Non-Small Cell Lung Cancer


Advanced EGFR-Mutated Non–Small Cell Lung Cancer: Strategies to Extend Responses to First-Line Tyrosine Kinase Inhibitor Therapy

clinical topic updates by Mark G. Kris, MD

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) that is highly effective in patients with non–small cell lung cancer with common activating EGFR mutations, and it is well tolerated. Researchers are focused on extending the efficacy of first-line osimertinib while avoiding added toxicities and treatment burdens that would undermine outcomes.

Expert Commentary
“The bottom line at this point in time is that there has been a lot of activity around finding treatments that improve on osimertinib in the first line for patients with common activating EGFR mutations, but we have no clear winner yet.”
— Mark G. Kris, MD

We are currently in a wonderful and unique situation when treating patients with EGFR-mutant lung cancers. We have a very well-tolerated, third-generation EGFR inhibitor, osimertinib, that can be relied on to benefit the vast majority of patients with EGFR mutations—not all patients, as there are some individuals with rarer EGFR mutations—but to be able to benefit such a large group with osimertinib has been truly wonderful. Additionally, it is an oral medication that is unlikely to cause major disruption to someone’s normal life, and we can pretty much rely on it to work for 1 to 2 years.


With the sadly inevitable regrowth of advanced cancer, people have looked for ways to extend that. We have tried adding antiangiogenesis drugs such as the VEGF inhibitors bevacizumab or ramucirumab to EGFR TKIs, but the degree of benefit is difficult to quantify. Generally, bevacizumab improves disease-free survival, and, while being disease free is beneficial, the addition of VEGF inhibitors makes treatment more cumbersome because patients have to come to the hospital every 2 to 3 weeks, and there is an added level of toxicity. So, the jury is still out on that.


Another strategy that has been tried, and we have been involved in some of these efforts, is the addition of a first-generation EGFR TKI (eg, gefitinib) to osimertinib. However, whenever you add a second agent to treat the cancer that was controlled with osimertinib alone, you do incur additional side effects. Thus, it is unclear whether the magnitude of the benefit warrants the intervention. And the same has been true in several other studies involving targeted combination therapy.


Adding chemotherapy to EGFR TKIs has been shown to make a difference in disease-free and overall survival in trials in Asia, but these regimens have not been widely adopted, as there is concern regarding whether the degree of benefit from adding cytotoxic chemotherapy is substantial enough to warrant the additional adverse effects. Currently, the randomized phase 3 FLAURA2 clinical trial is evaluating osimertinib alone or with chemotherapy for EGFR-mutated advanced non–small cell lung cancer. Results were recently published, and the addition of chemotherapy significantly lengthened the duration of time that people have their cancer controlled, as measured by progression-free survival.


One approach that my colleague Helena A. Yu, MD, has designed is starting patients on osimertinib and then checking for the presence of EGFR circulating tumor DNA. Patients who have persistent EGFR circulating tumor DNA even after having a response to osimertinib are being randomized to receive chemotherapy plus osimertinib or osimertinib alone (NCT04410796). The goal is to see if patients who are at higher risk could benefit from an intensification of therapy.


The bottom line at this point in time is that there has been a lot of activity around finding treatments that improve on osimertinib in the first line for patients with common activating EGFR mutations, but we have no clear winner yet. Of the treatments that are out there right now, I think that the one with the most likely chance of success is the addition of chemotherapy to osimertinib, but time will tell as additional clinical trial data come out.


ClinicalTrials.gov. A study of osimertinib with or without chemotherapy as 1st line treatment in patients with mutated epidermal growth factor receptor non-small cell lung cancer (FLAURA2). Updated November 18, 2023. Accessed November 28, 2023. https://clinicaltrials.gov/study/NCT04035486


ClinicalTrials.gov. Osimertinib alone or with chemotherapy for EGFR-mutant lung cancers. Updated September 21, 2023. Accessed November 28, 2023. https://www.clinicaltrials.gov/study/NCT04410796


Elkrief A, Makhnin A, Moses KA, et al. Brief report: combination of osimertinib and dacomitinib to mitigate primary and acquired resistance in EGFR-mutant lung adenocarcinomas. Clin Cancer Res. 2023;29(8):1423-1428. doi:10.1158/1078-0432.CCR-22-3484


Le X, Nilsson MB, Robichaux JP, Heymach JV. ARTEMIS highlights VEGF inhibitors as effective partners for EGFR TKIs in EGFR mutant NSCLC. Cancer Cell. 2021;39(9):1178-1180. doi:10.1016/j.ccell.2021.07.017


Papini F, Sundaresan J, Leonetti A, et al. Hype or hope – can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC? Crit Rev Oncol Hematol. 2021;166:103454. doi:10.1016/j.critrevonc.2021.103454


Passaro A, Leighl N, Blackhall F, et al. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer. Ann Oncol. 2022;33(5):466-487. doi:10.1016/j.annonc.2022.02.003


Planchard D, Jänne PA, Cheng Y, et al; FLAURA2 Investigators. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434


Soria J-C, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137


Wu Q, Luo W, Li W, Wang T, Huang L, Xu F. First-generation EGFR-TKI plus chemotherapy versus EGFR-TKI alone as first-line treatment in advanced NSCLC with EGFR activating mutation: a systematic review and meta-analysis of randomized controlled trials. Front Oncol. 2021;11:598265. doi:10.3389/fonc.2021.598265

Mark G. Kris, MD

Attending Physician, Thoracic Oncology Service
William and Joy Ruane Chair in Thoracic Oncology
Memorial Sloan Kettering Cancer Center*
Professor of Medicine
Weill Cornell Medical College
New York, NY