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Edyta Maria Urbanska
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.16 - EGFR-L858R NSCLC with Pleiotropic Resistance Mechanisms: T790M, C797S, SCLC-Transformation and KRAS, TP53, and BRAF Mutations. (ID 1181)
00:00 - 00:00 | Presenting Author(s): Edyta Maria Urbanska
- Abstract
Introduction
NSCLC patients with EGFR exon 19del or L858R mutations can achieve long survival under treatment with EGFR-TKI. However, different mechanisms of resistance may occur displaying the disease heterogeneity, but also representing potential targets for new therapies. We present a case of a 57-year-old woman, light smoker with disseminated EGFR L858R mutation-positive NSCLC treated with 1st line Erlotinib, 2nd line Osimertinib followed by TKI-chemotherapy combination, resulting in OS of 3 years. During the treatment we observed consecutive and coexisting mechanisms of acquired resistance indicative of disease complexity. Deeper knowledge of these TKI-resistance mechanisms is necessary for future combination therapies.
Methods
Diagnostic biopsy at baseline and subsequent tumor-rebiopsies at progressions were examined by targeted next-generation sequencing of genomic DNA (Oncomine™ Focus; ThermoFisher Scientific) and total RNA (Archer® FusionPlex Solid Tumor panel; ArcherDx). Circulating free DNA (cfDNA) from plasma was analyzed for relevant mutations by Oncomine Lung cfDNA NGS-assay (ThermoFisher Scientific).
Results
At diagnosis, the patient had multiple brain and bone metastases and was treated with Erlotinib, whole-brain-radiotherapy (WBRT) and palliative bone radiation. Despite radiological SD, a liquid biopsy (LB) six months later revealed persistent EGFR-L858R mutation in the cfDNA. After 9 months of Erlotinib treatment the tumor progressed with liver metastasis. The 1st rebiopsy revealed T790M mutation and the patient started Osimertinib. After 8 months, isolated metastatic adrenal progression was observed and 2nd rebiopsy revealed persistent EGFR-L858R, -T790M, and a new -C797S mutation in cis-position. The patient received stereotactic radiotherapy, continued Osimertinib, and after 11 months a new LB still showed EGFR-L858R, while after 14 months, progression emerged with new thoracic, hepatic and adrenal metastases. Rebiopsy of a thoracic lesion revealed phenotypic transformation to small-cell carcinoma (SCLC), while concomitant LB showed EGFR-L858R, -T790M, TP53 (Y220C), and KRAS (G12V) mutations. Carboplatin/Etoposide was initiated while continuing Osimertinib. After 3 cycles, a CT-scan showed PR in the thorax, but mixed response of liver metastases. The 4th hepatic rebiopsy only displayed NSCLC with EGFR-L858R. Osimertinib was continued and chemotherapy modified to Carboplatin/Pemetrexed. However, contemporaneous cfDNA contained persistent co-existing EGFR-L858R, EGFR-T790M, EGFR-C797S, KRAS-G12V, and TP53-Y220C, indicating multiclonal disease. The patient’s condition deteriorated with additional pulmonary embolism. Osimertinib was continued together with Gefitinib. The following CT scan showed thoracic SD, but new hepatic progression. The patient´s PS terminally worsened to 4. The last LB showed persistent EGFR-L858R, EGFR-T790M, KRAS-G12V, and TP53-Y220C clones, as well as newly appeared BRAF-V600E mutation.
Conclusion
1. EGFR-L858R NSCLC is biologically unstable disease and may display variable EGFR-dependent/-independent mechanisms of acquired TKI-resistance detectable both in tumor-rebiopsies and LBs, with the latter ones being more suitable for identifying multiple resistant clones and the former ones necessary for recognition of SCLC-transformation.
2. In our patient, persistent EGFR-L858R mutation in the cfDNA 6 months after Erlotinib-start and 11 months after Osimertinib-start correlated with aggressive disease course.
3. The TKI-resistance mechanisms observed in the terminal phase (KRAS- and BRAF-mutations) represent targets for emerging combination-treatment options that are appearing in the repertoire of targeted therapies for NSCLC and may lead extended control of this complex disease in the future.