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Wen Lin
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-11 - A Prospective Multicenter Study of Target-Capture Deep Sequencing in Paired Tissue and ctDNA to Guide EGFR-Mutated Lung Cancer Treatment (Now Available) (ID 1542)
09:45 - 18:00 | Author(s): Wen Lin
- Abstract
Background
TKIs have significantly improved the survival of NSCLC pts carrying sensitive mutations. However, heterozygous responses were observed. We conducted a prospective multicenter clinical trial to explore factors associated with the efficacy of EGFR-TKI, and assess the mutation and TMB concordance between plasma and tissue NGS.
Method
Paired tumor and plasma samples were obtained from treatment naïve advanced NSCLC pts whenever applicable. DNA was sequenced by target-capture deep sequencing of 1021 tumor-related genes (pan-cancer panel). PFS was estimated using Kaplan-Meier method and compared using log-rank test. Tissue TMB (tTMB) and plasma TMB (bTMB) analysis interrogated SNVs/Indels with VAF ≥3 % and ≥0.5 %, respectively. TMB-H pts were identified with ≥9 muts/Mb.
Result
From Feb. 2017 to Jan. 2019, 262 advanced NSCLC pts were enrolled from 12 centers. In 224 pts with paired tumor and plasma samples, 144 had EGFR sensitive mutations in tumor samples (L858R, 46%; Ex19Indel, 42%), of whom, 106 (74%) had the identical mutations detected in plasma. The detection rate of tissue EGFR mutations in paired plasma was significantly higher in pts with extrathoracic metastasis (81% vs. 61%, p = 0.03). In 38 pts lacking paired samples, 20 pts had EGFR sensitive mutations detected. Thus, 164 pts were identified as EGFR positive by either plasma or tissue NGS. One hundred of them were treated EGFR TKIs (ORR: 70%, mPFS: 20 mo). The ORR was affected by EGFR subtypes (Ex19Indel vs. L858R: 72% vs. 45%, p = 0.02), concomitant CNV/fusion (with vs. without: 11% vs. 68%, p = 0.002) and CDKN2A mutations (with vs. without: 0% vs. 66%, p = 0.007). Mutations in p53 pathway (p = 0.02), CDK12/13 (p = 0.0002), concomitant CNV/fusion (p = 0.003), and high number of alterations (≥ 5) (p = 0.003) significantly shortened mPFS. tTMB was correlated with bTMB (rPearson = 0.9, p < 0.0001), with a concordance rate of 90% for TMB-H and TMB-L classification. Interestingly, 9.8% of the EGFR positive pts were bTMB-H, and mPFS was shorter in bTMB-H pts (6 mo, 95% CI: 5 - NR) than in bTMB-L pts (NR, 95%: 13 - NR) (p = 0.2).
Conclusion
Deep sequencing with the pan-cancer panel effectively detected mutations and evaluated TMB in both tissue and plasma with a high consistence. Moreover, the presence of structure variation, high tumor heterogeneity and concomitant mutations in genes such as CDKN2A were associated with worse prognosis. Further studies of predictive factors are ongoing (NCT03059641).
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-54 - Characteristic of MSI-H Lung Cancer Patients Identified with Targeted Next-Generation Sequencing (Now Available) (ID 2435)
10:15 - 18:15 | Author(s): Wen Lin
- Abstract
Background
MSI-H/dMMR predicts response to immune oncology (IO) agents and is an approved biomarker for pembrolizumab therapy irrespective of histologic diagnosis. In this study, we retrospectively analyzed a large cohort of lung cancer patients using targeted next generation sequencing to examine the prevalence and clinicopathologic associations of MSI-H in lung cancers.
Method
MSI and TMB status was derived from a 1021 gene targeted next generation sequencing panel. MSI was analyzed using MSIsensor 0.5, that relies on an empirically defined cutoff of MSI score>10%, as MSI-H. TMB analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3 %. TMB-H pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).
Result
5592 lung cancer patients were interrogated in the study, with 4753 lung adenocarcinoma, 559 lung squamous cell carcinoma, 112 small cell lung carcinomas (SCLC), and 168 rare lung cancer types including pulmonary sarcomatoid carcinoma, carcinoid and so on. A total of 12 lung tumors were identified as MSI-H (0.21%), and 5 were lung adenocarcinoma (0.1%), 3 were small cell lung cancer (2.7%), 1 was lung squamous cell carcinoma (0.18%), 2 were pulmonary sarcomatoid carcinomas, and 1 was pulmonary carcinoid (1.8%). The incidence was higher in small cell lung cancer and rare lung cancer subtypes. The average diagnosis age of the 12 patients were 53 years (range: 16-74). All the patients were TMB-H, with the TMB averaged 51.23 mut/Mb (range: 10-70 mut/Mb). Two of the 5 lung adenocarcinoma patients carried EGFR L858R or 19del mutation. One patient who had both NRAS G12V and EGFR Ex20 mutation had tried nivolumab (120mg) for one cycle with deteriorating of cough and progression of disease.
Conclusion
MSI-H is very rare in lung tumors, where it appears to enrich in small cell lung cancer and rare lung cancer subtypes. MSI-H lung cancer patients tend to have a younger diagnosis age. MSI-H may coexist with other driver alterations, including those negatively associated with IO response. Additional investigation is needed to determine efficacy of IO in these patients.
