Precise Management of EGFR exon 20-Positive Non–Small Cell Lung Cancer

Research shows that methods used to treat the wide epidermal growth factor receptor-positive population are often not successful for patients with specific biomarkers like EGFR exon 20 insertion mutations, highlighting an ongoing need for more targeted therapies.

Non–small cell lung cancer (NSCLC) carries many disease variations that each require slightly different treatment strategies. Research shows that methods used to treat the wide epidermal growth factor receptor (EGFR)-positive population are often not successful for patients with specific biomarkers like EGFR exon 20 insertion mutations, highlighting an ongoing need for more targeted therapies.

For patients with NSCLC, EGFR genetic alterations are present in 10 to 15 percent of cases. EGFR exon 20 insertions are the third most prevalent activating EGFR mutation. Non-small cell lung cancer driven by this mutation carries a worse prognosis and shorter survival rate compared with lung cancer driven by more common EGFR mutations, such as exon 19 deletions and L858R substitution.1-8 In addition, these patients have a real-world 5-year overall survival of 8%, which is worse than patients with more common EGFR mutations, who have a real-world 5-year overall survival of 19%.9

“The prognosis for these patients is unfavorable – with overall survival rates much lower than seen in non-small cell lung cancer where more common EGFR mutations are present - and is similar to what we see with wild-type lung cancer, prior to the advent of the new agents,” said Alexander Spira, M.D., Ph.D., FACP, Director of the Virginia Cancer Specialists Institute.

Testing in Patients With EGFR Exon 20 Insertion-Positive NSCLC

Precision medicine for EGFR exon 20-insertion positive NSCLC begins with biomarker testing that can inform treatment decisions and later improve treatment outcomes.

Testing for EGFR mutations is the leading form of biomarker testing being implemented in clinical practice settings compared with other biomarkers for NSCLC like ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as PD-L1 status. Wider testing practices for EGFR mutations may be directly related to the 2013 guideline from the College of American Pathologists, which clearly recommends EGFR testing for patients, but leaves the decision about testing for other biomarkers up to the expert.10

Roughly 15% of patients with nonsquamous NSCLC undergo testing for an EGFR mutation, while only 5.5% or fewer are tested for other biomarkers. In patients with squamous histology, about 4.4% of patients are tested for an EGFR mutation compared with less than 1% who are tested for all other biomarkers. The method of testing also matters. A wide variety of unique EGFR exon 20 insertion variants have been identified by next-generation sequencing (NGS) testing methods, 50% of which would have been missed if using polymerase chain reaction (PCR) based assays.5

“We always need to do more testing as it is likely to help us identify which therapy may be best suited to a patient’s specific needs. It’s also important to understand the differences between exon 20-mutated EGFR and exon 19/21-mutated EGFR when testing,” Spira explained.

Many treatment guidelines omit testing for EGFR exon 20 insertion mutations and only recently, as new targeted therapies have been introduced, have the guidelines from the National Comprehensive Cancer Network (NCCN) been updated to call out the importance of testing for these mutations.11 Despite this update, the lack of guidelines requiring oncologists to test for EGFR exon 20 insertion mutations may be keeping novel therapies from moving forward in development. Thus, outcomes for patients with EGFR exon 20 insertion-positive NSCLC are subpar.4

Treating EGFR exon 20 Insertion-Positive NSCLC

Joshua K. Sabari, MD, assistant professor, Department of Medicine, NYU Grossman School of Medicine, and Spira, explained the key challenges they observe with treating EGFR exon 20 insertion-positive NSCLC.

EGFR exon 20 insertion-positive non–small cell lung cancer is a rare disease. The current standard of care in most countries is chemotherapy alone and the median progression-free survival on standard chemotherapy doublet is about 7 months. So, in most of the world, we need better therapeutics for this patient population,” said Sabari.

Further, some oncologists have frustration around treating the disease. “The key challenge is that EGFR exon 20 insertion-positive non–small cell lung cancer is just treated like other lung cancer [subtypes]. We know there's a targetable mutation, and it's been very frustrating because we can’t act on it,” Spira expressed.

With EGFR exon 20 insertion mutations, targeting the disease is challenging as patients have different outcomes following treatment with the available EGFR inhibitors. In a retrospective study of uncommon EGFR mutations, 12 patients with EGFR exon 20 insertion mutations who were treated with EGFR inhibitors showed lower overall and progression-free survival compared with patients who had EGFR G719X and EGFR L858R mutations.12

“Patients who have EGFR exon 20 insertion-positive non–small cell lung cancer do not respond to standard tyrosine kinase inhibitors, or TKIs, that are typically highly effective in EGFR exon 19 and exon 21. Globally, there is a need for additional exon 20-specific inhibitors or EGFR inhibitors that have more broad activity in exon 20,” Sabari commented.

Other challenges exist in the treatment of this patient population, Spira noted. “Getting people to test and understand the role of exon 20 is a key challenge.”

The future of treating this patient population rests in the continued advancement of clinical trials.

“There's an explosion of therapeutic opportunities in development for patients with EGFR exon 20 insertion-positive non–small cell lung cancer. Avenues of therapy include TKI therapy that is directly targeted to EGFR exon 20 insertion mutations and other small molecules that specifically inhibit these mutations. There are many exon 20-specific TKIs in development,” Sabari shared. “Another avenue of therapeutic approach is to use an antibody that blocks EGFR,” he added.

References:

1. Duma N, et al. Mayo Clin Proc. 2019;94(8):1623-1640. 9

2. Chan B, et al. Transl Lung Cancer Res. 2015;4(1):36-54

3. Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013;12(2):220-229.

4. Oxnard GR, Lo PC, Nishino M, Dahlberg SE, Lindeman NI, Butaney M, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013;8(2):179-184.

5. Riess JW, Gandara DR, Frampton GM, Madison R, Peled N, Bufill JA, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of non-small cell lung cancer. J Thorac Oncol. 2018;13(10):1560-1568.

6. Burnett H, Emich H, Carroll C, Stapleton N, Mahadevia P, Li T. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.

7. Bauml JM, Viteri S, Minchom A, Bazhenova L, Ou SI, Schaffer M, et al. Underdiagnosis of EGFR exon 20 insertion mutation variants: estimates from NGS-based real-world datasets. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 28, 2021; Singapore

8. Vyse, S., Huang, P.H. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Sig Transduct Target Ther 4, 5 (2019).

9. Girard N, Bazhenova L, Minchom A, Ou SI, Gadgeel SM, Trigo J, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.

10. Griesinger F, Eberhardt W, Nusch A, et al. Biomarker testing in non-small cell lung cancer in routine care: Analysis of the first 3,717 patients in the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315). Lung Cancer. 2020:152; 174-184. doi: 10.1016/j.lungcan.2020.10.012

11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® Non-Small Cell Lung Cancer Version 5.2021- June 2021. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

12 Tu HY, Ke EE, Yang JJ, et al. A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer. Lung Cancer. 2017. 114:96-102. doi: 10.1016/j.lungcan.2017.11.005.