CG Consult of the week 16.09.2023

Case history:

68-year old male diagnosed with EGFR-mutated lung adenocarcinoma (Del19). Started on 2nd generation EGFR TKI, 9 months later CT scan showed disease progression in CN. Plasma PCR-based testing showed a new EGFR T790M mutation. Treatment changed to 3rd generation EGFR TKI due to liquid findings and the patient’s partial respons. CT scan 7 months post treatment showed further disease progression in brain and lung. A repeat lung biopsy was sent for clinically validated molecular profiling. Pathology results suggest SCLC transformation.

Genomic Profiling Results

  • EGFR del E756_A750
  • TP53 splice site 375G>T
  • RB1 Y446*
  • TET2 L1398fs*50


Why might this oncologist choose a 2nd-gen TKI to start?
Where did the EGFR-T790M mutation go in the latest results?

First, advise the oncologist that patient advocacy groups exist for patients with EGFR-mutated lung cancers at and the

Acquired resistance mechanisms to osimertinib can be broadly classified into two groups: (I) on-target or EGFR-dependent and (II) off-target or EGFR-independent mechanisms, which utilize pathways or methods to overcome dependence on EGFR signalling (1).

Histologic transformation from NSCLC to small-cell lung cancer (SCLC) has been reported as an important cause of resistance to osimertinib(1). Therapy-resistant cells can accumulate genomic alterations which enable them to differentiate into a lineage that does not depend on EGFR signalling(2). The acquisition of RB and TP53 alterations appear to be prerequisites for transformation(2).
In this case, it appears the transformed SCLC tumor sample retained its original EGFR-activating mutation, suggesting that this tumor underwent a transformation of the primary adenocarcinoma, as opposed to a de-novo separate SCLC.

RB1 and TP53 loss suggest small cell transformation, so it is important to examine the repeat biopsy to select a subsequent therapeutic strategy. 

There are no approved targeted therapies available for SCLCs, platinum-based chemotherapy is still considered the standard of care. Immunotherapy has been disappointing in SCLC, but based on the recent positive results of the CASPIAN and Impower133 trials, the combination of etoposide and platinum with either durvalumab or atezolizumab may emerge, though neither trial included patients with transformed SCLC (3, 4).

Strong preclinical and limited clinical data suggest that RB1 inactivation may be associated with sensitivity to inhibitors of Aurora kinase A, particularly in SCLC. Early-phase clinical trials showed promising results, but require further validation. A clinical trial of Aurora A kinase-directed therapy may be an option when other options are exhausted.


  • Osimertinib resistance can be mediated by EGFR-independent mechanisms including histologic transformation, and can co-occur within the same tumor
  • Tumor re-biopsy should be performed routinely when EGFR TKI therapy fails in NSCLC


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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