Complex EGFR mutations in non-small cell lung cancer: a distinct entity?

Complex EGFR mutations in non-small cell lung cancer: a distinct entity?

Michał Bieńkowski1, Rafał Dziadziuszko2, Jacek Jassem2

1Department of Pathomorphology, Medical University of Gdańsk, Gdańsk, Poland; 2Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland

Correspondence to: Prof. Jacek Jassem, MD, PhD. Department of Oncology and Radiotherapy, Medical University of Gdańsk, Smoluchowskiego 17, 80-214 Gdańsk, Poland. Email:

Comment on: Li HS, Li JL, Yan X, et al. Efficacy of dacomitinib in patients with non-small cell lung cancer carrying complex EGFR mutations: a realworld study. J Thorac Dis 2022;14:1428-40.

Submitted Apr 02, 2022. Accepted for publication Jun 28, 2022.

doi: 10.21037/jtd-2022-05

Small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have revolutionized the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). Consequently, EGFR TKIs currently constitute standard therapy in this group of patients. There are three generations of EGFR-TKIs approved for this indication: the first generation (erlotinib, gefitinib, and icotinib), the second generation (afatinib, and dacomitinib), and the third generation (osimertinib).

EGFR-activating mutations are typical for lung adenocarcinomas and are relatively frequent in non-smokers, females, and East Asian patients. Common (classical) mutations, constituting up to 90% of EGFR mutations, include small in-frame deletions within exon 19 (codons 746-750) and a point mutation within exon 21 (L858R) (1). The remaining EGFR mutations (uncommon; non-classical) may be intrinsic (primary) or secondary, related to acquired resistance to EGFR TKIs (2-4). A small subset of EGFR-mutated tumors (1% to 9%) harbor two or more different primary EGFR mutations (5-9). Such complex mutations include double common, double uncommon, or mixed EGFR mutations. Complex mutations involving L858R have been consistently found to be more frequent than those involving exon 19 deletions (8-10).

Due to the rarity of complex mutations, their biological significance remains unclear. The combination of both common mutations (L858R and exon 19 deletions) seems to be more sensitive to TKIs than other combinations (9), and the coexistence of two uncommon mutations shows a better response to TKIs than single uncommon mutations (10,11). The latter may be due to a lower activating potential (and thus a lower extent of oncogene addiction) of single uncommon mutations (10,11). Most recently, data on a large cohort of NSCLC patients with uncommon and very rare mutations and their combinations (n=856) have been reported (12). The study indicated a general benefit of EGFR-TKI treatment (versus chemotherapy) for NSCLC with any mutation other than exon 20 insertions, for which new treatment modalities (i.e., mobocertinib and amivantamab) have been recently approved by the Food and Drug Administration. In turn, the clinical data on the combination of common and uncommon EGFR mutations are scarce.

The retrospective study by Li et al. (13) provides real-world data on the efficacy of a second-generation TKI dacomitinib in NSCLC patients with single common and complex (common plus uncommon) EGFR mutations in the Chinese population. The reference group in this study were patients with common EGFR mutations. Dacomitinib has been less frequently used than other EGFR TKIs, and there is relatively little post-marketing information on this compound. However, the genuine values of this study are novel data on dacomitinib efficacy in a subset of patients with unique complex EGFR mutations. The response rate of 40% argues for the moderate activity of dacomitinib in this population, but this outcome should be interpreted cautiously. The study group was small (15 evaluable patients), heterogeneous in stages (III and IV), location of metastases, number and type of prior therapies, and drug dosing. Somewhat surprisingly, there was an apparent overrepresentation of patients with L858R mutation in both subgroups (76% of cases with single and 89% with complex mutations). The latter may be explained by a generally lower occurrence of exon 19 deletions within complex mutations (8-10). On the other hand, L858R mutation in general East Asian populations is less frequent than exon 19 deletions (1), indicating a possible selection bias.

A few randomized studies compared first- vs. second- and third-generation EGFR TKIs (14-18). Second-generation compared with first-generation EGFR-TKIs have shown higher antitumor activity, but at the expense of increased toxicity, likely due to their irreversible mode of EGFR inhibition. There have been no direct comparisons of second- vs. third-generation EGFR TKIs. Several network meta-analyses using indirect comparisons have consistently shown the superiority of osimertinib over any other EGFR-TKI, including dacomitinib (19-21). Additionally, osimertinib can overcome T790M mutation, which is resistant to first- and second-generation EGFR-TKIs, and has an acceptable safety profile. Finally, as opposed to other EGFR TKIs, osimertinib shows impressive efficacy against brain metastases (22). Several other third-generation EGFR-TKIs have demonstrated promising activity in preclinical and clinical trials (23). Hence, whether dacomitinib or other first- or second-generation TKIs should still be considered the first-line option in EGFR-mutated NSCLC patients is questionable.

Different mutations seem to have disparate effects on EGFR activity and sensitivity to individual TKIs (3,4). However, the majority of industry-sponsored randomized clinical trials (with the exception of the afatinib development program) allowed exclusively common EGFR mutations. The largest report on the afatinib activity in EGFR uncommon mutations (24) included 693 patients from prospective Lux-Lung studies, cohort studies, and case series. Of those, 35 subjects with complex mutations were identified, including 23 with major uncommon mutations. About half of these patients were TKI-pretreated. The objective response rate of 77% and median duration of response of 16.6 months appear to be at least equal to the afatinib outcomes in patients with common EGFR mutations. Since afatinib and dacomitinib have a similar mechanism of action (both are irreversible second-generation EGFR inhibitors), their clinical activity is likely comparable. With virtually no clinical data on dacomitinib in this patient subset, the study by Li et al. (13) provides further insight into this underexplored area.

Despite impressive responses, most patients managed with EGFR TKIs will develop drug resistance via acquired EGFR mutations or other non-EGFR mediated molecular mechanisms. Thus, there is a sore need for new therapies targeting such resistance-related EGFR mutations. Novel third and fourth-generation EGFR TKIs, or other targeted agents against non-EGFR pathways may contribute to achieving this goal (25).


Funding: None.


Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at RD declares advisory roles for AstraZeneca, Roche, Boehringer-Ingelheim, MSD, Amgen, Pfizer, Bristol-Myers Squibb, Karyopharm, Bayer and FoundationMedicine. JJ declares advisory roles for AstraZeneca, MSD and Exact Sciences. MB has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See:


  1. Melosky B, Kambartel K, Häntschel M, et al. Worldwide Prevalence of Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer: A Meta-Analysis. Mol Diagn Ther 2022;26:7-18. [Crossref] [PubMed]
  2. 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. [Crossref] [PubMed]
  3. Gristina V, Malapelle U, Galvano A, et al. The significance of epidermal growth factor receptor uncommon mutations in non-small cell lung cancer: A systematic review and critical appraisal. Cancer Treat Rev 2020;85:101994. [Crossref] [PubMed]
  4. Passaro A, Mok T, Peters S, et al. Recent Advances on the Role of EGFR Tyrosine Kinase Inhibitors in the Management of NSCLC With Uncommon, Non Exon 20 Insertions, EGFR Mutations. J Thorac Oncol 2021;16:764-73. [Crossref] [PubMed]
  5. Beau-Faller M, Prim N, Ruppert AM, 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. [Crossref] [PubMed]
  6. Shen YC, Tseng GC, Tu CY, 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. [Crossref] [PubMed]
  7. Zhang B, Wang S, Qian J, et al. Complex epidermal growth factor receptor mutations and their responses to tyrosine kinase inhibitors in previously untreated advanced lung adenocarcinomas. Cancer 2018;124:2399-406. [Crossref] [PubMed]
  8. Wu SG, Yu CJ, Yang JC, et al. The effectiveness of afatinib in patients with lung adenocarcinoma harboring complex epidermal growth factor receptor mutation. Ther Adv Med Oncol 2020;12:1758835920946156. [Crossref] [PubMed]
  9. Hata A, Yoshioka H, Fujita S, et al. Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer. J Thorac Oncol 2010;5:1524-8. [Crossref] [PubMed]
  10. Chen Z, Feng J, Saldivar JS, et al. EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids. Oncogene 2008;27:4336-43. [Crossref] [PubMed]
  11. Chiu CH, Yang CT, Shih JY, et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations. J Thorac Oncol 2015;10:793-9. [Crossref] [PubMed]
  12. Janning M, Süptitz J, Albers-Leischner C, et al. Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM). Ann Oncol 2022;33:602-15. [Crossref] [PubMed]
  13. Li HS, Li JL, Yan X, et al. Efficacy of dacomitinib in patients with non-small cell lung cancer carrying complex EGFR mutations: a real-world study. J Thorac Dis 2022;14:1428-40. [Crossref] [PubMed]
  14. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020;382:41-50. [Crossref] [PubMed]
  15. Park K, Tan EH, O'Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016;17:577-89. [Crossref] [PubMed]
  16. Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015;16:897-907. [Crossref] [PubMed]
  17. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:1454-66. [Crossref] [PubMed]
  18. Ramalingam SS, O'Byrne K, Boyer M, et al. Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials. Ann Oncol 2016;27:1363. [Crossref] [PubMed]
  19. Lin JZ, Ma SK, Wu SX, et al. A network meta-analysis of nonsmall-cell lung cancer patients with an activating EGFR mutation: Should osimertinib be the first-line treatment? Medicine (Baltimore) 2018;97:e11569. [Crossref] [PubMed]
  20. Holleman MS, van Tinteren H, Groen HJ, et al. First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis. Onco Targets Ther 2019;12:1413-21. [Crossref] [PubMed]
  21. Zhao Y, Liu J, Cai X, et al. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. BMJ 2019;367:l5460. [Crossref] [PubMed]
  22. Mok T, Ahn MJ, Han JY, et al. CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3). J Clin Oncol 2017;35:9005. [Crossref]
  23. Du X, Yang B, An Q, et al. Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors. Innovation (Camb) 2021;2:100103. [Crossref] [PubMed]
  24. Yang JC, Schuler M, Popat S, et al. Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases. J Thorac Oncol 2020;15:803-15. [Crossref] [PubMed]
  25. Li R, Zhou X, Yao H, et al. Four generations of EGFR TKIs associated with different pathogenic mutations in non-small cell lung carcinoma. J Drug Target 2020;28:861-72. [Crossref] [PubMed]
Cite this article as: Bieńkowski M, Dziadziuszko R, Jassem J. Complex EGFR mutations in non-small cell lung cancer: a distinct entity? J Thorac Dis 2022;14(8):2738-2741. doi: 10.21037/jtd-2022-05

Download Citation