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OA08 - Targeted Therapies in Brain Metastases (ID 381)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
OA08.03 - MET Copy Number Gain Associates with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR Mutant Lung Cancer (ID 4364)
16:00 - 17:30 | Author(s): A. Hata
Central nervous system (CNS) metastasis, such as brain metastasis and leptomeningeal carcinomatosis (LMC), occurs frequently in EGFR mutant lung cancer. EGFR-TKIs are generally effective to CNS metastasis in EGFR mutant lung cancer patients who are naïve to TKI treatment. Nevertheless, progression of CNS lesions are frequently observed during EGFR-TKI treatment. Brain metastases are manageable by concomitant use of EGFR-TKI and local intervention, including whole brain irradiation and stereotactic radiotherapy. There is, however, no established therapy for LMC, which is resistant to first and second generation EGFR-TKIs. Therefore, novel and effective therapies need to be developed for managing LMC in EGFR mutant lung cancer patients who become refractory to these EGFR-TKIs. The purpose of this study is to clarify the mechanism of EGFR-TKI resistance in LMC and establish novel therapeutic strategy.
We examined EGFR mutations, including T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 LMC and 20 extracranial lesions (e.c., lung metastasis and malignant pleural effusions) of EGFR mutant lung cancer patients who became refractory to EGFR-TKI treatment. To clarify molecular mechanisms of acquired EGFR-TKI resistance in LMC, we utilized in vivo imaging model of LMC with EGFR mutant lung cancer cell line PC-9/ffluc and induced acquired resistance to gefitinib by continuous oral treatment.
We found that all 32 re-biopsy specimens had the same baseline EGFR mutations and that T790M was less frequent in LMC specimens than extracranial specimens (8% vs 55%). Compared with subcutaneous tumors, T790M was less frequent in LMC which acquired resistance to gefitnib. We further established PC-9/LMC-GR cells from the gefitinib-resistant LMC model and found that PC-9/LMC-GR cells were intermediately resistant to gefitinib and osimertinib (3[rd] generation EGFR-TKI). While EGFR-T790M was negative, MET copy number gain associated MET activation was involved in the gefitinib resistance in PC-9/LMC-GR cells. Moreover, combined use of EGFR-TKI and crizotinib, having inhibitory activity against MET, dramatically regressed LMC which already acquired resistance to gefitinib or osimertinib.
These findings suggest that combined use of MET inhibitors may be promising for controlling LMC which acquires resistance to EGFR-TKIs including osimertinib.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
P2.06-015 - The NICE Salvage Study: A Phase II Trial of Weekly Nab-Paclitaxel in the Salvage Setting for Advanced Non-Small Cell Lung Cancer (ID 4566)
14:30 - 15:45 | Author(s): A. Hata
The standard chemotherapy for advanced NSCLC after the failing of second or third line chemotherapy has yet to be established. In these salvage setting patients the acceptable safety and efficacy of solvent-based paclitaxel (sb-P) monotherapy have been previously reported as one possible treatment option (Anticancer Res 2005). Compared with sb-P, nab-paclitaxel(nab-P) yielded a higher mean maximal circulating concentration of free paclitaxel and delivered higher drug concentration to tumors in preclinical xenograft models (Clin. Cancer Res. 2006). Moreover, a large multicenter international phase III study (CA031) of nab-P + carboplatin (C) vs sb-P + C, nab-P + C produced a significantly higher overall response rate (ORR) compared with sb-P + C, and had an acceptable safety profile as a first line chemotherapy (J. Clin. Oncol. 2012) .These results suggest that nab-P monotherapy have possibility to be more efficacious and tolerable compared to sb-P monotherapy. KTOSG trial 1301 has recently revealed weekly nab-P as a second line chemotherapy is associated with acceptable toxicity and a favorable ORR in patients with advanced NSCLC (Lung Cancer 2016). However, there are no reports of nab-P monotherapy after the failing of second or third line chemotherapy. We therefore planned this study aiming to assess the efficacy and safety of nab-P monotherapy for patients in the salvage setting.
This multicenter single arm phase II study assesses the efficacy of nab-P in pts with PS 0-2 and aged < 75 years with advanced non-small cell lung cancer. Pts must have failed two or three prior lines of therapy including at least a platinum- containing chemotherapy. Pts pretreated with sb-P or nab-P, or tumors harboring EGFR mutation or ALK fusion gene are excluded. Pts receive nab-P 80 mg/m2 on days 1,8 and 15 of a 28-days cycle. The primary endpoint of the trial is progression-free survival in an intent-to-treat analysis using the Kaplan-Meier method and log-rank test. Secondary endpoints include overall survival, ORR, disease control rate, efficacy according to prior docetaxel, quality of life, and safety. The study is powered to detect a 1.5-month improvement in median PFS in this investigational arm beyond the 2.0-month median PFS estimated from historical data. Assuming a one-sided 0.10 level of Type I error and 80% power, the sample size was calculated to be 35 pts based on the Brookmeyer-Crowley method. The target sample size is established as 38 pts. As of June 2016, 14 pts were registered and recruitment is ongoing (UMIN000016173).
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