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Shigeki Nanjo
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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.01-13 - A Phase 2 Trial Assessing Osimertinib Activity Against Leptomeningeal Carcinomatosis in EGFR-Mutant Lung Cancer (Now Available) (ID 470)
08:00 - 18:00 | Author(s): Shigeki Nanjo
- Abstract
Background
Leptomeningeal carcinomatosis (LMC) occurs in 10 % of EGFR-mutant lung adenocarcinoma (LA). Retrospective studies have suggeted a clinical benefit of osimertinib in treating LMC in patients with EGFR-mutant LA. We conducted a phase 2 prospective trial to demonstrate the clinical efficacy, activity, and LMC-specific mechanisms of resitance to osimertinib in EGFR-mutant LA patients.
Method
We performed gadalidium-enhanced brain MRIs at the time of enrollment, followed by scheduled brain imaging once every six weeks. Clinical neurological exams were performed every four weeks. Adverse Events (AEs) were assessed by NCI-CTCAE Ver. 4. Cerebral spinal fluid (CSF) and plasma was obtained on day 1 and 21 for all patients. The CSF osimertinib penetration rate was measured by liquid-chromatography mass spectrometry (LC-MSMS) and compared to plasma osimertinib levels. Targeted droplet digital PCR (ddPCR) was used to detect copy number changes of Met and the EGFR C797S mutation in patients CSF-DNA and plasma cell free (cf) DNA.
Result
We enrolled six pre EGFR-TKI treated EGFR mutant LA with LMC. We observed a LMC-specific progression free survival of 3.7 months and overall survival of 6.2 months or longer with osimertinib. Four and three of six patients showed neurological and radiological responses, respectively. No patients had any AEs greater than grade 3 and all patients continued osimertinib beyond PD. The osimertinib CSF penetration rate was 1.2±0.5%. Met copy number was normal in plasma, but increased in the CSF of 2/6 patients prior to progression. Met copy number was confirmed in 1/6 patients at the time of progression. An aquired EGFR C797S mutation was observed in 1/6 patients prior to progression.
Conclusion
Osimertinib 80 mg is efficacious in the treatment of LMC in EGFR mutated LA. CSF-specific MET copy number gain and EGFR C797S mutations arise prior to progression in EGFR-mutant LA patients treated with osimeritinib.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-35 - Epithelial-To-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status (ID 671)
09:45 - 18:00 | Author(s): Shigeki Nanjo
- Abstract
Background
ALK rearrangement, most commonly EML4-ALK, is detected in approximately 3%–5% of NSCLC. ALK tyrosine kinase inhibitor (TKI), shows dramatic clinical efficacy, however, almost all patients acquire resistance over time. The most defined mechanism of crizotinib resistance is secondary ALK mutations. A recent study reported that epithelial-to-mesenchymal transition(EMT) and ALK resistance mutation were simultaneously detected in a single tumor lesion in patients with ALK-rearranged lung cancer who were resistant to ALK-TKIs. However, it is still unknown whether ALK-TKI resistant tumor cells combine mesenchymal phenotype with ALK resistance mutation, or each of the mesenchymal type tumor cells and ALK resistance mutation–positive cells coexist in a single lesion. In any of these cases, no therapy for EMT-associated targeted drug resistance has yet been established.
Method
Specimens from a patient with ALK-rearranged lung adenocarcinoma who acquired resistance to crizotinib were stained with IHC, and the epithelial regions (ALK+, vimentin+, and E-cadherin－) and the mesenchymal regions (ALK+, vimentin－, and E-cadherin+) were collected by microdissection. The DNA from the each regions were isolated and the ALK L1196M mutation was detected by degital PCR analysis. Crizotinib-resistant cell line was developed by continuous treatment with crizotinib in the pleural carcinomatosis mouse model inoculated with the crizotinib-sensitive human lung cancer cell line, A925LPE3, which harbors the EML4-ALK gene fusion. The clones were estabilish by limiting dilution and the mechanism of crizotinib resistance was examined by microarray analysis, miRNA array analysis, western blot, and MTT assay. Compounds that overcame crizotinib resistance were screened from a library of 200 kinase inhibitors.
Result
Digital PCR analyses combined with microdissection after IHC staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial-type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor–resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new-generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Moreover, pretreatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo.
Conclusion
These findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor.
