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Y. Huang
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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Crinò, C.P. Belani
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI15.04 - Phase I Study of Continuous Intravenous Infusion of Rh-Endostatin Combined with Pemetrexed and Carboplatin in Advanced NSCLC (ID 2652)
17:00 - 17:05 | Author(s): Y. Huang
- Abstract
- Presentation
Background:
Endostar [TM ](rh-endostatin, 7.5mg/m[2], 3-hour intravenous infusion (IV) daily for 14 days) was approved by Chinese FDA for treatment of advanced NSCLC in 2005. Considering continuous intravenous infusion (CIV) may be a more favorable way to deliver Endostar, we designed the phase I study to evaluate pharmacokinetics, tolerability and efficacy of Endostar CIV at different doses combined with pemetrexed and carboplatin in untreated advanced non-squamous NSCLC patients.
Methods:
In phase Ia, 19 patients were assigned to 4-6 cycles (21 days/cycle) of pemetrexed (500mg/m[2], day 1), carboplatin (AUC 5, day 1), and CIV Endostar from day 2 to day 21 at doses of 7.5mg (8 patients), 15mg (6 patients), 30mg (5 patients) /m[2]/d, respectively. Serum samples were obtained 0h、1h、2h、4h、8h、24h、48h、72h、96h、120h、122h、124h、128h、132h and 144h after the Endostar infusion. In phase Ib, another 21 patients received CIV Endostar at doses of 7.5mg (10 patients) or 15mg (11 patients) /m[2]/d with pemetrexed + carboplatin.
Results:
The AUC~0-120h~ of Endostar 7.5mg/m[2] CIV and 7.5mg/m[2] 3-hour IV daily were comparable (12.6±7.6 vs 13.3±8.8 ug/mL × hour). C~max~ (ng/ml) (7.5mg: 152.4±83.7; 15mg: 287.2±122.6; 30mg: 398.2±52.6) and AUC~0-120h~ (ug/mL × hour) (7.5mg: 12.6±7.6; 15mg: 21.2±10.8; 30mg: 33.4±8.5) were linear with dose. In phase Ia, the most common adverse events were anemia (78.9%, G3/4 10.5%), neutropenia (68.4%, G3/4 31.6%), thrombocytopenia (63.2%, G3/4 10.5%), LDH increase (47.4%), aminotransferase increase (42.1%), and supraventricular arrhythmia (26.3%). No grade 3 or 4 non- hematologic adverse event was observed. The incidence of supraventricular arrhythmia in 30mg cohort (40%) was higher than the other two cohorts. Thus 30mg cohort was excluded in Ib phase. Totally, 15 patients in 7.5mg cohort and 17 patients in 15mg cohort were evaluable for treatment response. The DCR and ORR were 80.0% and 60.0% in 7.5mg cohort, 94.1% and 76.5% in 15mg cohort, respectively.
Conclusion:
The pharmacokinetics of Endostar CIV and daily IV were comparable. At doses of 7.5mg and 15mg/m[2]/d, Endostar CIV was well tolerated with encouraging anti-tumor efficacy. Increasing dose of Endostar might lead to better response.
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MINI 26 - Circulating Tumor Markers (ID 148)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M. Macmanus, C. Aggarwal
- Coordinates: 9/09/2015, 16:45 - 18:15, 205+207
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MINI26.02 - Deep Sequencing Reveals the Significance of Plasma DNA Concentration and Mutational Burden in Advanced Non-Small-Cell Lung Cancer Patients (ID 1409)
16:45 - 16:50 | Author(s): Y. Huang
- Abstract
- Presentation
Background:
Plasma cell-free DNA (cfDNA) contains genetic information from primary and metastatic cancer foci. We utilized multiplex deep sequencing technology to investigate the clinical significance of cfDNA concentration and mutational burden in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors (TKIs).
Methods:
Between January 2012 and February 2014, seventy-one eligible patients from Sun Yat-sen University Cancer Center were enrolled. All the patients provided written informed consent and donated 2 ml plasma before taking EGFR-TKIs. Plasma DNA was isolated and purified using QIAamp Circulating Nucleic Acid Kit. CfDNA concentration was determined by Qubit Fluorometer. A set of 234 primer pairs were designed to amplify sequences covering hotspots of 35 genes. The amplicon libraries were prepared and entered into deep sequencing on Ion Torrent PGM chip. Variants were called by established bioinformatics methods. Circulating DNA mutational burden was defined as the number of somatic variants other than EGFR mutations. Objective response rate (ORR) and disease control rate (DCR) between different groups were compared using Fisher’s exact test while progression-free survival (PFS) and overall survival (OS) between different groups were compared by Kaplan-Meier curves and log-rank tests. Multivariate stepwise Cox regression analyses were performed to identify independent prognostic factors.
Results:
Forty-nine out of 71 patients were observed to harbor at least one variant and at most 7 variants, involving 10 genes (totally 124 variants). Higher cfDNA concentration was associated with impaired DCR (18.6% vs 81.4%; p=0.008), PFS (median PFS, 3.5 vs 15.2 months; HR=3.03; p=0.001) and OS (median OS, 27.3 vs not-reached; HR=2.38; p=0.042) compared with low cfDNA concentration group. Higher mutational burden was associated with unfavorable ORR (31.6% vs 73.7%; p=0.004) and PFS (median PFS; 8.6 vs 17.8 months; HR=1.61; p=0.050) compared with low mutational burden group. EGFR mutation conferred better ORR, DCR and PFS compared with EGFR wild-type (Figure 1). Multivariate analyses revealed that apart from EGFR mutation status, cfDNA concentration and mutational burden were also associated with the efficacy and/or the prognosis of EGFR-TKIs.Figure 1
Conclusion:
We for the first time showed that cfDNA concentration and mutational burden might influence the efficacy and prognosis of patients receiving EGFR-TKIs. These findings call for the need for the multiplex genetic analysis of patients’ cfDNA to tailor their treatment.
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