Lung cancer remains the leading cause of cancer-related death in the United States and is responsible for almost a quarter of all cancer deaths, according to the American Cancer Society. Lung cancer is divided into 2 main categories—small-cell lung cancer and non–small-cell lung cancer, or NSCLC for short. Most patients, up to 84%, have NSCLC, and only about 15% of the patients have small-cell lung cancer. This may explain why most of the drugs being developed for lung cancer are for NSCLC, not for small-cell lung cancer. But this may be changing.
Much of the progress in treating patients with lung cancer is the result of researchers uncovering many types of gene mutations and other DNA or genomic alterations (or biomarkers) that drive the development or the progression of lung cancer cells. These changes can now be treated by targeted therapies or immunotherapies that specifically target those mutations or changes on cancer cells and spare the patient’s healthy cells.
The most common gene changes in NSCLC include EGFR, ALK, ROS1, BRAF, as well as PD-1 or PD-L1 expression (a type of protein expressed on cancer cells). The more recent mutations discovered in lung cancer are RET, MET exon 14 skipping, EGFR exon 20, NTRK, and KRAS, all of which now have at least 1 targeted therapy or immunotherapy approved by the FDA.
These are called “driver mutations,” because they cause the development of NSCLC, and many targeted therapies or immunotherapies are now being developed to target those genetic or genomic changes.
This is why the National Comprehensive Cancer Network, the organization that develops guidelines for oncologists on best approaches to cancer therapies, now strongly recommends that all patients with NSCLC should have a test or a molecular profile to see if their cancer involves any of these genomic mutations, to select the best therapy for it.
“If a targetable oncogenic driver is detected, then targeted therapy is the best option,” said Gregory J. Riely, MD, PhD, Vice Chair, Clinical Research, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, who discussed this topic at the 2021 meeting of the American Society of Clinical Oncology.
EGFR Mutations in NSCLC
EGFR was the first targetable mutation identified in NSCLC. Different types of EGFR mutations have been discovered, and increasingly, new targeted therapies are approved by the FDA for new types of these EGFR mutations. These new-generation EGFR tyrosine kinase inhibitors (or TKIs) have improved outcomes for patients with NSCLC and EGFR mutations.
Several older-generation EGFR TKI inhibitors are available. However, newer TKIs have improved outcomes for patients.
“Now we have a better way to start treatment for newly diagnosed EGFR-positive NSCLC,” Dr. Riely said, discussing the newer, third-generation EGFR TKI Tagrisso (osimertinib), which was recently approved for patients with early-stage (stage IB-IIIA) NSCLC and EGFR mutations.
ALK & ROS1 Mutations
In March 2021, the FDA approved Lorbrena (lorlatinib), a third-generation ALK inhibitor, for first-line treatment of patients with NSCLC and ALK mutation. Lorbrena was previously approved for second- or third-line treatment for patients with this type of lung cancer.
As can be expected, the newer-generation ALK inhibitors are more effective in treating patients with ALK mutations than the older-generation drugs, and they may also have the advantage of reducing the spread of lung cancer to the central nervous system.
“Oncologists can look at the efficacy and toxicity of each of these agents in clinical trials to optimize the treatment choice,” Dr. Riely suggested.
Similarly, several ROS1 inhibitors are available today. Xalkori (crizotinib) was the first drug approved in 2016 for patients with NSCLC and ROS1 mutation.
Among the newer TKIs approved for NSCLC with a ROS1 mutation are Lorbrena and Rozlytrek (entrectinib).
EGFR Exon 20 Insertion Mutations
This year, the FDA approved the first 2 EGFR inhibitors for the treatment of patients with NSCLC and EGFR exon 20 insertion mutations. In May 2021, Rybrevant (amivantamab-vmjw), an antibody that targets mutations in the EGFR and MET pathways, was the first drug approved for adults with NSCLC and EGFR exon 20 insertion mutations.
“With today’s approval, for the first time, patients with non–small-cell lung cancer with EGFR exon 20 insertion mutations will have a targeted treatment option,” said Julia Beaver, MD, Chief of Medical Oncology of the FDA’s Oncology Center of Excellence.
And in September 2021, the FDA approved another new EGFR inhibitor, Exkivity (mobocertinib), for adults with locally advanced or metastatic NSCLC and EGFR exon 20 insertion mutations.
“EGFR exon 20 insertion-positive NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs. The approval of Exkivity...provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population,” Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute in Boston, said in a statement.
MET Exon 14 Skipping Mutations
In May 2020, the FDA approved Tabrecta (capmatinib) for the treatment of patients with NSCLC and MET exon 14 skipping alterations. This was the first drug approved for NSCLC with this type of mutation. Then in February 2021, the FDA approved a second drug, Tepmetko (tepotinib), for adults with metastatic NSCLC harboring MET exon 14 skipping alterations.
“METex14 skipping occurs in approximately 3% to 4% of NSCLC cases, and patients with this aggressive lung cancer are often elderly and face a poor clinical prognosis,” said Paul K. Paik, MD, Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York City. “There is a pressing need for targeted treatments that have the potential to generate durable anti-tumor activity and improve the lives of patients with this challenging disease.”
RET Mutations
In May 2020, Retevmo (selpercatinib) became the first targeted therapy to be approved by the FDA for patients with metastatic NSCLC and RET mutation. The second RET inhibitor, Gavreto (pralsetinib), was approved a few months later for patients with metastatic NSCLC and RET mutation.
KRAS Mutations
Approximately 25% of mutations found in patients with NSCLC are KRAS mutations, and approximately 13% of NSCLC-related mutations are KRAS G12C mutations. However, until recently it was thought that a KRAS mutation is resistant to any drug therapy.
But in May 2021, the FDA approved Lumakras (sotorasib), an oral KRAS inhibitor, for locally advanced or metastatic NSCLC and KRAS G12C mutation. Lumakras became the first KRAS inhibitor approved by the FDA for any type of cancer.
“KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer. Today’s approval [of Lumakras] represents a significant step toward a future where more patients will have a personalized treatment approach,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.
BRAF Mutations
BRAF mutation is also common in patients with NSCLC. Among the different types of BRAF mutations, the BRAF 600E is most common, accounting for about half of BRAF mutations found in NSCLC. Currently, 2 targeted therapies—Tafinlar (dabrafenib) and Mekinist (trametinib)—are available for the treatment of patients with this type of lung cancer.
Small-Cell Lung Cancer
As noted earlier, few new therapies have been approved for patients with small-cell lung cancer. Chemotherapy remains the main treatment for patients with this type of lung cancer. But progress is on the way. Several newer types of therapies have received FDA approval for extensive-stage small-cell lung cancer.
This type of lung cancer refers to small-cell lung cancer that has spread through the lung or both lungs, and possibly to the lymph nodes on the chest or to other body parts, including the bone marrow. According to the American Cancer Society, about 66% (or two-thirds) of patients with small-cell lung cancer have extensive-stage cancer.
In February 2021, the FDA approved Cosela (trilaciclib), a CDK4/6 inhibitor, for patients with extensive-stage small-cell lung cancer, to be used before chemotherapy to reduce the risk of myelosuppression (damage to the bone marrow) that is often caused by chemotherapy. Cosela can prevent damage to bone marrow cells by blocking the CDK4/6 enzyme on the cells and is the first CDK4/6 inhibitor to be approved for lung cancer.
“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer, and allow them to complete their course of treatment on time and according to plan,” said Albert Deisseroth, MD, PhD, Medical Officer at the FDA’s Center for Drug Evaluation and Research, after the approval of Cosela. “Today’s approval of Cosela will give patients a treatment option that can reduce the occurrence of a common, harmful side effect of chemotherapy.”
In addition, the PD-L1 inhibitors Imfinzi and Tecentriq are the only 2 immunotherapies that are approved by the FDA for use, in combination with a chemotherapy regimen, as first-line treatment of adults with extensive-stage small-cell lung cancer.
