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M. Nishino
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-059 - T790M and C797S as Mechanisms of Acquired Resistance to Dacomitinib in Cell Models (ID 10314)
09:30 - 09:30 | Author(s): M. Nishino
- Abstract
Background:
The ARCHER 1050 trial demonstrated the superiority of dacomitinib to gefitinib in terms of PFS. Lung cancers inevitably acquire resistance to these TKIs after an initial dramatic response. We previously reported that L792F and C797S, in addition to the major T790M, can develop in afatinib-resistant cells (Mol Cancer Ther 2017; 16: 357-64). This study aimed to clarify the mechanisms of acquired resistance to dacomitinib.
Method:
EGFR Del19, L858R, and G719A were introduced into Ba/F3 cells using retroviral vector. Dacomitinib-resistant clones were established from these Ba/F3 cells by exposure to fixed concentrations of dacomitinib (20nM or 200nM) using N-ethyl-N-nitrosurea (ENU) mutagenesis. EGFR secondary mutations were analyzed by Sanger sequence.
Result:
ENU mutagenesis screening established 21 dacomitinib-resistant clones so far: 10 Del19 clones with 20nM, 9 Del19 clones with 200nM, and 2 L858R clones with 20nM. T790M and each original mutation were detected in all of these resistant clones by mutational analyses.
Conclusion:
These preliminary data demonstrate that dacomitinib can directly induce T790M secondary mutation without selecting de novo T790M clones. Osimertinib could be potentially effective for a subset of lung cancers which acquired resistance to dacomitinib. Updated additional data will be presented.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-049 - Surgery with Continued TKI Therapy After Acquiring Resistance to EGFR or ALK TKI (ID 10461)
09:30 - 09:30 | Author(s): M. Nishino
- Abstract
Background:
Lung cancer with ALK or EGFR activation inevitably acquires resistance to respective TKIs despite an initial good response. Relapses with only a limited number of regions, so-called oligo-recurrences, occur in a subset of such patients. Here, we present two cases of lung cancer treated with surgery and continued TKI therapy after acquiring resistance to EGFR or ALK TKI.
Method:
Retrospecive review of patient charts.
Result:
Case1: A 46-year-old man was diagnosed as having ALK-positive adenocarcinoma with pleural dissemination by exploratory thoracotomy. After 2.5 years’ treatment with alectinib, the primary tumor in the left lower lobe gradually progressed. Left S6 segmentectomy was performed. Genetic analyses of resected specimens revealed ALK G1202R resistant mutation. Alectinib treatment was resumed after surgery and the patient is free of disease 1.5 year after surgery. Case2: A 65-year-old woman presented with lung cancer with ureteral metastasis. Genetic analyses of resected ureteral tumor revealed EGFR L858R point mutation. Gefitinib was initiated and partial response was observed. After 1 year treatment with gefitinib, right middle lobectomy was performed to resect the remaining tumor. Gefitinib treatment was continued and recurrence-free survival of 2 years was achieved.
Conclusion:
These two patients appear to benefit from surgery and continued TKI therapy after acquiring resistance to EGFR or ALK TKI. It may be one of the treatment strategy in selected patients.
