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Liang Zeng
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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
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-22 - Investigation of Acquired Resistance for EGFR-TKI Plus Bevacizumab as 1st Line Treatment in Patients with EGFR Sensitive Mutant NSCLC (ID 2852)
09:45 - 18:00 | Author(s): Liang Zeng
- Abstract
Background
The progression-free survival (PFS) advantage of EGFR-TKI plus Bevacizumab (A+T) over standard TKI monotherapy (T) in the 1st line treatment of EGFR mutant non-small cell lung cancer (NSCLC) has been confirmed in prospective clinical trials. However, the acquired resistance mechanism which impacts the subsequent management was poorly understood. We did the first analysis to unveil it using next generation sequencing (NGS).
Method
256 EGFR sensitive mutant (EGFR 19del and L858R) NSCLC patients received NGS of 168 genes panel of tumor tissue in baseline from Jan, 2015 to Aug, 2018 was enrolled in this study. 60 patients treated with A+T were recognized as cohort A. Using Propensity Score Matching (Ratio of 1:2), 120 patients treated with single T were chosen as cohort B. Clinical outcomes and resistance mechanism (also by the 168 genes NGS panel) were evaluated.
Result
Newly present alterations in cohort A % N EGFR amp 3.2% 1 MET amp 3.2% 1 MET amp+EGFR amp+TP53 3.2% 1 RB1 3.2% 1 RB1+TP53 3.2% 1 RB1+TP53+EGFR amp 3.2% 1 SMAD4 3.2% 1 T790M 22.6% 7 T790M+BRAF V600E 3.2% 1 T790M+EGFR exon 18 p.V834L+TP53 3.2% 1 T790M+TP53 6.5% 2 TP 53 16.1% 5 unknown 25.8% 8 Total 1 31 Newly present alterations in cohort B % N EGFR amp 6.8% 7 EGFR exon 7 p.T263P 1.0% 1 EGFR exon18 p.G724S 1.0% 1 ERBB2 amp 1.0% 1 KRAS 1.0% 1 MET amp 4.9% 5 MET skipping 1.0% 1 RET+KRAS 1.0% 1 SCLC 2.9% 3 T790M 37.9% 39 T790M+BRAF V600E 1.0% 1 T790M+EGFR amp 8.7% 9 T790M+MET amp 1.9% 2 T790M+TP53 1.9% 2 TP53 4.9% 5 TP53+RB1 1.0% 1 unknown 22.3% 23 Total 1 103 There was no different for clinical characteristics between Cohort A and B. Comparing with single T, A+T significantly prolonged the medium PFS (16.5m vs.12.0m, HR=0.7, p=0.001). A+T significantly increased the overall response rate (95% vs 74.2%, p<0.05). Until Jan 2019, 31 patients in cohort A, 103 patients in cohort B were evaluated with progressed disease and received tissue re-biopsy for NGS with the same 168 genes panel. In cohort B, T790M was defined as the domain acquired resistance mechanism, contributing to 51.5% (53/103) of progressed patients, followed by EGFR amplification 15.5% (16/103), MET amplification 6.8% (7/103), TP53 mutations 6.8% (7/103) and small cell lung cancer transformation 2.9% (3/103). However, in cohort A, although T790M was also defined as the domain acquired resistance mechanism, the mutation ratio was decreased to 35.5% (11/31), followed by TP53 mutations 29.0% (9/31), RB1 mutations 9.7% (3/31), EGFR amplification 9.7% (3/31), MET amplification 6.5% (2/31), and novel SMAD4 mutations 3.2% (1/31), EGFR uncommon mutation (p.V834L) 3.2% (1/31).
Conclusion
Treatment of 1st line A+T significantly extends the time to progression and increases the response rate with acceptable safety profile. The dominant acquired resistance mechanism retained in T790M but with lower probability. SMAD4 mutation and EGFR p.V834L were considered as novel resistant mechanism to A+T.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-51 - Dual ALK Fusion Partners as Poor Predictive Marker in First Line Crizotinib Treated ALK Rearranged Non-Small Cell Lung Cancer (ID 2971)
10:15 - 18:15 | Author(s): Liang Zeng
- Abstract
Background
First line crizotinib response duration time differs with different fusion patterns in ALK-rearranged advanced non-small cell lung cancer (NSCLC) patients. Some former researches have elucidate the impact of EML4-ALK variants on crizotinib efficacy, however, there was little data about the efficacy of crizotinib considering different fusion partners including one patient with two or more fusion partners or non-EML4 partners.
Method
150 patients with NGS-identified ALK-rearranged NSCLC from March 2014 to July 2018 in Hunan Cancer Hospital were enrolled in this study. Among them, 112 patients received crizotinib as first-line treatment. Efficacy of crizotinib was evaluated and categorized according to different fusion partners.
Result
Among 150 advanced NSCLC patients with NGS-identified ALK-rearranged, 181 fusion partners were detected including 43 novel fusion partners. 122 patients (81.3%) were identified with single ALK fusion partners, 28 patients (18.7%) were identified with dual or triple ALK fusion partner patients. Among 112 patients received first line crizotinib treatment, 89 patients were identified with single fusion partner (79 for EML4, 10 for non-EML4). 23 patients were identified with dual fusion partner (20 patients with dual fusion partners, 3 patients with triple fusion partners). The overall response rate (ORR) was 85.2% and the median progression-free survival time (mPFS) was 11.7 months. The frequency of brain metastasis was high in dual fusion partner patients. Patients with dual ALK fusion partners have a significantly shorter mPFS compared with patients carrying single ALK fusion partner (6.1m vs. 12.0m, p=0.001). Patients with EML4 partners have a significantly longer mPFS compared with patients carrying non-EML4 fusion partners (12.6m vs. 6.1m, p=0.004).
Fusion partners EML4-ALK fusion variants Number of patient Percentage of patient(%) C9orf3-ALK 2 1.3% CLIP1-ALK 1 0.7% CYBRD1-ALK 1 0.7% DEFA5-ALK 1 0.7% EML4-ALK V1 31 20.7% EML4-ALK V2 10 6.7% EML4-ALK V3 47 31.3% EML4-ALK V5 11 7.3% EML4-ALK V7 3 2.0% EML4-ALK E3:A20 1 0.7% EML4-ALK E7:A20 1 0.7% EML4-ALK，APOB-ALKE V5 1 0.7% EML4-ALK,ATXN1-ALK V7 1 0.7% EML4-ALK，BIRC6-AS2-ALK V3 1 0.7% EML4-ALK,C1QC-ALK V3 2 1.3% EML4-ALK,COL22A1-ALK V3 1 0.7% EML4-ALK,COL22A1-ALK V1 1 0.7% EML4-ALK,DIRC3-AS1-ALK,CDC42EP3-ALK V3 1 0.7% EML4-ALK,EHBP1-ALK V3 1 0.7% EML4-ALK,FLJ14082-ALK V3 1 0.7% EML4-ALK,LBH-ALK V1 1 0.7% EML4-ALK,LINC00486-ALK V3 1 0.7% EML4-ALK,LINC01121-ALK V1 1 0.7% EML4-ALK,LOC102467222-ALK V3 1 0.7% EML4-ALK,LOC388942-ALK V1 1 0.7% EML4-ALK,LOC388942-ALK, V3 1 0.7% EML4-ALK,LRRTM4-ALK V3 1 0.7% EML4-ALK,MBOAT2-ALK V2 1 0.7% EML4-ALK,MTA3-ALK,SP3-ALK V1 1 0.7% EML4-ALK,MYH7-ALK V2 1 0.7% EML4-ALK,PDE6D-ALK V1 1 0.7% EML4-ALK,QPCT-ALK V1 1 0.7% EML4-ALK,RC3H2-ALK V1 1 0.7% EML4-ALK,SGPP2-ALK V3 1 0.7% EML4-ALK,SIX3-AS1-ALK V2 1 0.7% EML4-ALK,SRBD1-ALK V3 1 0.7% EML4-ALK,THADA-ALK V3 1 0.7% EML4-ALK,TSPYL6-ALK,ABCG8-ALK V3 1 0.7% FAM179A-ALK 1 0.7% GBE1-ALK 1 0.7% KLC1-ALK 1 0.7% LOC388942-ALK 1 0.7% NCOA1-ALK 1 0.7% RP11-433C9.2-ALK 1 0.7% RPSA-ALK 1 0.7% SLC8A1-ALK 1 0.7% STRN-ALK 1 0.7% THADA-ALK 1 0.7% UBXN2A-ALK 1 0.7% USP34-ALK 1 0.7% WDR37-ALK 1 0.7%
Conclusion
Efficacy of first-line crizotinib in ALK-rearranged NSCLC patients differs based on different ALK fusion partners. Dual ALK fusion partners were poor prognostic factors in first-line crizotinib treatment NSCLC. It also correlated with more brain metastasis compared with single fusion partners.
