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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 (

)-positive population are often not successful for patients with specific biomarkers like 

 exon 20 insertion mutations, highlighting an ongoing need for more targeted therapies.

 genetic alterations are present in 10 to 15 percent of cases. 

 exon 20 insertions are the third most prevalent activating 

 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 

 mutations, such as exon 19 deletions and L858R substitution.

 In addition, these patients have a real-world 5-year overall survival of 8%, which is worse than patients with more common 

 mutations, who have a real-world 5-year overall survival of 19%.

“The prognosis for these patients is unfavorable – with overall survival rates much lower than seen in non-small cell lung cancer where more common 

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.

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

 mutations is the leading form of biomarker testing being implemented in clinical practice settings compared with other biomarkers for NSCLC like 

, HER2, as well as PD-L1 status. Wider testing practices for 

 mutations may be directly related to the 2013 guideline from the College of American Pathologists, which clearly recommends 

 testing for patients, but leaves the decision about testing for other biomarkers up to the expert.

Roughly 15% of patients with nonsquamous NSCLC undergo testing for an 

 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 

 mutation compared with less than 1% who are tested for all other biomarkers. The method of testing also matters. A wide variety of unique 

 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.

“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 

Many treatment guidelines omit testing for 

 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.

Despite this update, the lack of guidelines requiring oncologists to test for 

 exon 20 insertion mutations may be keeping novel therapies from moving forward in development. Thus, outcomes for patients with 

 exon 20 insertion-positive NSCLC are subpar.

Joshua K. Sabari, MD, assistant professor, Department of Medicine, NYU Grossman School of Medicine, and Spira, explained the key challenges they observe with treating 

 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 

 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.

 exon 20 insertion mutations, targeting the disease is challenging as patients have different outcomes following treatment with the available 

 inhibitors. In a retrospective study of uncommon 

 exon 20 insertion mutations who were treated with 

 inhibitors showed lower overall and progression-free survival compared with patients who had 

 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 

 exon 19 and exon 21. Globally, there is a need for additional exon 20-specific inhibitors or 

 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 

 exon 20 insertion-positive non–small cell lung cancer. Avenues of therapy include TKI therapy that is directly targeted to 

 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 

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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. 

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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

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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.

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Articles

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.

Sponsored Content by The Janssen Pharmaceutical Companies of Johnson & Johnson | Authors

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