Researchers have made tremendous progress in treating lung cancer by identifying key mutations in genes that drive the growth of lung cancer. Once these “driver” mutations are identified, researchers can work to target these mutations with specific treatments, called targeted therapies.
FDA-approved targeted therapies exist for treating EGFR-positive NSCLC, or non-small cell lung cancer (NSCLC) patients whose tumors test positive for exon19 and exon21 L858R mutations in the EGFR (epidermal growth factor receptor) gene. But there are patients with NSCLC whose tumors have other EGFR mutations, such as EGFR exon20 insertion mutations.
Historically, these mutations haven’t responded well to the EGFR treatments approved by the FDA. Researchers have been working to improve treatment options for this unique group of patients. In 2021, advances in targeted therapies have progressed to offer new treatment options for NSCLC patients with EGFR exon20 driver mutations.
LUNGevity Foundation spoke to John Heymach, MD, PhD, professor and chair of the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center and member of LUNGevity’s Scientific Advisory Board, to learn more about these new treatments and the exciting research that is underway.
LUNGevity Foundation: Please describe the approved treatments for metastatic NSCLC with EGFR exon20 driver mutations. How do they work?
Dr. John Heymach: There are two targeted therapies currently approved by the U.S. Food and Drug Administration (FDA) to treat these patients – amivantamab and mobocertinib.* Mobocertinib falls in the group of tyrosine kinase inhibitors, or TKI drugs. These drugs typically include small molecules that bind to and block an important pocket of the EGFR protein. Blocking this pocket stops the EGFR protein from triggering uncontrolled cancer cell growth. Amivantamab is an antibody that binds to both MET and the EGFR receptors on the surface of the cell and inhibits their activities. This antibody belongs to a new group of drugs called bispecifics and is given as an infusion into the vein.
LF: Do tumors develop drug resistance to these targeted therapies?
JH: Unfortunately, as with most targeted therapies, patients do typically see their tumors develop resistance to these treatments. But we haven’t yet discovered what those mechanisms of resistance are. We look forward to seeing that data, because it will help us to select which treatment may be better suited for a patient, and it may give other clues about how to optimize treatment plans.
LF: Once a patient develops resistance to the treatment, what are their options?
JH: Patients should consider clinical trials. They can also consider the other FDA-approved treatment. Because the two treatments work in different ways, it’s possible that resistance to one treatment might not mean resistance to both treatments.
LF: Who is likely to have actionable EGFR exon20 driver mutations?
JH: Exon20 mutations don’t seem to be related to tobacco exposure. These mutations are often found in non-smokers and former smokers. While lung cancer as a whole tends to be more common in men, exon20 mutations are more likely to be found in NSCLC in women. Also, there is a higher incidence in patients of Asian descent, although exon20 mutations occur in every ethnicity. More studies are needed to understand why some populations have a higher incidence rate of exon20 driver mutations.
LF: How can patients find out if they have one?
JH: Every patient who is diagnosed with non-small cell lung cancer now should get comprehensive biomarker testing. Ideally, it should include nine common oncogenes (genes known to harbor driver mutations): EGFR including EGFR exon20 mutations, HER2, KRAS, BRAF, RET-fusions, ALK-fusions, ROS1-fusions, NTRK-fusions, and METexon14 alterations.
We used to sequence, or study the code of genes, individually, to look for mutations in each gene. But now that we have so many genes to consider, it’s better to use next-generation sequencing (NGS) techniques and get them all sequenced at once. These tests can be done using tissue samples or blood samples. Sometimes it can be useful to test both tissue and blood because one test could catch something that the other test missed.
Patients should also get PD-L1 testing to help inform immunotherapy options.
LF: If a patient’s cancer tests positive for an EGFR exon20 driver mutation – what should they do next?
JH: They should see a physician, and it may be beneficial to see one with experience and knowledge of the latest lung cancer therapies. There have been many FDA approvals for treating patients with NSCLC in the past few years. And it’s very hard for a general medical oncologist to keep up with all the different approvals in all the different diseases. So, I think it’s important for patients to see a physician who has knowledge of all the treatment options for NSCLC and specifically EGFR exon20.
Also, in my practice, we always recommend that patients should consider clinical trials. There are often some great treatments still in the clinical trial pipeline that patients can get access to.
LF: What other promising research is on the horizon for patients with EGFR exon20 mutations?
JH: The focus has largely been on TKIs (tyrosine kinase inhibitors) because the pharmaceutical industry has a lot of experience with engineering this class of treatments. But researchers are also looking at other options for therapy as well. There is a lot of interest in leveraging the patient’s natural defenses, the immune system, in fighting off the cancer. There are also ongoing studies looking at combining different treatments to optimize outcomes for patients.
Recently, my team has been studying the effect of driver mutations on the 3D structure of the EGFR protein to help us predict how effective a treatment will be in patients.
LF: What are challenges in the field?
JH: As our therapies begin to get more personalized and refined, it becomes more difficult to keep up with the drugs and their applications. Also, clinical trials have become more challenging. In the past, we would do clinical trials for all lung cancer patients batched together – it was easy to find and enroll patients who matched the criteria for the clinical trial. Now we are doing clinical trials where only 1%-2% of lung cancer patients are even eligible for the trial, so the clinical trials are more difficult to fill.
LF: How can nonprofits, like LUNGevity, help us overcome these challenges?
JH: First, we should continue to increase awareness of progress in the field. As new therapies evolve, lung cancer is breaking into smaller and smaller subgroups. It is critical that patients and their caregivers know about these subgroups, like EGFR exon20 or other types of less common mutations.
Second, it’s important to recognize that pharmaceutical companies are not always able to go after these smaller subtypes; they often end up going after the largest unmet need. When organizations, like LUNGevity, support early-stage researchers who are studying these less common mutations, we can keep the efforts going and continue to make progress in the field.
LF: Is there anything you’d like to add?
JH: For lung cancer investigators, the most tenuous part of our careers is the early stage of being a faculty member. It can be difficult to get the funding you need to establish yourself in the field. This is particularly true for researchers who are trying to study a smaller subtype of lung cancer.
Early-stage research funding is valuable support that allows promising scientists to establish themselves in an area that will hopefully blossom into a long, impactful career.
When I was a junior investigator, I was supported in part by LUNGevity. That support helped me establish my laboratory and laid the groundwork for a lot of exciting research that my team does today. That is why research funding from groups like LUNGevity is so central to driving innovation in the field of lung cancer research and treatment.
*Following discussions with the US Food and Drug Administration, EXKIVITY will be officially withdrawn from the market in the United States no later than March 2024. EXKIVITY remains available to prescribe until the official withdrawal; moreover, after withdrawal patients will be able to maintain access through an established compassionate use program. All current patients on the drug whom Takeda has contact information for will have received an official communication. For more information, please visit www.exkivity-update.com.