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Dongqing Lv
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-90 - Update Phase II Results of Early Primary Tumor Stereotactic Body Radiotherapy Combined with First-Line EGFR-TKI in Advanced EGFR Mutated NSCLC (Now Available) (ID 903)
09:45 - 18:00 | Presenting Author(s): Dongqing Lv
- Abstract
Background
Our previous work (ChiCTR-OIN-17013920) has reported the efficacy and safety of early primary tumor stereotactic body radiotherapy (SBRT) combined with Icotinb in advanced EGFR mutated (EGFRm) NSCLC patients (2018 IASLC WCLC Abstract #11985). Hani Ai-halabi et al. reported that about 80% of EGFR TKI drug resistance was at the primary site. Here we report the updated results.
Method
Patients with pathologically confirmed advanced NSCLC with 19/21 EGFRm were enrolled between September 2016 and March 2019. SBRT was performed during the first month of oral first-line EGFR-TKI (Icotinib 125mg three times daily or Gefitinib 250mg once daily) in patients who were assessed as partial response or stable disease according to RECISE v1.1 assessment. The primary tumor was given SBRT at dose of 50Gy/5F or 60Gy/8F for peripheral and central primary, respectively. The primary endpoints were progression free survival ] (PFS) and pattern of failure, while the second endpoints were overall survival time (OS) and adverse events (AEs).
Result
36 patients were recruited in this study. The follow-up time was 14.5 months (range 3.4-30.4). Median age was 66 years (range 49-83). There were 20 males and 16 females. Eighteen patients with 19-del mutation and 18 had L858R mutation. Overall, median PFS and median OS was 14.1 months and 26.3 months (Figure 1), respectively. Three patients had progression at the primary site, 5 patients had mixed progression and 19 patients with distant progression only. In subgroup analysis, the median PFS was 14.1 months vs. 12.8 months in 19-del vs. L858R mutation patients. The median OS was 19.4 months in L858R mutation group while that in 19-del mutation was immature. Additionally, there was no ≥grade 3 AEs in patients treated with this regimen.
Conclusion
This study suggested that early primary tumor SBRT may play a role to delay resistance of first-line EGFR-TKI in advanced EGFRm NSCLC patients. Patients with 19-del mutation may gain a better survival time compared with L858R mutation. The promising results are to be validated in a multi-center, comparable randomized phase III clinical trial (Target-SBRT, NCT03727867).
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P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.16-24 - Detection of Plasma T790M Mutation After the First Generation EGFR-TKI Resistance of Non-Small Cell Lung Cancer in the Real World (Now Available) (ID 304)
09:45 - 18:00 | Author(s): Dongqing Lv
- Abstract
Background
The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has shown efficacy in mutation non-small cell lung cancer(NSCLC), but acquired resistance is inevitable. It has been confirmed that the secondary EGFR Thr790Met (T790M) mutation accounted for about 50% at acquired resistance in tumor tissue. The third generation EGFR-TKI had significantly efficacy in T790M positive NSCLC . The purpose of this study was to investigate the positive rate of plasma T790M mutation and its relationship among the clinical characteristics and the frequency of T790M mutation in acquired resistance after first line EGFR‒ TKI treatment in the real world.
Method
Patients were recruited prospective from September 2017 to June 2018.The eligibility criteria of the trial included:1. Older than 18 years, histologically confirmed NSCLC stageⅢB/Ⅳ, EGFR mutation positive; 2.Had progressive disease (PD) after first generation EGFR-TKI by RECIST, PFS>3months; 3.excluded patients who had recevied the third generation TKI treatment. All patients take 10 ml of blood, and detected the T790M gene by amplification refractory mutation system(ARMS). The study was approved by the Ethics Committee of Taizhou Hospital, ethical batch number: 201637.
Result
189 patients are in the analysis (Table 1). The overall plasma T790M mutation rate was 36.51 % (69/189). The positive rate of T790M mutation after the failure of first generation EGFR-TKI treatment was not correlated with the patient's age, sex and the type of first generation TKI drugs. However, it is related to the mutation type of EGFR in baseline and the mode of progression according to Wu YL et al. reports. The frequency of T790M mutation among patients with initial exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 45.44%, 26.19% and 33.33%. The mutation rate of T790M in 19del mutant patients was higher than that of L858R mutation and other mutations (p=0.026). The frequency of T790M mutation in local progression patients was 50% after the first generation EGFR TKI was resistant to drug, when in gradual progression was 26.92%, and in dramatic progression was 38.10%. The frequency of T790M mutation of patients with local progression was significantly higher (p=0.031).
ConclusionTable 1 Univariate analysis of the association between patients' characteristics and plasma T790M status.
Characteristics
NO.
Plasma T790M mutation states
P value
Positive (+)
Negative(-)
Age（yr）
≤60
64
25(39.1%)
39(60.9%)
P=0.438
＞60
125
44(35.2%)
81(64.8%)
Sex
Male
64
27(42.19%)
37(57.81%)
P=0.246
Female
125
42(33.6%)
83(66.4%)
Baseline EGFR mutation status
19-del
99
45(45.45%)
54(54.55%)
P=0.026
21-L858R
84
22(26.19%)
62(73.91%)
others
6
2(33.33%)
4(66.67%)
First generation TKI
Lcotinib
96
28(29.17%)
68(70.83%)
P=0.074
Gefitinib
90
39(43.33%)
51(56.67%)
Erlotinib
3
2(66.67%)
1(33.33%)
Disease progression modes
Gradual progression
78
21(26.92%)
57(73.08%)
P=0.031
Local progression
48
24(50%)
24(50%)
Dramatic progression
63
24(38.10%)
39(61.90%)
The overall plasma T790M mutation rate was 36.51% after first generation of EGFR-TKI acquired resistance of NSCLC in the real world. The frequency of T790M mutation with initial mutation of 19 Del was higher than that of L858R mutation, and local progression was higher than gradual progression and dramatic progression.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-05 - PHLPP1 Expression Through AKT and ERK Dual Signaling Pathways May Slow Down the Resistance to TKI in EGFR-Mutated Lung Adenocarcinoma (ID 298)
10:15 - 18:15 | Author(s): Dongqing Lv
- Abstract
Background
The epidermal growth factor receptor (EGFR) kinase inhibitors are effective treatments for lung cancers with EGFR activating mutations, but the magnitude of tumor regression varies and drug resistance is unavoidable. Multiple mechanisms of resistance to EGFR-TKIs have been identified, including the occurrence of secondary mutations in the EGFR gene, MET amplification, acquired BRAF rearrangements and activation of bypass pathways. Central to these mechanisms of resistance is the re-activation of AKT and ERK signaling, which enables escape of tumor cells from EGFR inhibitor treatment. However, the mechanisms of reactivation of PI3K-AKT and ERK/MAPK pathway are unclear.
Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase (PHLPP) acts as tumor suppressors in various types of human cancer by suppressing cell survival pathways and promoting apoptosis through inhibiting AKT and ERK pathway activation. Here, we hypothesize that PHLPP is a key regulator of EGFR-TKI resistance in lung cancer and a potential treatment target for overcoming resistance to EGFR-TKI treatment.
Method
A transcriptomic of PHLPP1 in non-small lung cancer cell according to gefitinib sensitivity obtained from Gene Expression Omnibus (GEO) database under accession number GSE4342 were analysis. The lentivirus-mediated delivery of shRNA was used to generated stable knockdown of PHLPP1 expression lung cancer cells, and retrovirus-mediated delivery was used to generated stable overexpression of PHLPP1 lung cancer cells. Western blotting, real-time PCR (RT-PCR) and immunofluorescence were used to determined PHLPP expression in vitro. PHLPP1 expression in clinical sample was determined by Immunohistochemical (IHC) staining. MTT assay was conducted to determine the cell proliferation. Xenografts bearing PHLPP overexpression and control were evaluated EGFR-TKI induced tumor regression.
Result
PHLPP1 gene expression was higher in gefitinib-sensitive NSCLC cell lines than gefitinib-resistant NSCLC cell lines from a GEO public database. In vitro, EGFR mutated NSCLC cell line HCC827 continuously exposing to gefitinib exhibited dramatically reduced expression of PHLPP1 and increased phosphorylation AKT and ERK. Knockdown of PHLPP1 decreased cell death induced by the EGFR-TKI in EGFR-mutant lung cancer cells, overexpression of PHLPP1 enhanced gefitinib-induced apoptosis in gefitinib-resistance EGFR-mutant lung cancer cells. In xenograft model, overexpression of PHLPP showed significantly more tumor regression after gefitinib treatment at 1-week time point compared to control group. In patients, PHLPP1 were highly expressed in tumors with EGFR common mutations pre- and post-development of resistance to EGFR TKIs. PHLPP1 expression were down regulated in the post-relapse tumor samples compared to that of pre-treatment, and patients with higher PHLPP1 expression in pre-treatment had significantly longer progression-free survival (PFS).
Conclusion
PHLPP loss may be a key molecule contributing to the resistance of EGFR-TKI by activating PI3K-AKT and ERK/MAPK signaling pathway. PHLPP may serve as a potential predictor of EGFR-TKI treatment response in these patients. Up-regulating PHLPP expression may prevent or /and delay the emergence of EGFR-TKI resistance. Further study is warranted to prove PHLPP as an effective strategy.
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P2.12 - Small Cell Lung Cancer/NET (ID 180)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.12-08 - Surprisingly Promising Tumor Control Rate of S1 Combination with Anlotinib with Refractory Relapsed SCLC Who Failed ≥ 2 Lines Chemotherapy (Now Available) (ID 885)
10:15 - 18:15 | Author(s): Dongqing Lv
- Abstract
Background
Patients with refractory relapsed small cell lung cancer (SCLC) who failed more than 2 lines chemotherapy have limited options. Objective Response Rate (ORR) of Immunotherapy (CheckMate-032 and Keynote-158) was only 20%. Anlotinib is a novel TKI on multi-kinase (VEGFR, c-Kit, PDGFR, FGFR) angionesis inhibitor, had ORR of only 4.9% in ALTER1202 for the third-line and further-line treatment of SCLC. S-1, a combination of three pharmacological compounds, namely tegafur (prodrug of 5-fluorouracil), gimeracil, and oteracil potassium, is a new oral fluoropyrimidine derivative designed to enhance anticancer activity and reduce gastrointestinal toxicity, has been used for treatment of SCLC with ORR of 4% (MOLECULAR AND CLINICAL ONCOLOGY 1: 263-266, 2013). In patients without any option of systemic therapy, our clinic started combined use of these drugs. This study aimed to report the preliminary results of combined S1 and anlotinib therapy in these refractory released SCLC.
Method
This study retrospectively analyzed refractory relapsed in SCLC who failed to more than 2 lines’ chemotherapy. Eligible patient must have received Anlotinib (12 mg PO QD from day 1 to 14, every 3 weeks) and S1(60mg PO Bid from day 1 to 14, every 3 weeks) combined therapy. The primary endpoints were ORR and disease control rate (DCR). The secondary endpoints were PFS, OS, and safety and tolerability.
Result
A total of 12 patients were recruited from Nov 2018 in this study. There were 2 females and 10 males. The median age was 64 years (37-75 years). 6 patients had failed 2 lines of refractory diseases and 6 cases failed 3 lines’s chemotherapy. Until 31 March 31, 2019, 2, 3, 3, 2, and 2 cases had accomplished 6, 5, 4, 3, and 2 cycles, respectively. The ORR and DCR were 50% and 100%, respectively (Figure 1). The median PFS and OS were not reached at the time of data analysis. The most common Treatment-related adverse events (TRAEs) were hypertension, anorexia, fatigue, blurred vision, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 5 (41.7%) of patients. Anlotinib was reduced to 8mg in 2 patients and 10mg in 3 patients due to grade 3 TRAEs.
Conclusion
The study demonstrates that S1 combination with anlotinib seemed to be an effective treatment option for patients with surprisingly promising response rate in refractory relapsed SCLC. Prospective clinical trial (SALTER Trial, ClinicalTrials.gov ID: NCT03823118) is ongoing to confirm the promising results.
