Recently, the FDA approved osimertinib (Tagrisso®, AstraZeneca) as the first adjuvant therapy for patients with surgically resected early-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. In this interview, Roy Herbst, MD, PhD, Chief of Medical Oncology at Yale Cancer Center and lead investigator of the ADAURA trial, on which the approval was based, speaks with i3 Health about the significance of the approval of osimertinib for this patient population.
What are some of the most challenging aspects of treating patients with early-stage EGFR-mutated NSCLC?
Roy Herbst, MD, PhD: First of all, we want to identify every patient with EGFR-mutated disease so that we can give them the option of targeted treatment. In the United States, only 10% to 15% of patients with NSCLC have EGFR mutations, so it's important to screen for them. We have to make sure that at the time of surgery, hospitals and providers are screening for EGFR mutations in every patient. We've always done that in the advanced metastatic setting, but now I would suggest that at the time of operation, when a tissue goes to pathology, profiling for genetic mutations should also be done for those with early-stage disease. Patients should know about this before the surgery so that they can be prepared.
Can you comment on the significance of the approval of adjuvant osimertinib for patients with early-stage EGFR-mutated NSCLC?
Dr. Herbst: The significance is huge; it's paradigm-shifting. This is the first approval we've seen for a targeted therapy in the early stage of lung cancer. The EGFR receptor was discovered over 30 years ago, and then EGFR inhibitors entered the clinic about 20 years ago. In 2004, we learned about specific mutations that signify who responds best to which treatments, and we now have advanced agents that are available even in the earliest settings of disease. With precision medicine, we have the ability to target patients who already have a good chance of doing well in order to do even better and hopefully even cure the disease.
Osimertinib is a third-generation drug, and it targets the brain, which makes it less toxic to the rest of the body. It's an oral medication that's given for three years, and many times, patients will also receive chemotherapy, depending on their disease stage. In the ADAURA trial, we saw an 83% decrease in disease recurrence for patients receiving osimertinib compared with placebo. There was also a significant decrease in the rate of metastasis to the brain. Overall, this approval is really a historic event.
Are there any particular adverse events that should be monitored for in patients receiving osimertinib?
Dr. Herbst: We didn't observe any major adverse events in the ADAURA trial. We looked for interstitial lung disease and cardiac issues, and there were no significant events across the worldwide study. There were some minor events, including rash and diarrhea, but they were very minor. There will always be a little more toxicity with an experimental drug when it's compared with placebo, but the safety was consistent with what we've seen with this drug in the past. Quality of life data will be presented at the International Association for the Study of Lung Cancer World Conference in Singapore at the end of January. Even though the data aren't out yet, knowing my experience from leading the trial, I would predict that patients can tolerate this drug quite well. We didn't see such positive results with the earlier generations of EGFR inhibitors because they did have more side effects, but in this trial, osimertinib was so well tolerated that it really represents a significant advance.
What questions do you commonly encounter from patients with early-stage EGFR-mutated NSCLC, and how do you counsel them?
Dr. Herbst: For years, patients whose tumors were resected knew that there was a 50% chance that their disease would come back in five years. They would say, "I know I have an EGFR mutation; why don't you treat me with something?" I would have to say, "Well, we don't have anything approved yet." Then once the patient progresses and the disease metastasizes in the brain, liver, or bone, it becomes almost impossible to treat and cure. Now, with the approval of osimertinib, we have an option for treating patients while their disease is still in the early stage.
Now many people will say, "Does this drug improve long-term survival?" We don't know that yet, because the trial has to continue for another few years. That said, as a clinician, I have to believe that if we avoid brain disease, it's going to have a significant effect on survival. I think most patients with early-stage EGFR-mutated NSCLC are going to want to be treated with osimertinib, and of course, FDA approval is always the first step towards that.
About Dr. Herbst
Roy Herbst, MD, PhD, is Chief of Medical Oncology at Yale Cancer Center, where he is also a Professor of Pharmacology and Ensign Professor of Medicine. Additionally, he serves as Associate Director for Translational Research at Yale Cancer Center. Dr. Herbst is a nationally recognized expert in the treatment of lung cancer, with particular expertise in personalized therapy for NSCLC. His research focuses on the development of novel therapeutics for lung cancer, and his work has been instrumental in the approvals of several therapies, including gefitinib, cetuximab, bevacizumab, axitinib, and osimertinib. Dr. Herbst serves as Vice Chair for Developmental Therapeutics for the Southwestern Oncology Group (SWOG) Lung Committee, and he serves on the Board of Directors for the American Association of Cancer Research (AACR) and the International Association for the Study of Lung Cancer (IASLC). He has received several awards, including the 2020 AACR Distinguished Public Service Award for Exceptional Leadership in Cancer Science Policy. Dr. Herbst has authored or coauthored more than 350 publications in peer-reviewed journals.
For More Information
Herbst RS, Tsuboi M, John T, et al (2020). Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol (ASCO Virtual Scientific Program Abstracts), 38(suppl_18). Abstract LBA5. DOI:10.1200/JCO.2020.38.18_suppl.LBA5
Clinicaltrials.gov (2020). AZD9291 versus placebo in patients with stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy (ADAURA). NLM identifier: NCT02511106.
Goldman JW, John T, Grohe C, et al (2020). Patient-reported outcomes from ADAURA: osimertinib as adjuvant therapy in patients with resected EGFR-mutated (EGFRm) NSCLC. International Association for the Study of Lung Cancer World Conference Abstracts. Abstract OA06.
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.