CG Consult of the week 24.11.2023

Case History:

A 74-year-old male was diagnosed with stage IV lung adenocarcinoma.
Pathology results were wild-type for EGFR/ALK/ROS1 (using a hotspot lung panel) with high PD-L1 expression. Based on these results, the patient received 4 cycles of immune checkpoint inhibitor (PD-L1). Immunotherapy treatment was discontinued due to pseudoprogression, and later MRI confirmed disease progression. At this stage, a blood-based genomic profiling test was performed using a clinically validated, high-quality broad-panel liquid biopsy service (see below). Based on the genomic findings, the patient was started on second-generation EGFR TKI, based on existing evidence in NSCLC with kinase domain duplications. Unfortunately, soon after a follow-up PET-CT showed continued disease progression.

Genomic Profiling Results:

  • EGFR kinase domain duplication
  • TET2 S1848*
  • MYC amplification
  • TP53 P151S

Questions from the oncologist:

  • Considering the treatment history so far, what do the genomics tell us about this patient’s lack of response to EGFR TKIs?
  • Might this patient benefit from a 3rd-generation EGFR TKI?
  • Are there any novel therapeutic combinations we should be aware of?


First, advise the oncologist that patient support and advocacy groups exist for patients with EGFR+ lung cancer at and

EGFR kinase domain duplication (EGFR-KDD) is well recognized as a novel activation mechanism of EGFR (1), and as an oncogenic driver in lung cancer (2). This chromosomal rearrangement typically harbors two tandem, in-frame copies of the complete wild-type EGFR kinase domain. It is important to note that the mechanism of activation is quite distinct from the molecular mechanisms driving activation of EGFR kinase domain mutations (1).
Although several case studies have reported the efficacy of second generation EGFR-TKI, afatinib, in advanced lung adenocarcinoma harboring EGFR-KDD, antitumor responses were variable (2, 3, 4). In comparison to 2nd generation EGFR TKIs, the third-generation TKI osimertinib, showed early promise but has only delivered partial responses up to now (3). Germane to this case, co-alterations in MYC may preclude benefit from osimertinib (5). Collectively, these observations suggest that more potent EGFR blockade is necessary to overcome the oncogenic activity of EGFR-KDD.
These cases are rare, and there are few studies on the acquired resistance mechanism of EGFR-KDD tumors. The amplification of EGFR and/or the existence of EGFR C797S mutations in post-TKI biopsies were reported as acquired resistance mechanisms of EGFR-KDD in patients with NSCLC (6). Of note, none of these aberrations in EGFR were detected in liquid biopsy-based NGS.
Based on the mechanism of activation, one potential strategy to achieve maximum inhibition of EGFR-KDD activity could be to block both intra- and inter-molecular dimerization. A recent study showed that EGFR-KDD functions by forming EGFR-independent intra-molecular and EGFR-dependent inter-molecular dimers, posing a unique therapeutic challenge (7). With this functional information in mind, a combination of EGFR monoclonal antibody with a TKI would simultaneously reduce activity. Hence, this study reported the combination of cetuximab + afatinib yielding significant inhibitory effects when these two inhibitors combined (7).

Learnings From This Case: 

  • EGFR-KDD is a rare oncogenic driver alteration and serves as a potential therapeutic target
  • Not all mutations within a given gene can be therapeutically targeted in the same manner
  • EGFR-TKIs in advanced lung adenocarcinomas with EGFR-KDD yielded variable antitumor responses



Disclaimer: all CGCotW cases are based on a true story. No resemblance to persons alive or deceased is intended or should be inferred. ©️ CGC Genomics Consults AG

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