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Xinghao Ai
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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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P1.01-126 - The Co-Occurring Genomic Landscape of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib (Now Available) (ID 1284)
09:45 - 18:00 | Author(s): Xinghao Ai
- Abstract
Background
Human epidermal growth factor receptor 2 (ERBB2, HER-2) 20 exon insertion (ERBB2ex20ins) has been identified as an oncogenic driver in lung cancer, for which no valid therapy is currently approved. Concurrent alterations may elucidate its refractory features. Previous studies on Afatinib, a pan-ERBB inhibitor, have revealed an inconsistent clinical activity of it for this group of patients.
Method
Plasma or tissue samples of 112 patients with ERBB2ex20ins were performed next generation sequencing (NGS) for 59 or 1021 cancer-related genes in a Clinical Laboratory Improvement Amendments-certified Laboratory from July 2016 to December 2018. The sequencing data of MSKCC Cohort was downloaded from the public Cancer Genome Atlas Database. The clinical outcomes of 18 patients receiving Afatinib treatment were collected by each contributing doctor in charge and pooled for analysis.
Result
Among the 112 patients, most of cases were female (54%, 60/112) and adenocarcinoma (68%, 76/112). Considering the insertions sites, three subtypes were A775ins (71%; 79/112), G776indel (17%; 19/112) and P780ins (12%; 14/112) in the order of frequency. 80.4% (90/112) of patients had at least one additional alteration. The most frequent co-occurring genes were TP53 (66.1%, 74/112), LRP1B (18.2%, 10/55), EPHA5 (9.1%, 5/55), MLL3 (9.1%, 5/55) and RB1 (8.0%; 9/112). Putative other driver aberrations were mutually exclusive from ERBB2ex20ins. Furthermore, cell cycle pathway was the most commonly involved pathway (84.0%; 94/112) of all the concurrent genes. No substantial differences of concurrence in genomic or pathway level were observed among the three ERBB2 insertion subtypes. The co-occurring genomic feature of ERBB2ex20ins in Our Cohort of Chinese people had an overall strong concordance with the MSKCC Cohort from the United States (R2=0.74, P<0.01). For the prognosis, patients had a worse OS when co-occurring mutation in TP53 [median OS:14.5m (95%CI: 12.7m-16.3m) vs 30.3m (95% CI: not reached)], while the OS was not significantly different among three subtypes. The median duration time for patients with disease control of Afatinib was 4.5 months (95%CI: 3.6m-5.4m; range: 2.5m-13.4m). Of note, ERBB2ex20ins in subclonal status was a significantly independent factor relating to shorter PFS of Afatinib [median PFS: 1.2m (95%CI: 0.8-1.6m) vs 4.3m (95%CI: 3.3m-5.3m), P<0.05]. Dynamic detection in two patients found ERBB2 amplification may be a resistance mechanism for Afatinib.
Conclusion
Concurrence of genetic alterations in NSCLC patients with ERBB2ex20ins was common. The complex genomic characteristic should be fully considered by stratifying patients according to potentially relevant co-mutations other than ERBB2 insertion sites in the designing regimens for them. In addition, the therapeutic effect of Afatinib on patient with ERBB2ex20ins is limited, the clonal status of ERBB2ex20ins may be an important factor with prognosis value.
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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): Xinghao Ai
- 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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P2.14 - 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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P2.14-09 - Concurrent TP53 Mutation Adversely Impact the Efficacy of Crizotinib in ROS1-Rearranged Lung Cancer Patients (ID 2158)
10:15 - 18:15 | Author(s): Xinghao Ai
- Abstract
Background
ROS1 tyrosine kinase inhibitors (TKIs) are now standard of care for patients with advanced ROS1-rearranged NSCLC. But factors that may affect the efficacy of ROS1 TKIs remain to be explored.
Method
We conducted a retrospective multicenter study of lung cancer patients with ROS1 rearrangements. Treatment and survival follow-up was done and clinical records were reviewed. PFS distribution was analyzed by Kaplan-Meier method with log-rank test.
Result
In total, we included 94 lung cancer patients with ROS1 fusion genes profiled by next-generation sequencing from May 2016 to September 2018. Fifty of them were female. The median diagnosis age was 54 (25-83). The most common histologic type was adenocarcinoma, which was confirmed in 75 of 78 patients with available pathological results. The most common fusion partners were CD74, EZR, SDC4 and SLC34A2 identified in 42, 19, 12 and 8 patients respectively. Concurrent actionable mutations were uncommon for ROS1 fusion-positive patients. The most frequent concomitant mutated gene was TP53, which was detected in 33% of all the patients. After excluding 29 patients who were lost to follow-up at the very start, the median follow-up time was 8.5 (0-28) months from the moment when mutation profiling was performed. Thirty-nine patients received treatment with crizotinib, among whom 27 were treatment-naïve patients. The median PFS of the 39 patients with crizotinib was not reached yet. Patients with baseline CNS metastasis tend to have shorter PFS compared to patients without (median, 12 vs NR, p = 0.0073). Besides, concurrent TP53 mutations were correlated with worse PFS (median, both NR, p = 0.0417). Mutation profiles of 10 patients were derived from ctDNA testing. No difference was found in PFS between these 10 patients with others whose genomic profiles were based on fresh tissue or FFPE specimens, suggesting that plasma ctDNA serves as good specimen source for mutation profiling to monitor clinical treatment.
Conclusion
Concurrent TP53 mutation and presence of CNS metastasis are associated with decreased PFS of ROS1-positive patients treated with crizotinib.
