Overcoming Mechanisms of Resistance Remains at the Forefront for EGFR-Mutant NSCLC

Although next-generation TKIs have helped to overcome resistance in EGFR-mutated non–small cell lung cancer, a more complete understanding of resistance mechanisms may lead to the ability to overcome resistance to the next generation of these drugs.

Although next-generation TKIs, such as osimertinib (Tagrisso), have helped to overcome resistance in EGFR-mutated non–small cell lung cancer (NSCLC), a more complete understanding of resistance mechanisms may lead to the ability to overcome resistance to the next generation of these drugs, as well, according to Roy S. Herbst, MD, PhD.1

“Everyone with an EGFR mutation gets an EGFR inhibitor, and we are moving them to the earliest setting,” Herbst, the Ensign Professor of Medicine, professor of Pharmacology, director of Center for Thoracic Cancers, and chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, said during the 16th Annual New York Lung Cancers Symposium, program developed by Physicians’ Education Resource® LLC. “There are a multitude of resistance mechanisms, and personalized therapy and upon resistance is probably going to be the norm going forward.”

Biopsy, either liquid or tissue, remains an important part of care for patients with EGFR-mutant disease, as it can help to detect actional mechanisms of resistance. Furthermore, similar strategies may be relevant for overcoming resistance to targeted therapy in other oncogene-driven lung cancers, Herbst noted.

Osimertinib Moves to the Forefront

EGFR TKIs began to be studied in the 1990s, with first-generation drugs like gefitinib (Iressa) and erlotinib (Tarceva). These were followed by second-generation agents, such as afatinib (Gilotrif) and dacomitinib (Vizimpro), and finally, the third-generation EGFR TKI osimertinib. In the phase 2 AURA2 trial (NCT02094261), the agent showed activity in patients with EGFR T790M-mutant NSCLC, with an overall response rate (ORR) of 61% (95% CI, 54%-68%), and a disease control rate (DCR) of 91% (95% CI, 85%-94%).2

Then came the large, phase 3 FLAURA trial (NCT02296125) which established the agent as the standard of care for first-line treatment for this patient population in the United States and Europe. The study enrolled patients 18 years or older with a World Health Organization (WHO) performance status of 0 or 1, exon 19 deletion- or L858R-postive disease, and no prior systemic anti-cancer or EGFR TKI treatment. Those with stable central nervous system (CNS) metastases were eligible to enroll.

Patients were randomized 1:1 to receive either osimertinib or gefitinib or erlotinib every 6 weeks until objective progressive disease. Patients were stratified by mutational status (exon 19 deletion or L858R), and race (Asian or non-Asian), and crossover was allowed for patients in the gefitinib or erlotinib arm who could receive open-label osimertinib upon central confirmation of progression and T790M positivity.3

The primary end point of the study was investigator assessed progression-free survival (PFS), and secondary end points included ORR, duration of response (DOR), DCR, depth of response, overall survival, patient-reported outcomes, and safety.

Results showed that the median PFS in the osimertinib arm was 18.9 months (95% CI, 15.2-21.4) vs 10.2 months (95% CI, 9.6-11.1) in the gefitinib or erlotinib arm, which led to the FDA approving the agent in this patient population in 2018. Additionally, the median OS in the osimertinib arm was 38.6 months (95% CI, 34.5-41.8) vs 31.8 months (95% CI, 26.6-36.0) in the gefitinib or erlotinib arm.

“For all the different markers—whether it be sex, age, race, smoking history, CNS metastases, performance status, mutation type—all of them favored the osimertinib,” Herbst said. “Toxicity wise, with the third-generation drugs that are TKI mutation–specific, we still get some rash, diarrhea, and occasional interstitial lung disease [ILD].”

“Moving the Best Therapy Earlier”

The significant benefit demonstrated by EGFR TKIs in those with EGFR-mutant advanced NSCLC provided rationale for testing these agents in patients with early-stage disease, according to Herbst.

Surgery and adjuvant cisplatin-based chemotherapy are the recommended treatment strategy for those with stage II to stage IIIa disease, as well as some select patients with stage Ib disease. However, rates of disease recurrence and death following these treatment strategies remain high, across stages. Similarly, the prevalence of EGFR mutations appears similar across disease stages.4

“If EGFR TKIs were available in the resectable setting, a similar proportion of patients may be able to benefit compared to the advanced setting,” Herbst said.

Investigators tested this hypothesis in the phase 3 ADAURA trial (NCT02511106), which examined osimertinib in patients with completely resected stage Ib, II, and IIIa NSCLC, with or without adjuvant chemotherapy. The study enrolled those 18 years or older with a WHO performance status of 0 or 1 and confirmed primary non-squamous NSCLC with exon 19 deletions or L858R-positivity. Brain imaging was required, if not completed pre-operatively, as well as complete resection with negative margins. The maximum interval between surgery and randomization were 10 weeks for those without adjuvant chemotherapy, and 26 weeks for those with adjuvant chemotherapy.5

Patients were stratified by disease stage, EGFR mutation status, and race, and randomized 1:1 to received either daily osimertinib or placebo. The planned treatment duration was 3 years, and treatment continued until recurrence, completion, or discontinuation.

The primary end point of the study was disease-free survival (DFS) in patients with stage II/IIIa disease, and secondary end points included DFS in the overall population, DFS at 2, 3, 4, and 5 years, OS, safety, and health-related quality of life.

Results showed that osimertinib improved DFS in patients with stage II/IIIa disease, with the median DFS not reached (NR; 95% CI, 38.8–not calculable [NC]) vs 19.6 months (95% CI, 16.6-24.5) with placebo. Additionally, the median DFS was not reached in the overall population (95% CI, NC–NC) with osimertinib vs 27.5 months (95% CI, 22.0-35.0) with placebo.

When broken down by stage, the 2-year DFS rate for those in the osimertinib arm was 87% (95% CI, 77%-93%) for those with stage Ib disease, 91% (95% CI, 82%-95%) for those with stage II disease, and 88% (95% CI, 79%-94%) for those with stage IIIa disease, compared with 73% (95% CI, 62%-81%), 56% (95% CI, 45%-65%), and 32% (95% CI, 23%-42%), respectively.

For patients enrolled on this study, additional considerations beyond the study treatment included local vs distance recurrence, sites of disease recurrence, including incidence of CNS metastases, subsequent therapies, and quality of life, Herbst said.

For those with resected NSCLC, the type of recurrence is a key consideration, as local vs distant recurrence has an impact on post-surgery outcomes. For example, local/regional occurrence is associated with longer post-recurrence survival compared with distance recurrence.6,7 Moreover, because CNS is a common site of metastases among those with EGFR-mutant NSCLC receiving EGFR TKIs, preventing recurrence in the CNS is a significant unmet need.8

On the ADAURA trial, 11% of patients on the osimertinib arm experienced disease progression or death vs 46% on the placebo arm. Additionally, a majority of those who experienced recurrence on the osimertinib arm had local/regional recurrence, with 38% experiencing metastatic recurrence vs 61% on the placebo arm. The most common sites of recurrence in the osimertinib and placebo arms included the lungs (6% vs 18%, respectively), lymph nodes (3% vs 14%, respectively), and CNS (1% vs 10%, respectively).

Next Steps? Targeting Resistance

Currently, there are several ongoing trials further examining osimertinib, such the phase 3 NeoADAURA (NCT04351555) trial, and the phase 3 LAURA trial (NCT03521154), as well as other studies looking at combination strategies and other EGFR TKIs. However, one of the biggest areas of research going forward will be targeting mechanisms of resistance to these agents, Herbst says.

Mechanisms of acquired resistance to first- and second-generation TKIs include secondary mutations in the drug target, activation of bypass signaling pathways, mutations in downstream pathways, and phenotypic changes in the tumor.9

For patients who are TKI-naïve with an EGFR mutation and receive a first- or second-generation EGFR TKI, a physician would perform a biopsy upon progression to determine if the patient was T790M-postive, in which case the patient would move on to osimertinib. After progression on osimertinib, a clinical trial would likely be recommended, according to Herbst. For those who are T790M-negative after the repeated biopsy, a clinical trial would also be recommended, as well as for those who initially receive osimertinib and then develop resistance.

Most (30%-40%) mechanisms of resistance to second-line osimertinib are unknown. Known mechanisms include acquired EGFR mutations (10%-26%), acquired amplifications (5%-50%), transformations (4%-15%), acquired cell cycle gene alterations (12%), acquired oncogenic fusions (3%-10%), and acquired MAPK-PI3K mutations (2%-10%).

Similarly, mechanisms of resistance to first-line osimertinib are largely unknown (40%-50%). Known mechanisms include acquired EGFR mutations (6%-10%), acquired amplifications (8%-17%), transformations (15%), acquired cell cycle gene alterations (10%), acquired oncogenic fusions (1%-8%), and acquired MAPK-PI3K mutations (13%%-14%).

However, strategies for overcoming these mechanisms remain unclear.

“Patients will get a liquid biopsy or repeat tumor biopsy, we will figure out what is the mutation that they have, and perhaps we will know which drug to pull off the shelf, or which combination of drugs to use,” Herbst said. “I rarely will use immunotherapy in these patients, although if there is really nothing else to do, we done it on very few occasions.”


  1. Herbst RS. EGFR Mutation-Positive NSCLC, Including Managing Progression on Osimertinib. Presented at: 16th Annual New York Lung Cancers Symposium; November 6, 2021; virtual.
  2. Yang JC, Ahn M, Ramalingam SS, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study Phase II extension cohort. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 943.
  3. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378:113-125. doi:10.1056/NEJMoa1713137
  4. Li T, Kung HJ, Mack P, et al. Genotyping and genomic profiling of non–small-cell lung cancer: implications for current and future therapies. J Clin Oncol. 2013;31(8):1039-1049. doi:10.1200/JCO.2012.45.3753
  5. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non–small-cell lung cancer. N Engl J Med. 2020;383:1711-1723. doi:10.1056/NEJMoa2027071
  6. Choi PJ, Jeong SS, Yoon SS, et al. Prediction and prognostic factors of post-recurrence survival in recurred patients with early-stage NSCLC who underwent complete resection. J Thorac Dis. 2016; 8(1): 152–160. doi:10.3978/j.issn.2072-1439.2016.01.10
  7. Sekihara K, Hishia T, Yoshida J, et al. Long-term survival outcome after postoperative recurrence of non-small-cell lung cancer: who is 'cured' from postoperative recurrence? Eur J Cardiothorac Surg. 2017;52(3):522-528. doi:10.1093/ejcts/ezx127
  8. Xu ST, Xi JJ, Zhong WZ, et al. The Unique Spatial-Temporal Treatment Failure Patterns of Adjuvant Gefitinib Therapy: A Post Hoc Analysis of the ADJUVANT Trial (CTONG 1104). J Thorac Oncol. 2019;14(3):503-512. doi:10.1016/j.jtho.2018.11.020
  9. Ohashi K, Maruvka Y, Michor F, et al. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol. 2013 Mar 10;31(8):1070-80. doi:10.1200/JCO.2012.43.3912.