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Y. Shi
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-002 - Is T790M Mutation A "Regulator" for EGFR Signal Pathway Not an Oncogene? (ID 3786)
14:30 - 14:30 | Author(s): Y. Shi
- Abstract
Background:
Threonine 790 is regarded as a “gatekeeper” to inhibit ATP from binding to EGFR Tyrosine kinase domain. T790M mutation could increase the affinity for ATP. About 30% de novo T790M mutation was detected in NSCLC patients and showed spatiotemporal heterogeneity and variation in individual NSCLC patients. We hypothesize that T790M mutation may be a “regulating” mechanism for EGFR signal transduction pathway and is probably cleared quickly by DNA repair system in healthy persons.
Methods:
Peripheral blood samples were taken from 50 healthy volunteers, 12 resectable lung adenocarcinoma (LADC), 100 advanced LADC (11/100 acquired resistance for gefitinib). A novel cSMART assay (circulating single-molecule amplification and resequencing technology, which counts single allelic molecules in plasma base on next generation sequencing) was performed for detection and quantitation of EGFR mutation in ctDNA from plasma. Matching tumor biopsy samples were obtained from 100 advanced LADC, the EGFR gene mutations were determined by amplification refractory mutation system (ARMS) -PCR analysis.
Results:
The sensitivity and specificity of cSMART plasma assay for EGFR L858R, 19del and T790M was showed in Table 1. The sensitivity and specificity for T790M was obviously lower (50.0% and 72.9% respectively). No L858R and 19del but 14.0% T790M DNA copies were found in plasma from 50 healthy volunteers, and only 1 copy T790M was detected. The T790M positive rate of resectable and advanced LADC patients were almost similar (33.3% and 28.0%) in plasma, 1 or 2 T790M copies were found in the resectable patients and varied from 1 to 622 T790M copies with an average of 34.0 in advanced LADC patients. Patients with acquired resistance to gefitinib, 45.4% harbored T790M with an average of 268.2 copies in plasma. All but one advanced patients harboring T790M mutation were accompanied with other EGFR mutations.
Conclusion:
T790M mutation may be of a “regulator” and has physiological function.Table 1 EGFR mutations detection by plasma cSMART assay and tumor samples ARMS-PCR in advanced LADC patients
EGFR mutations Sensitivity Specificity L858R 91.7%(22/24) 100.0%(76/76) 19Del 79.2%(19/24) 100.0%(76/76) T790M 50.0%(2/4) 72.9%(70/96)
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-001 - A Randomized Phase III Clinical Trial of Anlotinib Hydrochloride in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 4722)
14:30 - 14:30 | Author(s): Y. Shi
- Abstract
Background:
Anlotinib hydrochloride, a novel multi-targeted tyrosine kinase inhibitor (TKI) was found to exhibit excellent inhibitory efficiency on a variety of receptor tyrosine kinases (RTK) involved in tumor progression, especially the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and stem cell-factor receptor (c-Kit). This ongoing trial aimed at evaluating the efficacy and safety of anlotinib hydrochloride comparing with placebo in advanced NSCLC patients who had received at least two previous chemotherapy and EGFR/ALK targeted therapy regimens.
Methods:
This Phase III, randomized, double-blind, placebo-controlled study (NCT 02388919) is ongoing in 31 centers in China under the supervision of Independent Data Monitoring Committee (IDMC). Pathological stage IIIB/IV adult advanced NSCLC patients (Pts) who had failed with at least two previous chemotherapy and EGFR/ALK targeted therapy regimens were eligible. The status of EGFR and ALK genes should be clear in all enrolled pts. Pts with sensitive EGFR or ALK mutations must had received and appeared intolerance to pervious targeted therapies. Pts were randomized (2:1) to receive Anlotinib hydrochloride or placebo once daily (12 mg) from day 1 to 14 of a 21-day cycle until progression. Dose reduction to 8 or 10 mg/day could be applied when grade 3 or 4 treatment-related toxicities were observed. The minimal sample size was estimated to 450 patients. The primary endpoint is overall survival (OS) and second endpoints are progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and quality of life (QoL). Quality of life was assessed via EORTC QLQ-C30, safety is determined using standard NCI-CTCAE v4.02, and responses are evaluated according to RECIST v1.1.
Results:
This study started in February 2015, up to early July 2016, a total of 420 pts have been enrolled (93.3 % of 450 pts). Among enrolled pts, about 80 % were diagnosed as adenocarcinoma, EGFR mutation or ALK rearrangement was found in 1/3 of the pts. The overall analyses will start after 300 OS events.
Conclusion:
Anti-angiogenesis is the main mechanism of Anlotinib hydrochloride for preventing the tumor progression. Results of randomized, placebo-controlled Phase II trial (NCT01924195) has been reported in WCLC 2015, however, advantages in PFS (4.8 vs. 1.2 months) and OS (9.3 vs. 6.3 months) were observed in Anlotinib arm from the renewed data. Based on these exciting data, we are looking forward for the results of the Phase III trial
