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Kai Wang
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JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)
- Event: WCLC 2019
- Type: Joint IASLC-CSCO-CAALC Session
- Track:
- Presentations: 1
- Moderators:Chunxue Bai, Tony Mok, Yi-Long Wu, Qing Zhou, Nan Wu
- Coordinates: 9/07/2019, 07:00 - 11:15, Toronto (1985)
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JCSE01.25 - TP53/KMT2C Co-Mutation as a Novel Biomarker for Immunotherapy in Non-Small Cell Lung Cancer Patients (ID 3862)
07:00 - 11:15 | Author(s): Kai Wang
- Abstract
Abstract
Background
Immune checkpoint inhibitors (ICIs) have shown remarkable antitumor effects in non-small cell lung cancer (NSCLC), however only a subset of patients respond. Genomic alterations (GAs) detected by targeted next-generation sequencing (NGS) is increasingly used in clinical practice, but its correlation with recognized immune biomarkers and predictive value for ICIs response in NSCLC is unclear.
Methods
FFPE tumor and matched blood samples of 637 NSCLC patients (84 squamous cell and 553 non-squamous cell) were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. TMB high (TMB-H) was defined as ≥10 muts/Mb. Positive PD-L1 expression was defined as ≥1% of tumor cells with membranous staining (22C3/28-8, DAKO). Genomic data and ICIs treatment outcome from a 240 NSCLC patient cohort was derived from cBioPortal (MSKCC, J Clin Oncol 2018).
Results
In 637 NSCLC patients, the prevalence of PD-L1≥1% was 26.5% and the median TMB was 4.6 muts/Mb (IQR, 2.3-10). Recurrent TP53, KRAS, LRP1B and KEAP1 mutations were significantly correlated with higher TMB (p value). TP53, KRAS and KEAP1 mutations were significantly enriched in the TMB-H/PD-L1+ subset while STK11 mutations were enriched in TMB-H/PD-L1- subset (p value). KMT2C, also known as MLL3, belongs to the mixed‐lineage leukemia (MLL) family of histone methyltransferases and its GAs was found in 5% of our cohort. Tumors with KMT2C and TP53 co-mutations (co-MUT) had a significantly higher TMB (15.1 muts/Mb) than TP53/KMT2C single-MUT (8.7 muts/Mb) and TP53/KMT2C co-WT (3.1 muts/Mb) tumors. Moreover, TMB-H/PD-L1+ subset was enriched in KMT2C and TP53 co-MUT (25%) comparing to TP53/KMT2C single-MUT (14.7%) and TP53/KMT2C co-WT (3.3%) tumors. Survival analysis from public clinical trials confirmed that patients with TP53/KMT2C co-MUT had remarkable clinical benefit to ICIs in both progression free survival (PFS) and durable clinical benefit (DCB). The median PFS was 7.3, 4.2 and 2.5 months for TP53/KMT2C co-MUT, TP53/KMT2C single-MUT and TP53/KMT2C co-WT patients, respectively (p=0.0032). TP53/KMT2C co-MUT was an independent variable of PFS (TP53/KMT2C co-MUT vs. TP53/KMT2C co-WT, HR: 0.47, 95%CI: 0.25-0.89, p=0.0199). Furthermore, TP53 with KMT2C or KRAS co-MUT expanded the patient population benefiting from ICIs (mPFS = 7.2 months, p=0.00042; DCB = 51.2%, p= 0.0195).
Conclusion
This study provides evidence that TP53/KMT2C co-MUT may serve as a predictive biomarker for ICIs in NSCLC. GAs detected by targeted NGS could illuminate insight for immunotherapy.
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-33 - More than 40% of Locally Advanced or Metastatic NSCLC Patients Without EGFR/ALK Alterations Have PD-L1 TPS >= 1% in China (Now Available) (ID 2955)
09:45 - 18:00 | Author(s): Kai Wang
- Abstract
Background
Very recently, it was suggested that pembrolizumab monotherapy can be extended as first-line therapy to patients (pts) with locally advanced or metastatic non-small-cell lung cancer (NSCLC) without sensitizing EGFR or ALK alterations and with low PD-L1 Tumor Proportion Score (TPS). Then screening the subset of pts with PD-L1 TPS >= 1% from all the EGFR-, ALK- locally advanced or metastatic NSCLC pts became important. However, less was known about the percentage of this subset in China. We investigated this percentage taking advantage of the retrospective NSCLC cohort collected by Origimed.
Method
The Origimed-based NSCLC cohort was a retrospective cohort consisted of more than one thousand Chinese NSCLC pts who underwent both NGS panel sequencing and PD-L1 immunohistochemistry (IHC) in a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory during the year 2017 and 2018. Antibodies used in the PD-L1 IHC assay included 22C3 and 28-8. TPS was applied. All the slides were reviewed by the same senior pathologist. All the EGFR and ALK alterations were manually reviewed in Integrated Genomics Viewer for confirmation. Stage III or IV at diagnosis was used as an approximation to the criteria "locally advanced or metastatic".
Result
Excluding sensitizing EGFR/ALK alteration carriers, there were totally 27 locally advanced or metastatic NSCLC pts whose 22C3 PD-L1 TPS were available and 202 locally advanced or metastatic NSCLC pts whose 28-8 PD-L1 TPS were available in the cohort. Among them, 55.6% (15/27) 22C3 stained samples had TPS >= 1%, and 40.6% (82/202) 28-8 stained samples had TPS >= 1%.
Conclusion
More than 40% of locally advanced or metastatic NSCLC pts without EGFR/ALK alterations have PD-L1 TPS >= 1% in China. These pts may benefit from first-line pembrolizumab monotherapy.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-10 - The Landscape of RET Genomic Alterations in Chinese Non-Small Cell Lung Cancer Patients (ID 1262)
09:45 - 18:00 | Author(s): Kai Wang
- Abstract
Background
RET is known as a driver gene which accounts for 1-2% in NSCLC. Recently, RET inhibitors such as LOXO-292 and BLU-667 demonstrated promising efficacy in NSCLC and medullary thyroid cancer. The landscape of RET alterations of the Chinese NSCLC population will be explored in this study.
Method
FFPE tumor and matched blood samples of 3433 Chinese NSCLC patients were collected for performing next-generation sequencing (NGS) based targeted panel sequencing. The genomic variants including single nucleotide variations, indels, copy number alterations and gene rearrangements were analyzed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were calculated and assessed by NGS algorithms.
Result
The patients with RET alterations, including 61 males and 57 females with a median age of 59.5 years, were identified in approximately 3.4% (118/3433) of the Chinese NSCLC cohort. In this study, 58 out of 118 (1.7%) patients, including 21 males and 37 females with a median age of 58 years, harbored RET rearrangements, which is slightly higher than the published data of MSKCC (1.2%). The partner genes of RET rearrangements were identified by NGS, including KIF5B (38/58), CCDC6 (6/58), and other genes (14/58). TP53 was the most common compound gene with RET rearrangements. Two co-existing EGFR mutations, L858R and L861Q, were identified in 2 RET rearrangement patients without previous treatments. Harbored alterations in the cell cycle pathway and in the PI3K/mTOR pathway were found in 15.5% (9/58) and 12.1% (7/58) of patients, respectively. In addition, 8 patients with RET rearrangements had no other co-occurring common cancer gene mutations. Meanwhile, 56 (1.6%) patients carried RET mutations and 5 (0.2%) patients presented RET amplifications. The median TMB of patients with RET alteration was 4.6 muts/Mb, which was exactly the same as all the 3433 patients (4.6 muts/Mb). Interestingly, patients with RET rearrangements had lower TMB (2.3 muts/Mb, 0-16.2 muts/Mb). All patients with RET alternations were microsatellite stable (MSS).
Conclusion
This is the first study to reveal RET genomic profiling in a large Chinese NSCLC cohort. RET rearrangements were found in 1.7% of Chinese NSCLC. Besides the most common partner genes, 14 RET rearrangements (24%) with uncommon or novel partner genes were identified by NGS. TMB of the patients with RET rearrangements was relatively lower.
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P1.14-34 - The Landscape of MET Alterations in Chinese Non-Small Cell Lung Cancer Patients (ID 2088)
09:45 - 18:00 | Author(s): Kai Wang
- Abstract
Background
Mesenchymal-to-epithelial transition (MET) is a therapeutic target in non-small cell lung cancer (NSCLC), which has a variety of genomic variants. MET amplification and MET exon 14 skipping (MET ex14) have been notable for meaningful clinical response to MET inhibitor therapy. However, comprehensive molecular characteristics of MET variants of Chinese NSCLC patients are not well understood.
Method
FFPE tumor and matched blood samples from 3433 Chinese NSCLC patients were collected for targeted next generation sequencing (NGS). Genomic variants including single nucleotide variations (SNV), short/long insertion/deletions (Indel), copy number alterations and gene rearrangements were analyzed. MET amplification, MET ex14 skipping and gene fusion were defined as MET druggable variations. Tumor mutational burden (TMB) was analyzed in all patients.
Result
In total, MET variations were identified in 3.3% (115/3433) of Chinese NSCLC patients. Mutation rates varied in different histological types: 3.3% (N=95)in adenocarcinoma, 1.7% (N=7) in squamous cell carcinoma, 10.1% (N=7) in adenosquamous carcinoma and 15.0% (N=3) in sarcomatoid carcinoma. MET druggable variations had been found enriched at an advanced clinical stage accounted for 3.8% of stage IV cases while only 1.2% of cases at earlier stages. Consistent to the previous studies, MET amplification and MET ex14 skipping were identified in 1.5% and 0.8% of NSCLC patients respectively. MET rearrangement was identified in seven patients in this cohort with partner genes as CD47, ST7, TMEM168, MYTKL and FOXP2. Moreover, 39.5% of MET point mutations resulting in pathway activation (D1010, D1228 and H1094) in this cohort could then be potential targets for MET inhibitors. Twenty six percent of all MET variations co-mutated with EGFR sensitive mutations, which may be a resistance mechanism for EGFR-TKI therapy. The median TMB of patients with MET variations was 6.1 muts/Mb. Cases with MET SNV/Indel alterations had higher median TMB than wild type MET (8.1 vs. 4.6 muts/Mb, respectively, P = 0.03). In particular, a newly acquired MET fusion was detected in a 60-year old female NSCLC patient when disease progressed on TKI against the original EGFR L858R-mutant. She achieved a partial response to crizotinib plus osimertinib treatment.
Conclusion
Our study revealed that MET variations occurred in 3.3% of Chinese NSCLC patients. Besides MET amplification and MET ex14 skipping, MET rearrangements and targetable point mutations we identified might be potential therapeutic targets for these patients.
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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
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-20 - TP53/KMT2C Co-Mutation as a Novel Biomarker for Immunotherapy in Non-Small Cell Lung Cancer Patients (ID 2081)
10:15 - 18:15 | Author(s): Kai Wang
- Abstract
Background
Immune checkpoint inhibitors (ICIs) have shown remarkable antitumor effects in non-small cell lung cancer (NSCLC), however only a subset of patients respond. Genomic alterations (GAs) detected by targeted next-generation sequencing (NGS) is increasingly used in clinical practice, but its correlation with recognized immune biomarkers and predictive value for ICIs response in NSCLC is unclear.
Method
FFPE tumor and matched blood samples of 637 NSCLC patients (84 squamous cell and 553 non-squamous cell) were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. TMB high (TMB-H) was defined as ≥10 muts/Mb. Positive PD-L1 expression was defined as ≥1% of tumor cells with membranous staining (22C3/28-8, DAKO). Genomic data and ICIs treatment outcome from a 240 NSCLC patient cohort was derived from cBioPortal (MSKCC, J Clin Oncol 2018).
Result
In 637 NSCLC patients, the prevalence of PD-L1≥1% was 26.5% and the median TMB was 4.6 muts/Mb (IQR, 2.3-10). Recurrent TP53, KRAS, LRP1B and KEAP1 mutations were significantly correlated with higher TMB (p value). TP53, KRAS and KEAP1 mutations were significantly enriched in the TMB-H/PD-L1+ subset while STK11 mutations were enriched in TMB-H/PD-L1- subset (p value). KMT2C, also known as MLL3, belongs to the mixed‐lineage leukemia (MLL) family of histone methyltransferases and its GAs was found in 5% of our cohort. Tumors with KMT2C and TP53 co-mutations (co-MUT) had a significantly higher TMB (15.1 muts/Mb) than TP53/KMT2C single-MUT (8.7 muts/Mb) and TP53/KMT2C co-WT (3.1 muts/Mb) tumors. Moreover, TMB-H/PD-L1+ subset was enriched in KMT2C and TP53 co-MUT (25%) comparing to TP53/KMT2C single-MUT (14.7%) and TP53/KMT2C co-WT (3.3%) tumors. Survival analysis from public clinical trials confirmed that patients with TP53/KMT2C co-MUT had remarkable clinical benefit to ICIs in both progression free survival (PFS) and durable clinical benefit (DCB). The median PFS was 7.3, 4.2 and 2.5 months for TP53/KMT2C co-MUT, TP53/KMT2C single-MUT and TP53/KMT2C co-WT patients, respectively (p=0.0032). TP53/KMT2C co-MUT was an independent variable of PFS (TP53/KMT2C co-MUT vs. TP53/KMT2C co-WT, HR: 0.47, 95%CI: 0.25-0.89, p=0.0199). Furthermore, TP53 with KMT2C or KRAS co-MUT expanded the patient population benefiting from ICIs (mPFS = 7.2 months, p=0.00042; DCB = 51.2%, p= 0.0195).
Conclusion
This study provides evidence that TP53/KMT2C co-MUT may serve as a predictive biomarker for ICIs in NSCLC. GAs detected by targeted NGS could illuminate insight for immunotherapy.
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-32 - Higher Prevalence of EGFR Mutations Significantly Correlates with Lower PD-L1 Expression in Chinese Lung Adenocarcinoma (Now Available) (ID 191)
10:15 - 18:15 | Author(s): Kai Wang
- Abstract
Background
EGFR mutations are more prevalent in lung adenocarcinoma compared with other non-small cell lung cancer and are more prevalent in East Asians compared with the other populations. At the same time, we observed lower PD-L1 Tumor Proportion Score (TPS) in Chinese lung adenocarcinoma patients (pts) compared with that in Chinese lung squamous cell carcinoma pts and we also observed the proportion of PD-L1 positive (TPS >= 1%) in Chinese lung adenocarcinoma pts was lower than that in other multicenter cohorts. Then we hypothesize that the higher prevalence of EGFR mutations in Chinese lung adenocarcinoma pts correlates with lower PD-L1 expression.
Method
The Origimed-based lung adenocarcinoma cohort was a retrospective cohort consisted of more than one thousand Chinese lung adenocarcinoma pts who underwent both NGS panel sequencing and PD-L1 immunohistochemistry (IHC) in a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory during the year 2017 and 2018. Antibodies used in the PD-L1 IHC assay included 28-8 (sample size = 883) and 22C3 (sample size = 158). Tumor Proportion Score (TPS) was applied. All the slides were reviewed by the same senior pathologist. All the EGFR mutations were manually reviewed in Integrated Genomics Viewer for confirmation. After confirmation, each pts was assigned to EGFR positive group or EGFR negative group. Fisher' s exact test and Student' s t-test were applied.
Result
For antibody 28-8, PD-L1 IHC was positive (TPS >= 1%) in 18% (66/370) EGFR positive pts and was positive in 35% (180/513) EGFR negative pts (fisher exact test p value = 1.6e-5). For antibody 22C3, PD-L1 IHC was positive (TPS >= 1%) in 14% (9/64) EGFR positive pts and was positive in 45% (42/94) EGFR negative pts (fisher exact test p value = 3.8e-3). And we observed a significantly lower PD-L1 TPS in EGFR positive pts for both antibodies (t-test p value = 3.5e-11 for PD-L1 antibody 28-8; t-test p value = 6.0e-5 for PD-L1 antibody 22C3).
Conclusion
The observation demonstrated that lower PD-L1 TPS in Chinese Lung Adenocarcinoma pts was significantly correlated with East-Asian-specific high prevalence of EGFR mutations. The observation reassured that EGFR mutation status should be examined simultaneously with PD-L1 IHC in lung adenocarcinoma pts because it was a confounding factor for predicting immunotherapy outcome using PD-L1 TPS. The observation partly explained the generally higher PD-L1 TPS in Chinese lung squamous carcinoma pts compared with that in Chinese lung adenocarcinoma pts.
