Cancer Res Treat.  2019 Apr;51(2):623-631. 10.4143/crt.2018.151.

Clinical Outcomes of EGFR Exon 20 Insertion Mutations in Advanced Non-small Cell Lung Cancer in Korea

• Byeon S
• Kim Y
• Lim SW
• Cho JH
• Park S
• Lee J
• Sun JM
• Choi YL
• Lee SH
• Ahn JS
• Park K
• Ahn MJ

• KMID: 2464409
• DOI: http://doi.org/10.4143/crt.2018.151

Abstract

PURPOSE
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFR mutations. Given the rarity of this mutation, its clinical outcomes are not fully established.
MATERIALS AND METHODS
Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy.
RESULTS
Of 3,539 NSCLC patients who harbored an activating EGFR mutation, 56 (1.6%) had an exon 20 insertion. Of the advanced NSCLC patients, 27 of 1,479 (1.8%) had an exon 20 insertion. The median overall survival was 29.4 months (95% confidence interval 9.3 to 49.6) for 27 advancedNSCLC patients. The 22 patientswho received systemic CTx achieved a 50.0% response rate and a 77.2% disease control rate, with 4.2 months of progression-free survival. Six patients received EGFR tyrosine kinase inhibitors (TKIs). Three of the four patients that had only an exon 20 insertion showed progressive disease, while one showed stable disease. The othertwo patients had an exon 20 insertion and another EGFR mutation and achieved a partial response.
CONCLUSION
The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common EGFR mutations. Although the response to systemic CTx. in these patients is comparable to that of patients with other mutations, the response rate to first- or second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed.

Keyword

Non-small cell lung cancer; Exon 20 insertion; Epidermal growth factor receptor; Mutation; EGFR tyrosine kinase inhibitor

MeSH Terms

Carcinoma, Non-Small-Cell Lung*
Disease-Free Survival
Drug Therapy
Exons*
Humans
Incidence
Korea*
Mutagenesis, Insertional*
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Retrospective Studies
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor

Figure

• 

  Fig. 1. Distribution of epidermal growth factor receptor (EGFR) mutations in advanced non-small cell lung cancer patients (n=1,479).

• 

  Fig. 2. Kaplan-Meier survival curves. (A) Progression-free survival of patients with an exon 20 insertion receiving systemic chemotherapy. (B) Overall survival of patients with an exon 20 insertion. NSCLC, non-small cell lung cancer.

Reference

References

1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65:87–108.

2. Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2014. Cancer Res Treat. 2017; 49:292–305.

3. Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015; 16:e165–72. .

4. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall-cell lung cancer to gefitinib. N Engl J Med. 2004; 350:2129–39.

5. Fukui T, Otani S, Hataishi R, Jiang SX, Nishii Y, Igawa S, et al. Successful rechallenge with erlotinib in a patient with EGFR mutant lung adenocarcinoma who developed gefitinib-related interstitial lung disease. Cancer Chemother Pharmacol. 2010; 65:803–6.

6. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009; 361:958–67.

7. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-smallcell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12:735–42.

8. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as firstline treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13:239–46.

9. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361:947–57.

10. Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010; 10:760–74.

11. Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ, et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res. 2008; 14:4877–82.

12. Naidoo J, Sima CS, Rodriguez K, Busby N, Nafa K, Ladanyi M, et al. Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib. Cancer. 2015; 121:3212–20.

13. Lund-Iversen M, Kleinberg L, Fjellbirkeland L, Helland A, Brustugun OT. Clinicopathological characteristics of 11 NSCLC patients with EGFR-exon 20 mutations. J Thorac Oncol. 2012; 7:1471–3.

14. Beau-Faller M, Prim N, Ruppert AM, Nanni-Metellus I, Lacave R, Lacroix L, et al. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol. 2014; 25:126–31.

15. 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; 12:220–9.

16. Lee JY, Lim SH, Kim M, Kim S, Jung HA, Chang WJ, et al. Is there any predictor for clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs? Cancer Chemother Pharmacol. 2014; 73:1063–70.

17. Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med. 2013; 5:216ra177.

18. Tu HY, Ke EE, Yang JJ, Sun YL, Yan HH, Zheng MY, et al. A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer. Lung Cancer. 2017; 114:96–102.

19. Kuiper JL, Hashemi SM, Thunnissen E, Snijders PJ, Grunberg K, Bloemena E, et al. Non-classic EGFR mutations in a cohort of Dutch EGFR-mutated NSCLC patients and outcomes following EGFR-TKI treatment. Br J Cancer. 2016; 115:1504–12.

20. 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; 8:179–84.

21. Lin YT, Liu YN, Wu SG, Yang JC, Shih JY. Epidermal growth factor receptor tyrosine kinase inhibitor-sensitive exon 19 insertion and exon 20 insertion in patients with advanced nonsmall-cell lung cancer. Clin Lung Cancer. 2017; 18:324–32.

22. Kosaka T, Tanizaki J, Paranal RM, Endoh H, Lydon C, Capelletti M, et al. Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors. Cancer Res. 2017; 77:2712–21.

23. Yang M, Xu X, Cai J, Ning J, Wery JP, Li QX. NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors. Int J Cancer. 2016; 139:171–6.

24. Masuzawa K, Yasuda H, Hamamoto J, Nukaga S, Hirano T, Kawada I, et al. Characterization of the efficacies of osimertinib and nazartinib against cells expressing clinically relevant epidermal growth factor receptor mutations. Oncotarget. 2017; 8:105479–91.

25. Shen YC, Tseng GC, Tu CY, Chen WC, Liao WC, Chen WC, et al. Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations. Lung Cancer. 2017; 110:56–62.

26. Janne PA, Boss DS, Camidge DR, Britten CD, Engelman JA, Garon EB, et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011; 17:1131–9.

27. Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med. 2018; 24:638–46.