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Yuankai Shi
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-028 - Third Generation EGFR Inhibitor AST2818 (Alflutinib) in NSCLC Patients with EGFR T790M Mutation: A phase1/2 Multi-Center Clinical Trial (ID 8968)
09:30 - 16:00 | Presenting Author(s): Yuankai Shi
- Abstract
Background:
AST2818 (Alflutinib) was designed to inhibit EGFR active mutations as well as the T790M acquired resistant mutation. The purpose of this study was to determine the safety and antitumor activity of AST2818 in EGFR T790M positive non-small cell lung cancer (NSCLC) patients after the first-generation EGFR-TKIs treatment failure.
Method:
Patients with histologically diagnosed, EGFR T790M mutant stage IV NSCLC were considered eligible, and they should have documented disease progression on EGFR-TKIs. In a 3+3 dose-escalation design, AST2818 was orally administered every day on a 21-day cycle at doses ranging from 20mg to 240 mg (NCT02973763). AST2818 was then explored in a dose-expansion cohort at doses ranging from 40 to 240 mg every day. Plasma samples were collected to evaluate pharmacokinetics of AST2818. EGFR T790M mutation in tissue samples was detected by amplification refractory mutation system. The primary endpoint was to determine dose limiting toxicity and objective response rate (ORR). Adverse events (AEs) were evaluated by CTCAE 4.03, and efficacy was assessed per RECIST v1.1 every 6 weeks.
Result:
From December 27, 2016 to August 21, 2017, 17 patients received at least one dose of AST2818 across four cohorts (20mg, 40mg, 80mg and 160 mg QD). Maximum tolerated dose has not been reached. The most common treatment-related AEs were grade 1 proteinuria (25%, 3/12). Other AEs included fatigue and prolonged Q-T interval, etc, all less than 10% and grade 1 or 2. The first 12 patients had been evaluated with an ORR of 58.3% (7/12) and a disease control rate of 91.7% (11/12). Profound and sustained tumor regression had already been observed at 20mg cohort. AST2818 plasma exposure, measured as Cmax and AUC 0-24h showed a dose-proportional increase. Figure 1
Conclusion:
AST2818 was well tolerated and had promising clinical activity with durable disease control in EGFR T790M mutant NSCLC after first-generation EGFR-TKIs treatment failure.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-087 - Impact Factor Analysis for Efficacy and Prognosis of Anlotinib in NSCLC as Third-Line Treatment: Data from Trial ALTER 0303 (ID 9129)
09:30 - 16:00 | Author(s): Yuankai Shi
- Abstract
Background:
Anlotinib hydrochloride is a novel TKI targeting the VEGFR, FGFR, PDGFR and c-Kit. With the capability of inhibiting the tumor angiogenesis and tumor cell itself, anlotinib had showed significantly improvement in OS (9.63 vs. 6.30 months, HR=0.68, 95%CI 0.54-0.87, p=0.0018) and PFS (5.37 vs. 1.40 months, HR=0.26, 95%CI 0.21-0.33, p<0.0001) in ALTER 0303 study for refractory cancer, a randomized, double-blind, placebo-controlled Phase Ⅲ trial in China. Here, we report the main impact factors affecting the efficacy and prognosis of anlotinib based on the data from ALTER0303 to elucidate the most benefit population.
Method:
Analyzed data were collected from 294 patients that were enrolled in ALTER0303 trial and received anlotinib treatment between 4[th] March 2015 and 15[th] August 2016. The statistical analysis was conducted using SPSS19.0 software, in which the measuring and enumeration materials were described with Mean±SD and frequency/percentage respectively, Kaplan-Meier method was used for survival curves in survival analysis. Independent impact factors of OS and PFS were identified by univariate and multivariate analysis in Cox proportional hazards regression model (Significant level, α=0.05).
Result:
Several factors were discovered to be associated with the efficacy of Anlotinib treatment. The impact factors were presented in Tab1.Tab1. Impact factors for PFS and OS analyzed by Cox proportional hazards regression model Independent risk factor Independent protective factor PFS Ratio of granulocytes to lymphocytes at PD (HR=1.07, 95%CI 1.041-1.100, p<0.0001) Elevated ALP level (HR=1.553, 95%CI 1.142-2.112, p=0.005) Baseline sum of longest diameters of target lesions (HR=1.004, 95%CI 1.001-1.006, p=0.007) Elevated TSH level (HR= 0.555, 95%CI 0.422-0.730, p<0.0001) Hypercholesteremia (HR=0.720, 95%CI 0.534-0.971, p=0.031) Hypertension (HR=0.482, 95%CI 0.370-0.628, p<0.0001) Hand-foot skin reaction (HR=0.489, 95%CI 0.373- 0.643, p<0.0001) Elevated LDL level (HR=0.630, 95%CI 0.437-0.909, p=0.014) Age (HR=0.987, 95%CI 0.975-0.999, p=0.039) OS Ratio of granulocytes to lymphocytes at PD (HR=1.116, 95%CI 1.081-1.151, p<0.0001) Baseline sum of longest diameters of target lesions (HR=1.006, 95%CI 1.003-1.008, p<0.0001) ECOG PS≥2 at PD (HR=2.245, 95%CI 1.704- 3.508, p<0.0001) Elevated TSH level (HR=0.725, 95%CI 0.524- 1.005, p=0.053) Hypertriglyceridemia (HR=0.601, 95%CI 0.440-0.821, p<0.0001) Rash (HR=0.581, 95%CI 0.369-0.916, p=0.019) Female (HR=0.713, 95%CI 0.533-0.953, p=0.022)
Conclusion:
This analysis explored the possible impact factors of PFS and OS in Anlotinib treatment. Moreover, we provide real data for the prediction of Anlotinib efficacy and most benefit population through the baseline characteristics and variety of clinical index. However, further analysis in the larger scale study is still looking forward.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-017 - Blood Samples NGS for Baseline Molecular Signature of Anotinib Treated Advanced NSCLC Patients in ALTER0303 Trial (ID 9670)
09:30 - 16:00 | Author(s): Yuankai Shi
- Abstract
Background:
Anlotinib hydrochloride, an oral multi-target TKI targeting VEGFR, FGFR, PDGFR and c-Kit, have demonstrated noticeable effects for advanced NSCLC as 3[rd] line treatment in phase III trial (ALTER0303). Anlotinib significantly improved OS (9.63 vs. 6.30 months, p=0.0018, HR=0.68) and PFS (5.37 vs 1.40 months, p<0.0001, HR=0.26) comparing to placebo. Here, we applied ctDNA-based NGS to investigate the association between baseline molecular signature and clinical parameters.
Method:
Blood samples were collected from patients who enrolled in Anlotinib arm in ALTER0303 trial. Total of 92 samples were analyzed by capture-based targeted ultra-deep sequencing using a panel consisting of critical exons and introns of 168 NSCLC-related genes for the baseline genetic profiling.
Result:
At baseline, ctDNA was detected in 85% samples (78/92), driver mutation was found in 58% (53/92) samples. POM121L12 and CDKN2A mutations showed a tendency of co-occurrence with TP53, and mutually exclusivity was found between KEAP1 and TP53. The correlation between baseline molecular signature and treatment efficacy measured by PFS or best response was also investigated. Maximum mutation allele frequency (MAF) at baseline was inversely correlated with PFS (P=0.006, HR=0.612, 95%CI: 0.402-0.932). Patients achieving SD or PR had a significantly lower MAF comparing to patients having PD as their best response (p=0.018). Tumor mutation burden (TMB) is positively correlated with age (p=0.016) and gender (p=0.01). POM121L12, TP53 and MYC statuses are correlated with metastases burden. Moreover, as an important drive gene, EGFR mutation and/or EGFR amplification was found in 36 patients at baseline. In 27 patients with sensitizing EGFR mutation (L858R or 19 del), no significant differences was found in PFS compare to those without this mutation (n=65) (5.53 vs 5.53 months, p=0.495, HR=1.16, 95%CI: 0.73-1.85). As well, no significant difference was found in PFS between the patients with (n=17) or without EGFR T790M mutation (5.53 vs 5.53 months, p=0.253, HR=1.35, 95%CI: 0.75-2.41). Interestingly, in patients with EGFR amplification (n=10), the PFS is significantly shorter than those with normal EGFR copy number (2.12 vs 5.57 months, p=0.002, HR=2.70, 95%CI: 0.99-7.36). However, a tendency of PFS benefit is still observed in patients with EGFR amplification treated by Anlotinib comparing placebo arm in ALTER0303 (1.40 months).
Conclusion:
According to available data, no correlation was found between PFS and EGFR sensitizing mutations or T790M in anlotinib treatment. The negative correlation of EGFR amplification and PFS is still need verification to eliminate the bias caused by the disparity and limitation of samples. A larger scale analysis is ongoing.
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-007 - A Prospective Study of Apatinib in Advanced Small Cell Lung Cancer Patients Failed from Two or More Lines of Chemotherapy (ID 10041)
09:30 - 16:00 | Author(s): Yuankai Shi
- Abstract
Background:
Small cell lung cancer (SCLC) is an aggressive and invasive variant of lung tumors，and its treatment strategy is poor. Apatinib is an oral TKI against VEGFR-2. We determined the efficacy of Apatinib as third- or later-line treatment in advanced SCLC.
Method:
The study was expected to enroll 30 patients diagnosed with advanced SCLC. Patients received oral Apatinib 500mg QD and make an efficacy evaluation after first cycle, then every two cycles once again. The primary endpoint was progression-free-survival (PFS).
Result:
From November 10, 2016 to June 18, 2017, 10 patients were enrolled. 1 patient showed PR when make efficacy evaluation the first time, 8 patients were evaluated SD and 1 patient showed PD due to liver metastasis. Although only one patient showed PR, all the patients’ target lesions were reduced, as figure 1. Figure 1 Up to June 18, 4 patients out of the group due to PD, the PFS is 28 weeks, 19.8 weeks, 13 weeks and 4.7 weeks respectively. Another 6 patients are still investigated, as figure 2, the blue bars are their PFS . Figure 2
Conclusion:
Apatinib in advanced SCLC is worth expecting.To further investigate the role of Apatinib in SCLC patients, large sample and additional clinical trials are needed.
