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Bo Yan
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MA25 - Precision Medicine in Advanced NSCLC (ID 352)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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MA25.09 - Navigating Anlotinib Precision Therapy Through the Genetic Profiling of Circulating DNA in Non-Small Cell Lung Cancer Patients (Now Available) (ID 1055)
14:30 - 16:00 | Author(s): Bo Yan
- Abstract
- Presentation
Background
Anlotinib is an oral multi-targeted anti-angiogenic drug, and its clinical predictor for non-small cell lung cancer (NSCLC) patients is still elusive. The aim of this study is to screen predictor for anlotinib via non-invasive genetic profiling of plasma cell free DNA and circulating tumor DNA (cfDNA & ctDNA).
Method
Tumor-specific target capture to profile the circulating DNA of ALTER0303 (Evaluating NSCLC clinical anti-tumor efficacy through anlotinib therapy) study participants. Acquired mutations were screened out via comparing genetic profiling between baseline (BL) and progression disease (PD), and were used for anlotinib stratification. Based on the sequencing data at BL, tumor mutation index (TMI) was established from three independent predictors germline and somatic mutation burden (G+S MB), nonsynonymous and synonymous mutation burden (N+S MB) and unfavorable mutation score (UMS), and was used for predicting anlotinib responders. In addition, TMI combined with IDH1Exon4 mutation status also be examined for serving as predictor for anlotinib stratification.
Result
Our data firstly indicated no benefit (NB, PFS ≤ 45 days) patients can be mainly excluded via analysis of ARID1A and BRCA2 genetic profiling. Secondly, for the no durable benefit (NDB, 45 days < PFS ≤ 130 days) and durable clinical benefit (DCB, PFS > 130 days) patients, harboring lower mutation burden (G+S MB, N+S MB, and UMS) received more benefit from anlotinib therapy. Subsequently, we found the predictor-TMI can predict anlotinib responders upon discovery cohort (Median PFS: 210 days vs 126 days; p = 0.0238; AUC = 0.77), and validation cohort (Median PFS: 210 days vs 127 days; p = 0.0352) and all patients (Median PFS: 210 days vs 127 days; p = 0.0044) more effectively. Furthermore, the IDH1Exon4 mutation was identified as an unfavorable factor to anlotinib therapy under TMI-based stratification. Lastly, the TMI plus IDH1Exon4 mutation status predict response to anlotinib significantly (Median PFS: 210 days vs 127 days, p < 0.0001, AUC = 0.90; Median OS: 423 days vs 162 days, p < 0.0001, AUC = 0.80).
Conclusion
This study provides circulating DNA sequencing-based stratification for underlying anlotinib responders via non-invasive approach, and thus potentially improve clinical outcome for NSCLC patients at 3rd line.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-31 - Preliminary Results of Second Generation ALK Inhibitor PLB1003: A Phase La Study (Now Available) (ID 1741)
10:15 - 18:15 | Author(s): Bo Yan
- Abstract
Background
ALK rearrangements have been described in approximately 4-5% of patients with non-squamous non-small cell lung cancer (NSCLC). Crizotinib is initially effective in the treatment of ALK-rearranged NSCLC, but the disease eventually progresses. PLB1003, a high-efficiency second generation ALK inhibitor, was developed due to the increased resistance of EML4-ALK fusion genes. Preclinical data show that PLB1003 is safe and effective in cell-based assays and Crizotinib-resistant animal models. This is the ongoing phase Ia study of PLB1003.
Method
An open-label, multicenter phase I clinical trial was conducted in patients with locally advanced or metastatic NSCLC who had previously failed or were intolerable to Crizotinib or chemotherapy. It consisted of dose-escalation cohorts and dose-expansion cohorts. In the dose-escalation cohorts, patients were orally given 50-500mg/d of PLB1003 at 6 dose levels . In each cohort, patients' plasma were collected for pharmacokinetic evaluation. The safety, tolerability, pharmacokinetics, maximum tolerated dose (MTD), dose limiting toxicities (DLT) and recommended phase 2 dose (RP2D) of PLB1003 were determined.
Result
A total of 21 patients were enrolled in dose-escalation cohorts as of 31 August 2018. The dose-escalation cohort is ongoing at the dose of 200 and 250 mg BID. A lipase elevation of DLT event was observed at 250 mg BID. MTD has not been reached in this study. Additionally, the most common treatment-emergent adverse events (TEAEs) (>10%) were grade1/2, including: (1) gastrointestinal toxicities: diarrhea (24%), vomiting (14%); (2) hepatotoxicity: increased GGT (g-glutamyltransferase) (48%), increased ALP (33%), elevated ALT (43%) and AST (33%); (3) others: increased blood glucose level (43%), hyperuricemia (24%), increased creatinine (19%), anemia (19%), hypercholesterolemia (14%). All the treatment-related adverse events (TRAEs) were reversible. TRAEs of grade 3, increasing of GGT (-glutamyl transferase) (33%), alkaline phosphatase (10%) and lipase (10%) , mostly appeared during 7-13 weeks of initial study. Patients all recovered from TRAEs of grade 3 with symptomatic treatments. Among the 14 evaluable patients in ≥200mg/d cohorts, 10 patients had PR (71%), 2 patients had SD (14%), and the disease control rate (DCR) was 86%. Among the 7 patients who progressed with previous treatment of Crizotinib, 5 patients had PR (71%), 1 patient had SD (14%), and the DCR was 86%.
Conclusion
PLB1003 is safe, tolerable and has potential clinical benefit to locally advanced or metastatic NSCLC patients with ALK rearrangement mutation and had disease progression or were intolerable to previously treatment of Crizotinib or chemtherapy. (ClinicalTrials.gov number, NCT03130881)
