Author of

• 25905

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  MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD

  • 26047

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    MA16.04 - Clinical and Molecular Characteristics of EGFR Mutant Lung Cancers with Concurrent TP53 and RB1 Mutations. (ID 12513)

    13:55 - 14:00  |  Author(s): Megan Tenet
    • Abstract
    • Presentation
    • Slides

    Background
    

    20% of patients with metastatic lung adenocarcinoma have activating EGFR-mutations. EGFR-mutant lung cancers can undergo histologic transformation to small cell lung cancer (SCLC) as a response to the selective pressure of EGFR-TKIs in <5% of patients after earlier-generation EGFR-TKIs and have been reported after osimertinib. SCLC nearly universally harbor TP53/RB1-alterations which are rarely seen in EGFR-mutant lung adenocarcinomas. We sought to identify this subset of patients, describe their clinical course and likelihood of SCLC transformation.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Retrospective review of targeted next generation sequencing (NGS, MSK-IMACT) at Memorial Sloan Kettering (MSK) was performed to identify patients with concurrent EGFR-activating mutations and TP53/RB1-mutations within the same tumor sample from NGS between April 2014 to February 2018 with a data cutoff of March 2018. For comparison, consecutive patients with lung cancers harboring EGFR-mutations who were EGFR-TKI naïve and TP53/RB1-wildtype were also collected during that time-period.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Of the 21% of lung cancer patients with activating EGFR-mutations (759/3662), 5% (40/759) had concurrent TP53/RB1-mutations. 43% (17/40) were female, 58% former-smokers (23/40, median pack-years: 8), and median age of 68 (range 25-86 years). 88% (35/40) were adenocarcinoma at diagnosis, of which 11% (4/35) transformed to SCLC during treatment; 10% (4/40) were de-novo SCLC at diagnosis, and 1 was large cell neuroendocrine. The transformation rate was significantly higher compared to previous work from MSK evaluating EGFR-mutant patients showing 4% (4/155) transformation (p=0.04). Concurrent PIK3CA mutations were more frequently seen in the EGFR/TP53/RB1 mutant group compared to the TP53/RB1-wildtype group (17% (n=6/35) vs 7% (n=4/60), p=0.11). 20 patients were EGFR TKI-naïve at the time of NGS; the median time on EGFR-TKI (ToT) was 7.6 months versus 14.2 months in the TP53/RB1-wildtype group (HR 4.48, p=0.0003). The overall survival (OS) of this cohort versus TP53/RB1-wildtype was not different (4.3 vs 4.1 years, HR 1.35, p=0.51). In the 4 patients with SCLC transformation, the median time to transformation was 2.4 years after a median of 1.5 EGFR-TKI therapies (range 1-5 lines). Median OS from time of transformation was 7 months. 63% (25/40) of the EGFR/TP53/RB1-mutant cohort had brain metastases during their disease course as compared to 50% (n=30) in the TP53/RB1-wildtype group (p=0.30).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    SCLC transformation is enriched in EGFR/TP53/RB1-mutant lung cancers, occurring in 11% of patients. Once SCLC transformation occurs, overall survival is short. Patients with EGFR/TP53/RB1 have a shorter time on EGFR-TKI. Further investigation into optimal treatment for this subset of EGFR/TP53/RB1 mutant lung cancers is critical.

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