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Shuhang Wang
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MA06 - PDL1, TMB and DNA Repair (ID 903)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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MA06.07 - Genetic and Epigenetic Alterations are Associated with Tumor Mutation Burden in Non-Small Cell Lung Cancer (ID 12822)
14:10 - 14:15 | Author(s): Shuhang Wang
- Abstract
- Presentation
Background
Although several studies have indicated that tumor mutation burden (TMB) is associated with non-small cell lung cancer (NSCLC) development and clinical efficacy of immune checkpoint inhibitors (CPIs), identification of factors associated with TMB is still a major biological issue. It is well-known that DNA transcription can be regulated through methylation and demethylation, gene silencing caused by DNA hypermethylation is associated with cancer development. However, the relationship between DNA methylation and TMB in NSCLCs remains unclear.
a9ded1e5ce5d75814730bb4caaf49419 Method
The landscape of DNA sequence in Chinese NSCLCs population were surveyed by using whole-exome sequencing (WES) by profiling 178 lung tissues (89 without any systemic anti-cancer therapy tumors and matched normal lung tissues). According to the 104 median-level of TMB in our cohort, high TMB (n=16, 252-465 range mutations per tumor) and low TMB (n=13, 57-79 range mutations per tumor) groups were divded. The NSCLC methylome between high and low TMB was characterized on a genome-wide scale using Illumina Infinium MethylationEPIC arrays combined with the WES data.
4c3880bb027f159e801041b1021e88e8 Result
The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures in high TMB lung cancer. Combining with clinical data, cigarette smoking associated with high TMB were observed in our cohort. Cancer-specific epigenetic alterations were observed in 294,141 CpG sites, comprising both tumor hyper- (769,38) and hypo- (217,203) methylation in high TMB lung cancer while none in low. These different methylations sites cover 1232 genes including 25 HOX genes.
8eea62084ca7e541d918e823422bd82e Conclusion
Global DNA hypomethylation and TP53 mutation, associated with increased chromosomal instability, were associated with TMB in NSCLCs.The high TMB NSCLCs are characterized by numerous copy number alterations and aberrantly methylated sites and display distinct mutational signatures. 25 hypermethylated HOX genes can be potentially useful as DNA methylation markers for prediction of TMB level. The results provide insights into the epigenetic impact of TMB, which may contribute to improve precison management of NSCLCs.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-11 - Named Patient Use Program for Afatinib in Advanced NSCLC with Progression on Prior Therapy: Experience from Asian Centers (ID 12968)
16:45 - 18:00 | Author(s): Shuhang Wang
- Abstract
Background
A global named patient use (NPU) program for afatinib in patients with advanced/metastatic NSCLC who had progressed during prior therapy was conducted between May 2010 and January 2016 (Cappuzzo F et al, Future Oncol 2018). Here we describe treatment outcomes for patients at Asian centers.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had an activating EGFR/HER2 mutation, had exhausted all other treatments, and were ineligible for afatinib trials. Patients received afatinib (starting dose:30-50 mg/day). Dose modifications were allowed as tolerated. Time to treatment failure (TTF) was calculated from treatment initiation to discontinuation. Adverse event (AE) reporting was mandatory.
4c3880bb027f159e801041b1021e88e8 Result
Data were collected from 2242 NSCLC patients across 10 Asian countries. Patients were heavily pretreated, 62% received ≥2 prior chemotherapy lines, and for most, afatinib was 4th-line therapy; almost all had received erlotinib/gefitinib (Table 1). 97% of patients with known tumor status were EGFR mutation-positive (m+). Median TTF was 7.6 months overall, and 7.2 months in patients with EGFR m+ tumors (Table 1). TTF was >12 months in patients with EGFR exon20 insertions and Her2 mutations. ORR was numerically higher in patients with exon20 insertions and G719X/L861Q/S761I mutations than other subgroups (Table 1). Disease control rate was 78% overall. The most frequently reported AEs were rash and diarrhea; no new/unexpected safety signals were identified.
Table 1. Named patient use (NPU) program for afatinib in advanced/metastatic NSCLC: results from Asian centers Total number of patients 2242 Age; years, median 61 Female/male; % 60/40 Any prior treatment; n (%) 2223/2242 (99.2) Prior erlotinib and/or gefitinib; n (%) 2202/2223 (99.1) Prior erlotinib only; n (%) 866/2202 (39) Prior gefitinib only; n (%) 927/2202 (42) Prior lines of chemotherapy ≥3, 32%; ≥2, 62%; 1, 23%; 0, 15% Prior lines of systemic therapy ≥4, 37%; ≥3, 65%; 2, 21%; 1, 14%; 0, 0% EGFR m+; n (%) 1240/1281 (97) Specified EGFR mutation; n (%) 1101/1240 (89) TTF; months* n ORR, % n All patients with data available 7.6 1550 24.4 431 EGFR m+ 7.2 834 27.7 267 EGFR mutation specified 6.5 740 - - Common mutations (Del19 or L858R) 6.4 692 27.4 230 Uncommon mutations (all) 8.0 84 30.3 33 T790M 6.0 34 21.1 19 G719X, L861Q, or S761I 7.8 28 42.9 7 Exon 20 insertion 18.0 25 42.9 7 Her2 m+ 12.2 12 14.2 7 p.A775 G776insYVMA 12.4 7 25.0 4 *median
m+ve, mutation-positive; ORR, objective response rate;
TTF, time to treatment failure
8eea62084ca7e541d918e823422bd82e Conclusion
This analysis from Asian countries in the afatinib NPU program revealed clinically meaningful TTF/ORR in this heavily pre-treated and refractory advanced NSCLC patient population, including activity in common and uncommon EGFR mutations. TTF was numerically longer in patients with uncommon mutations (particularly EGFR exon20 insertions) and HER2 mutations than in those with common EGFR mutations. The safety profile of afatinib was consistent with non-Asian centers.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-101 - Dynamic Monitoring of Gene Alterations with ctDNA by NGS for EGFR Mutated Lung Adenocarcinoma Treated with Gefitinib in BENEFIT Study (CTONG 1405) (ID 14347)
16:45 - 18:00 | Author(s): Shuhang Wang
- Abstract
Background
Blood-based cell-free tumor DNA (ctDNA) could be dynamically monitored to provide gene alterations during EGFR-TKI treatment, which might offer critical clue for prognosis and clinical treatment decision. Here we reported the dynamic gene alterations monitoring using next generation sequencing (NGS) in BENEFIT study to explore the mechanisms of different responses and resistances to EGFR-TKI in EGFR-sensitizing-mutated lung-adenocarcinoma (LADC) patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with systemic treatment-naïve, stage IV LADC and EGFR-sensitizing-mutation in ctDNA were enrolled to receive gefitinib. Blood samples were dynamically obtained at baseline, every 8 weeks and at disease progression (PD). The dynamic analysis of quantity of ctDNA, multiple driver genes and tumor suppressors were investigated with NGS (Nextseq500 sequencer, consisting of critical exons/introns of 168 genes), and were correlated with efficacy and resistance.
4c3880bb027f159e801041b1021e88e8 Result
Totally 181 LADC patients with EGFR-sensitizing-mutation (exon-19-deletion and exon-21-L858R-point-mutation) provided sufficient blood samples for NGS analysis at baseline, of which 143 patients obtained at least four timepoints of dynamic blood sample collection until PD (baseline, 8 weeks, 8 weeks before PD and PD). At baseline, 180 of patients (99.4%) were confirmed as EGFR-sensitizing-mutation with NGS (92 EGFR-19-deletion and 88 EGFR-L858R-point-mutation) including 44 (24.3%) EGFR-amplification, 116 (64%) TP53-mutation, or other known oncogenic drivers including MET (N=5, 2.8%), ERBB2 (N=7,3.9%), KRAS (N=6, 3.3%), BRAF (N=2, 1.2%), RET (N=1, 0.6%), ROS1 (N=1, 0.6%), or EGFR-T790M (N=4, 2.2%), which was correlated with poor efficacy compared with those with only EGFR-sensitizing-mutation (PFS 4.7 months [m] vs. 13.2m , p=0.002). Additionally, tumor suppressor genes exhibiting cumulative effect to poor prognosis: PFS for 164 patients with TP53&RB1&PTEN-mutation≤1 was 11.1m, while for 16 patients with TP53&RB1&PTEN-mutation＞1，PFS was 4.7 m, p<0.0001. To cut-off date, 117 patients had PD, among them, 63 (54%) patients acquired EGFR-T790M-mutation presented as dominant resistance mechanism besides MET-amplification/ERBB2-amplification/ERBB2-S310F (N=16, 14%), RET fusion/splice (N=2, 1.7%), ROS1-C2336F-mutation (N=1, 0.9%), RB1-nonsense-mutation (N=2, 1.7%), TP53-Y205S-mutation (N=1, 0.9%) and TP53-Y205S-mutation accompanied with FGFR1-amplification (N=1, 0.9%). The remaining resistance mechanisms (31%) were unknown. Patients with only T790M-mutation had a significantly longer PFS (11.5m) compared with patients obtaining other acquired resistant mechanisms (3.0m). Interestingly, seventy-five (53.2%) patients had molecular progression before radiographic progression, and the median time difference was 8.7 weeks.
8eea62084ca7e541d918e823422bd82e Conclusion
Dynamic alterations of multi-drivers and suppressors together with EGFR-sensitizing-mutation and T790M-mutation could separate LADC into different subgroups with distinguished molecular features, which may play a vital role during EGFR-TKI treatment for resistance-predicting, and initial/subsequent treatment decision-making.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-105 - Retrospective Analysis of Efficacy and Safety in Chinese Elderly Patients Treated with Nab-Paclitaxel (ID 12682)
12:00 - 13:30 | Presenting Author(s): Shuhang Wang
- Abstract
Background
Albumin-bound paclitaxel (nab-PC) could benefit advanced non-small cell lung cancer (NSCLC) either in first line or second line. However, the safety and efficacy in Chinese elderly population remains unclear. In this study, we retrospectively analyzed the efficacy and safety of nab-pc in Chinese elderly patients (≥65 year old) from a single cancer center.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively collected data from 75 patients who were treated with weekly nab-paclitaxel (125 or 130 mg/m2d1, d8) from Janurary 2010 to December 31, 2017 in Peking University Cancer Hospital. Among which, 33 patients were non-squamous NSCLC, and 42 patients were squamous NSCLC. Twelve of these patients received nab-paclitaxelas first line treatment (7 of which were combined with carboplatin) and 63 patients received single nab-paclitaxel as latter line treatment.
4c3880bb027f159e801041b1021e88e8 Result
Results: Sixty-eight out of 75 patients were available for efficacy evaluation, the overall objective response rate (ORR) was 13.1 (10/68), disease control rate (DCR) was 69.3%(52/68), median progression free survival (PFS) was 5.2 months and overall survival was 12.2 months in the entire population. For fist-line and latter line setting subgroup, the ORR, DCR, PFS and OS were 18.2% and 14.0%; 90.9% and 73.7%; 6.7 months and 5.0 months; 17.7 months and 12.2 months, respectively. For the patients ≥70 years old, the PFS significantly longer compared with patient ＜70 years old (6.3 months vs. 3.7 months p=0.021; the same trend was observed in OS, however the difference was not significant (13.3 months vs. 10.0 months, p=0.089). For all grade of adverse events (AEs), the most common AEs were leukopenia (37.3%, n=28), anemia (40%, n=30) fatigue (18.7%, n=14) and Peripheral neuritis (17.3%, n=13) which were all manageable, and the incidence of grade 3 were 13.3% (10/75), no grade 4 AEs were found and no AEs related death. Totally 7 patients discontinued treatment because of AEs. And the incidence of AEs was not different among subgroups of patients defined with age (65≤age＜70, 70≤age<75 and age≥75).
8eea62084ca7e541d918e823422bd82e Conclusion
The efficacy of nab-paclitaxel in Chinese elderly patients was desirable. The toxicity was tolerable and manageable. Patients over 70 may benefit more from nab-paclitaxel. Prospective clinical trials are expected to further confirm the results.
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