Cancer cells can produce proteins on their surface, which bind the PD-1 and effectively inactivate the T cells. However, when Libtayo attaches to the PD-1, it cannot bind to the cancer cell protein and the T cells can remain active. They can then destroy the tumor cells.
On the flip side, this means that healthy body cells may not be able to inactivate the T cells. This can cause the immune system to attack healthy body tissue, which is the biggest risk with immunotherapies.
The study combined Libtayo with traditional chemotherapy. “Chemotherapy works by killing cancer cells at different stages of the cell cycle, causing cancer growth to halt,” says Dr Sankar. To grow and multiply, tumor cells divide and propagate very rapidly. Each time they divide, they copy their DNA and give one copy to each "daughter" cell. Chemotherapy disrupts this process of DNA replication, which then kills the dividing tumor cells. However, normal body cells also divide, and chemotherapy is not specific to just the cancer cells. Thus, it can affect healthy body tissues, which is what usually causes the side effects attributed to this treatment form.
Together, chemotherapy and immunotherapy can attack cancer cells in multiple ways. This usually makes the combination more potent than either drug by itself. “Chemotherapy in combination with immunotherapy works synergistically by capitalizing on the body's immune system to achieve antitumor efficacy,” notes Dr. Sankar.
What are the Side-Effects?
Libtayo is not a benign drug. When combined with chemotherapy, which is known for side effects that can be very difficult, these side effects may be amplified.
In the study, treatment-related side effects were observed in almost 96% of the patients. However, ~94% of the patients who received chemotherapy alone also experienced adverse effects.
Some of the more common side effects observed with the combination treatment were a drop in red blood cell counts (anemia), hair loss, nausea, loss of appetite, muscle and bone pain, nerve pain, and fatigue. Anemia was by far the most common side effect observed in almost 44% of the patients.
As previously mentioned, Libtayo can cause the immune system to attack healthy body tissue. “The unique side effects introduced by Cemiplimab include ‘immune-mediated adverse effects,’ which basically means the generation of autoimmune attack of normal tissues by the immune system.” These are observed less often than the side effects listed above. However, they can be particularly life-threatening. Dr. Sankar concludes, “Approximately 18% of patients in EMPOWER-Lung 3 experienced immune-related side effects, and 2.9% experienced severe immune-related side effects.”
These side effects can also affect any organ system in the body, including the liver, gastrointestinal tract, lungs, kidneys, and skin. “This can manifest as inflammation of the skin (dermatitis), gut (colitis), lung (pneumonitis), etc,” according to Dr. Sankar.
“The side effects of this combination therapy are expected and are usually manageable,” continues Dr. Sankar. “Rarely, patients may experience serious immune-related side effects which are refractory to standard treatments.”
It is important however to note that 6% of the patients who received chemotherapy and immunotherapy died due to treatment-related toxicity, and 7.8% of the patients who received chemotherapy alone tragically suffered the same fate. Comparatively, though, “there was no increase in treatment-related deaths as compared to the [chemotherapy] arm,” emphasizes Dr. Schneider.
Libtayo and platinum-based chemotherapy “offer another option for patients with stage III/IV non-small cell lung cancer who do not have targetable mutations (EGFR, ALK, and ROS1),” says Dr. Sankar. If you or your loved ones have been diagnosed with advanced NSCLC, it may be worth it to discuss this treatment with your oncologist. Dr. Schneider advises, “If you are going to be treated with initial chemotherapy for lung cancer, you should also be receiving immunotherapy. There are a few exceptions.”
In closing, you should know that:
- The immunotherapy drug, Libtayo, in combination with chemotherapy, is now approved by the FDA as a first-line treatment for advanced NSCLC patients with certain characteristics.
- They must be ineligible for surgery or chemoradiation, which are traditionally used as curative treatments for stage III NSCLC patients. They must additionally not carry any mutations in their ROS1, EGFR, and ALK genes. Such mutations can be targeted more effectively with other highly specific drugs.
- Notably, according to Dr. Sankar, “this combination therapy is approved irrespective of PD-L1 level.”
- Libtayo binds to PD-1 proteins, which are present on cells of immune system cells. This binding inactivates the immune system, which in turn protects the tumor cells.
- This approval is based on the results of a rigorous phase III clinical trial, which is the highest level of evidence for the efficacy of any treatment.
- This combination treatment significantly improves overall survival, with patients receiving the treatment on aggregative living for 22 months. Patients receiving chemotherapy only live for 13 months.
- This treatment also increases the time patients can live without a worsening of their disease. With the combination, patients lived without worsening for 8 months. With chemotherapy, they lived without worsening for only 5 months.
- The most common side effects are a drop in red blood cell counts, hair loss, nausea, loss of appetite, muscle and bone pain, nerve pain, and fatigue.
- Libtayo carries the risk of causing the immune system to attack healthy tissues, including the liver, gastrointestinal tract, lungs, kidneys, and skin.
- Life-threatening side effects may also occur: 6% of the patients receiving the combination treatment, and 7.6% of the patients receiving chemotherapy alone died due to side effects.
- Dr. Schneider summarises, “The benefits of this therapy are very meaningful because the addition of immunotherapy adds significantly to both quality and quantity of life. [Moreover] it is safe. There is much more chance that a patient will die because [they] did not get this combination than because they did.”