About EGFR-Positive NSCLC

Approximately 15% of patients with NSCLC in the US and 35% of patients from East Asia have tumors with an EGFR (epidermal growth factor receptor) driver mutation. Regardless of the patient's ethnicity, EGFR driver mutations are more often found in tumors of women and nonsmokers. Most commonly, these patients have lung adenocarcinoma.1,2

How is it diagnosed?

Lung cancer is diagnosed using a variety of tests, including imaging, lab tests, and biopsies. Comprehensive biomarker testing can help determine if your lung cancer has an underlying biomarker or “driver mutation” that might make it respond to certain targeted treatments. It is important to know this information because it will help guide you and your doctor to the most appropriate treatments for your particular type of lung cancer.

There are a number of different EGFR mutations, with exon 19 deletions and L858R mutations being the most common, as shown below:

EGFR mutations

(Reproduced from Harrison et al, https://doi.org/10.1016/j.semcancer.2019.09.015)

Treatment options

Currently, EGFR-positive NSCLC responds best to targeted therapy with tyrosine kinase inhibitors (TKIs). There are currently five FDA-approved EGFR TKIs. All of them are approved for EGFR exon 19 deletion and exon 21 (L858R) substitution mutations. Afatinib (Gilotrif®) and osimertinib (Tagrisso®) have additional indications:

  • Afatinib (Gilotrif®):3 Approved for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR non-resistant mutations, as detected by an FDA-approved test. (The most common of these are the exon 19 deletion and the exon 21 (L858R) substitution mutations. The rarer mutations are S768L, L861Q, and G719X.)
  • Dacomitinib (Vizimpro®):4 Approved for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test
  • Erlotinib (Tarceva®):5,6 Approved for the treatment of patients with EGFR-positive metastatic NSCLC. This includes patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test, who are receiving first-line or maintenance treatment, or second- or subsequent-line treatment after progression following at least one prior chemotherapy regimen. Erlotinib (Tarceva®) is also approved in combination with ramucirumab (Cyramza®), an angiogenesis inhibitor, for the first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
  • Gefitinib (Iressa®):7 Approved for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test
  • Osimertinib (Tagrisso®):8 Approved for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test. It is also approved for second-line treatment of patients with metastatic NSCLC whose tumors are EGFR T790M-positive, as detected by an FDA-approved test, and whose disease has progressed on or after EGFR TKI therapy. 

Note: The US FDA granted approval for the use of osimertinib (Tagrisso®) as adjuvant therapy after surgical removal of a tumor in adult patients with stages 1b to IIIa NSCLC whose tumors are mostly nonsquamous and have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.9

Not all mutations in the EGFR gene respond to TKIs. Mutations referred to as exon 20 insertion mutations are one such group.10

There currently is also one FDA-approved EGFR bispecific antibody that targets exon 20 insertion mutations:

  • Amivantamb-vmjw (RybrevantTM):11 Approved for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy

Treatment side effects

Side effects of the EGFR drugs vary by drug and by patient. Some common side effects of EGFR drugs as a group include:3-5,7,8,11

  • Rash
  • Itching
  • Diarrhea
  • Mouth sores
  • Loss of appetite
  • Inflammation around nails
  • Weakness 
  • Cough

Among the more serious but less common side effects of EGFR TKIs as a group are:3-5,7,8

  • Interstitial lung disease
  • Vision toxicities
  • Severe skin lesions
  • Cardiomyopathy
  • Cough

Get more tips on managing treatment-related side effects.

Treatment challenges

Unfortunately, many patients on EGFR TKIs eventually develop drug resistance, meaning the drug stops working and their cancer progresses. Luckily, EGFR-positive NSCLC has a number of FDA-approved drugs, and patients are often able to switch to a different drug once one stops working.

Many research efforts are underway to understand drug resistance and find ways to combat it. For example, researchers are looking at various drug combinations that may help delay or prevent resistance from happening.

Another challenge for EGFR-positive NSCLC is that it doesn’t seem to respond to immunotherapy drugs. Researchers are actively exploring ways to open up immunotherapy options to patients with biomarker-driven NSCLC.

Questions to ask your doctor

  1. Did I receive comprehensive biomarker testing? If not, can I?
  2. Am I eligible for a clinical trial?
  3. Am I eligible for immunotherapy?

Updated August 8, 2021


References

  1. Hirsch FR, Suda K, Wiens J, Bunn PA Jr. New and emerging targeted treatments in advanced non-small cell lung cancer. Lancet. 2016:388(10048):1012-1024.
  2. Zhang Y-L, Yuan J-Q, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Onctotarget. 2016 Nov 29; 7(48): 78985-78993.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346692/. Accessed November 20, 2021.
  3. Gilotrif® (afatinib) tablets [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf. Revised January 2018. Accessed November 17, 2020.
  4. Vizimpro® (dacomitinib) tablets [package insert]. Pfizer Inc. New York, NY. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf. Revised September 2018. Accessed November 17, 2020.
  5. Tarceva® (erlotinib) tablets [package insert]. OSI Pharmaceuticals, LLC. Northbrook, IL. https://www.gene.com/download/pdf/tarceva_prescribing.pdf. Revised October 2016.  Accessed November 17, 2020.
  6. Cyramza® (ramurcirumab) injection [package insert]. Eli Lilly and Company, Indianapolis, IN. https://pi.lilly.cm/us/cyramza-pi.pdf. Posted May 2020. Accessed November 17, 2020.
  7. Iressa® (gefitinib) tablets [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206995s003lbl.pdf. Revised August 2018. Accessed November 17, 2020.
  8. Tagrisso® (osimertinib) tablets [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf. Revised April 2018. Accessed November 17, 2020.
  9.  FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. U.S. Food and Drug Administration website. https://www.fda.gov/drug-approvals-and-databases/fda-approves-osimertinib-adjuvant-therapy-non-small-cell-lung-cancer-egfr-mutations. Posted December 18, 2020. Accessed December 21, 2020.
  10. Vyse S, Huang PH. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Sig Transduct Target Ther. 4, 5 (2019). https://doi.org/10.1038/s41392-019-0038-9. https://www.nature.com/articles/s41392-019-0038-9. Accessed June 1, 2021.
  11. RybrevantTM (amivantamab-vmjw) injection [package insert]. Janssen Biotech, Inc, Horsham, PA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761210s000lbl.pdf. Revised May 2021. Accessed May 30, 2021.