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Jie Wang
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JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)
- Event: WCLC 2018
- Type: Joint IASLC/CSCO/CAALC Session
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
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JCSE01.22a - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 14702)
11:15 - 11:15 | Presenting Author(s): Jie Wang
- Abstract
Abstract not provided
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MA02 - Improving Outcomes for Patients with Lung Cancer (ID 895)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 201 BD
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MA02.06 - A Randomized, Double-Blind, Placebo-Controlled Trial of Chemotherapy Combined with Yangzheng Xiaoji in Advanced NSCLC (ID 13562)
11:05 - 11:10 | Author(s): Jie Wang
- Abstract
- Presentation
Background
Yangzheng Xiaoji (YZXJ) is a Chinese medicine formulation made of 16 herbs and used in patients with solid cancers. The aim of this randomized, double-blind and placebo-controlled multi-center trial (YANG-1，ClinicalTrials.gov registration No. NCT02195453) is to evaluate the impact of Yangzheng Xiaoji capsule on the quality of life (QoL) and treatment-related side effects in patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with advanced NSCLC and with Eastern Cooperative Oncology Group performance status 0 to 1, who receive first-line chemotherapy (gemcitabine or pemetrexed and cisplatin), were randomized (1:1) to Yangzheng Xiaoji (YZXJ) or placebo combined with chemotherapy. The primary endpoint was QoL (Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS)) after two or four cycles of chemotherapy. The second endpoints included overall response rate, progression free survival and toxicity.
4c3880bb027f159e801041b1021e88e8 Result
Between 10/2014 and 4/2017, the trial enrolled and randomized 504 patients from 25 centers in China. 397 patients received at least two cycles of chemotherapy and were included for final analysis. Baseline characteristics, including FACT-L and LCSS scores, were well balanced between two groups. The mean FACT-L scores were significantly changed in both groups from the baseline to that after chemotherapy (97.58 increase to 100.89 in YZXJ/chemotherapy arm, P<0.001; 93.83 decrease to 97.93 in placebo arm, P<0.001). The mean score of LCSS from baseline was significantly changed in YZXJ/chemotherapy groups(25.84 decrease to 22.31, P<0.001), but there was no statistical difference in the placebo group(25.59 vs. 26.45, P=0.136). The YZXJ/chemotherapy arm had a better QoL than the placebo/chemotherapy arm (FACT-L, 3.30 vs. -4.09; P<0.001) as well as improved lung cancer symptoms compared with placebo (LCSS, -3.53 vs. -0.86; P<0.001). There was no statistical difference in chemotherapy completion rate, ORR and PFS between two groups. The most common adverse events were bone marrow toxicity (70.92% vs. 67.59%) and gastrointestinal reaction (34.66% vs. 63.24%) (YZXJ vs. Placebo, P=0.441 and P<0.001, respectively). The rate of fatigue was significantly lower in YZXJ group than placebo group (4.38% vs. 30.04%, P<0.001).
8eea62084ca7e541d918e823422bd82e Conclusion
For patients with advanced NSCLC who received platinum-based chemotherapy, Yangzheng Xiaoji Capsule significantly improved the quality of life and symptoms, especially fatigue and gastrointestinal reaction.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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): Jie 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.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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OA13.03 - Anlotinib as Third-Line or Further-Line Treatment in Relapsed SCLC: A Multicentre, Randomized, Double-Blind Phase 2 Trial (ID 12102)
10:50 - 11:00 | Author(s): Jie Wang
- Abstract
- Presentation
Background
Treatment for patients with relapsed small cell lung cancer (SCLC) who failed ≥ 2 lines of chemotherapy have high unmet needs. Anlotinib is a novel TKI with highly selective inhibition effects on multi-targets, especially on VEGFR, c-Kit, PDGFR, FGFR. Here we report results of a phase 2 study of anlotinib for the third-line and further-line treatment of SCLC. (ALTER1202, NCT03059797).
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible either limited- or extensive-stage SCLC patients with disease progression after ≥ 2 lines of chemotherapy were randomized 2:1 to anlotinib or placebo (12 mg PO QD from day 1 to 14, every 3 weeks). The primary endpoint was PFS and secondary endpoints was OS, ORR, DCR, quality of life and safety.
4c3880bb027f159e801041b1021e88e8 Result
Between March 2017 and May 2018, 120 patients from 11 centers were randomized to either anlotinib arm (n=82) or placebo arm (n=38). Until the data cutoff date (30 Jun 2018), median PFS was 4.1 months (95%CI, 2.8 to 4.2 months) in anlotinib arm and 0.7 months (95% CI, 0.7 to 0.8 months) in placebo arm (HR, 0.19; 95% CI, 0.12 to 0.32, p<0.0001). OS data were not sufficiently mature for analysis. Although ORR was similar, considerable improvement in DCR was observed in anlotinib arm (71.6% vs 13.2%, p<0.0001). Treatment-related adverse events (TRAEs) occurred more frequently in anlotinib arm than that in placebo (87.7% and 74.4%). The most common TRAEs were hypertension, anorexia, fatigue, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 29 (35.8%) of patients in anlotinib arm and 6 (15.4%) in placebo arm, respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
ALTER 1202 study demonstrates anlotinib should be considered a treatment option for patients with relapsed SCLC who have experienced treatment failure with two lines of chemotherapy. The safety profile was consistent with the previous report and no newly adverse events were identified.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)
- 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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P1.04-36 - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 12092)
16:45 - 18:00 | Presenting Author(s): Jie Wang
- Abstract
Background
Immune checkpoint inhibitors have shown efficacy in patients with NSCLC as monotherapy and in combination with chemotherapy. Tislelizumab is a humanized IgG4 monoclonal antibody to PD‑1 specifically engineered to minimize FcϒR binding on macrophages, possibly minimizing negative interactions with other immune cells. In a phase 1 study, tislelizumab was generally well tolerated and showed antitumor activity; 200mg IV Q3W was established as the recommended dose.
a9ded1e5ce5d75814730bb4caaf49419 Method
This multi-arm phase 2 study, consisting of safety run-in and dose-extension phases, assessed tislelizumab in combination with platinum-based chemotherapy (by tumor histology) as a potential first-line treatment for Chinese patients with lung cancer. All patients received tislelizumab at 200mg Q3W in combination with 4–6 cycles of platinum-doublet until disease progression. Nonsquamous (nsq) NSCLC patients received pemetrexed + platinum Q3W for 4 cycles followed by pemetrexed maintenance, while squamous (sq) NSCLC patients received paclitaxel + platinum (A) or gemcitabine + platinum (B) Q3W, and small-cell lung cancer (SCLC) patients received etoposide + platinum Q3W. Tumor response (RECIST v1.1) and safety/tolerability were evaluated.
4c3880bb027f159e801041b1021e88e8 Result
As of 21 Feb 2018, 48 patients (median age, 62 years [range: 36–75], 71% male, 71% current/former smokers) received tislelizumab treatment (median, 3 cycles [range: 1–7]); 44 patients remain on the study. Across the four cohorts, confirmed and unconfirmed partial responses were observed in 13 and 9 patients, respectively (Table). The most frequent AEs were chemotherapy-related hematologic toxicities. The most commonly reported grade ≥3 treatment-related AEs were neutropenia (20.8%) and anemia (12.5%); the most common grade 3 immune-related AEs were pyrexia (6.3%) and rash (6.3%). One sq‑NSCLC patient experienced a fatal myocarditis/myositis following one cycle of paclitaxel/cisplatin; all other treatment-related AEs were managed/resolved by study-drug interruption (n=15) or discontinuation (n=4) and appropriate treatment.
8eea62084ca7e541d918e823422bd82e ConclusionBest Overall Response (Patients With ≥1 Post-Baseline Tumor Assessment)
nsq-NSCLC (n=9)
sq-NSCLC [A] (n=12 )
sq-NSCLC [B] (n=5 )
SCLC (n=8)
Total
(N=34)
PR
4 (44.4)
9 (75)
4 (80)
5 (62.5)
22 (64.7)
Confirmed PR
1 (11.1)
4 (33.3)
4 (80)
4 (50)
13 (38.2)
Unconfirmed PR
3 (33.3)
5 (41.7)
0 (0)
1 (12.5)
9 (26.5)
SD
3 (33.3)
2 (16.7)
1 (20)
2 (25)
8 (23.5)
PD
1 (11.1)
0 (0)
0 (0)
1 (12.5)
2 (5.9)
NE
1 (11.1)
1 (8.3)
0 (0)
0 (0)
2 (5.9)
Data presented as n (%).
Abbreviations: nsq-NSCLC, non-squamous non-small cell lung cancer; NE, not evaluable; PD, progressive disease; PR, partial response; SCLC, small cell lung cancer; SD, stable disease; sq-NSCLC, squamous non-small cell lung cancer.
Tislelizumab, in combination with platinum doublets, demonstrated preliminary antitumor activity and was generally well tolerated in patients with advanced lung cancer.
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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 | Presenting Author(s): Jie 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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P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.04-03 - NF-κB and HIF-1α Play Important Roles in Regulating PD-L1 Expression by EGFR or KRAS Mutants in Non-Small Cell Lung Cancer Cells (ID 12672)
16:45 - 18:00 | Presenting Author(s): Jie Wang
- Abstract
Background
Programmed death ligand 1 (PD-L1) is expressed in various human tumors and is of critical importance for the immune escape of tumor cells. Some driver gene mutations including EGFR and KRAS have been reported to be involved in PD-L1 expression regulation. However, the potential role and precise mechanism of EGFR and KRAS mutants in PD-L1 expression regulation in non-small cell lung cancer (NSCLC) remain obscure.
a9ded1e5ce5d75814730bb4caaf49419 Method
The expression levels of PD-L1 and key molecules of EGFR and KRAS signaling pathways were examined in 11 NSCLC cells with wild-type or mutant EGFR and KRAS genes. Additionally, ectopic expression or depletion of EGFR or KRAS mutants and pharmacological inhibitors of MEK/ERK, PI3K/AKT, IκBα, and HIF-1α were employed to elucidate the effects of activation or inhibition of EGFR or KRAS pathway on PD-L1 expression regulation in NSCLC cells. The effects of pathway inhibitors on tumorigenesis and PD-L1 expression of EGFR or KRAS-mutated NSCLC cells were also examined using xenograft mouse model, Furthermore, the correlations between EGFR and KRAS status and protein levels of HIF-1α and PD-L1 were analyzed in 97 NSCLC tissues.
4c3880bb027f159e801041b1021e88e8 Result
Examination of the EGFR and KRAS signaling cascades in NSCLC cells revealed an apparent association of PD-L1 overexpression with activation of MEK/ERK and PI3K/AKT pathways, especially with increased protein levels of p-IκBα and HIF-1α. Notably, ectopic expression or depletion of EGFR or KRAS mutants and administration of EGFR or KRAS pathway inhibitors showed important interplay and cooperation between NF-κB and HIF-1α in PD-L1 expression regulation in NSCLC cells. Furthermore, administration of EGFR or KRAS pathway inhibitors significantly inhibited xenograft tumor growth and PD-L1 expression of NSCLC cells in nude mice. Moreover, NSCLC tissues with positive HIF-1α staining presented significantly increased positive rate of PD-L1 expression compared with tissues scored HIF-1α negative (49.1% vs. 20.5%, P = 0.003). NSCLC tissues with EGFR or KRAS mutants showed obviously elevated expression levels of HIF-1α and PD-L1 compared with tissues carrying wild-type EGFR and KRAS genes (68.4% vs. 43.4%, P = 0.018 and 50.0% vs. 28.3%, P = 0.035, respectively).
8eea62084ca7e541d918e823422bd82e Conclusion
Taken together, both EGFR and KRAS mutants were identified to regulate PD-L1 expression via signaling effectors, NF-κB and HIF-1α, suggesting the correlation between driver gene mutations and tumor immune escape in NSCLC.
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P2.04-29 - Preliminary Results With Tislelizumab in Chinese Patients With Non-Small Cell Lung Cancer (NSCLC) (ID 11319)
16:45 - 18:00 | Author(s): Jie Wang
- Abstract
Background
NSCLC accounts for 80–85% of all lung cancers and has a poor prognosis at later stages. Immune checkpoint inhibitors have shown efficacy in patients (pts) with advanced NSCLC. Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for PD-1. Tislelizumab was specifically engineered to minimize FcϒR binding on macrophages that, based on preclinical evidence, is believed to minimize potentially negative interactions with other immune cells. In a phase 1 study, tislelizumab was generally well tolerated and showed antitumor activity in NSCLC pts; 200 mg IV Q3W was established as the recommended tislelizumab dose.
a9ded1e5ce5d75814730bb4caaf49419 Method
In the ongoing indication-expansion phase of this study, Chinese pts with histologically confirmed NSCLC were enrolled into PD-L1-high (PD-L1+; ≥10% tumor cells expressing PD-L1) and PD‑L1‑low (PD-L1–) cohorts. Antitumor activity (RECIST v1.1) and safety/tolerability (NCI-CTCAE v4.03) were assessed.
4c3880bb027f159e801041b1021e88e8 Result
As of 8 Dec 2017, 42 NSCLC pts (median age 54 yr [range 37–72]) were enrolled; 17 were PD-L1+ and 25 were PD-L1–. Most pts were male (69%), former/current smokers (57%), and had received prior therapy (95%). Adenocarcinoma was the most prevalent histology (57%). Median follow-up was 4.5 mo and 23 pts remain on treatment. Of the 39 response-evaluable pts, 4 (n=2/14, PD-L1+; n=2/25, PD-L1–) achieved confirmed PR and 20 (n=6/14, PD-L1+; n=14/25, PD‑L1–) achieved SD, including 4 (n=2, PD-L1+; n=2, PD‑L1–) with unconfirmed PR. Across the study population, ORR was 10% and DCR was 61.5%. ORRs by cohort were 14% (PD‑L1+) and 8% (PD-L1–), respectively. Common treatment-related AEs were increased AST (24%), increased ALT (19%), hypothyroidism (12%), and rash (12%). Five grade ≥3 treatment-related AEs occurred in 4 pts (increased AST [n=2], hyperglycemia, increased ALT, and increased GGT [n=1 each]). No treatment-related grade 5 events were reported.
8eea62084ca7e541d918e823422bd82e Conclusion
Tislelizumab was generally well tolerated and demonstrated antitumor activity in previously treated pts with advanced NSCLC. A global phase 3 study (NCT03358875) of tislelizumab vs docetaxel as potential second/third-line therapy in NSCLC pts who progressed after a platinum-based regimen is ongoing.
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