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Jin-Ji Yang
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JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)
- Event: WCLC 2019
- Type: Joint IASLC-CSCO-CAALC Session
- Track:
- Presentations: 3
- Now Available
- 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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JCSE01.09 - A Phase II Umbrella Study of Camrelizumab in Different PD-L1 Expression Cohorts in Pre-Treated Advanced/Metastatic Non-Small Cell Lung Cancer (Now Available) (ID 3423)
07:00 - 11:15 | Author(s): Jin-Ji Yang
- Abstract
- Presentation
Abstract
Background
The role of PD-L1 expression in 2nd line and beyond non-small cell lung cancer (NSCLC) remains controversial. Camrelizumab (SHR-1210) is a potent anti-PD-1 monoclonal antibody and has shown promising activity in NSCLC in Phase I studies. We report results from the SHR-1210-201 study (NCT03085069), a phase II umbrella study of camrelizumab monotherapy in different PD-L1 expression cohorts in Chinese patients with previously treated advanced or metastatic NSCLC.
Methods
Patients who progressed during or following platinum-based doublet chemotherapy were enrolled and assigned to one of 4 cohorts based on PD-L1 expression. Patients with EGFR or ALK genomic alterations were eligible provided they had disease progression with at least one approved tyrosine kinase inhibitor and with ≥50% PD-L1 expression in tumor. All enrolled patients received camrelizumab at 200 mg IV Q2W until loss of clinical benefit. The primary endpoint was objective response rate (ORR), other endpoints included progression-free survival (PFS) and overall survival (OS).
Results
As of Aug 1st 2018, of all the 259 patients who underwent screen, 229 cases could be pathologically evaluated. PD-L1 expression were 47.6% (109/229) in PD-L1 < 1%, 27.1% (62/229) in PD-L1 ≥1-<25%, 8.7% (20/229) in ≥25-<50% and 16.6% (38/229) in ≥50%. A total of 63.8% (146/229) patients were enrolled. 89.0% of patients had stage IV NSCLC and 54.8% had non-squamous tumor histology. ORR was 18.5% (95%CI: 12.6%–25.8%) in ITT population. Subgroup analysis showed increased PD-L1 expression was associated with better response rate (Table 1). No response was observed in patients with EGFR mutation. The responders had durable response (median: 15.1 months; 95%CI: 5.5–not reached). Median PFS was 3.2 months (95%CI: 2.0–3.4) and median OS was 19.4 months (95%CI: 11.6–not reached) (Table 1). Treatment-related adverse events (AEs) occurred in 87.7% of patients (all Grade); 20.5% had ≥G3 related AE; and 15.8% had related SAE. 21.2% of AEs led to dose interruption and 7.5% led to treatment discontinuation.Table 1 - Efficacy data in subgroups Population No of pts ORR, % (95%CI) PFS (month),
median (95%CI)
1YOS, % (95%CI) OS (month),
median (95%CI)
PD-L1<1% 74 12.2% (5.7%, 21.8%)
2.1 (1.9, 3.2) 47.1% (33.8%, 59.2%) 11.6 (7.8, NR) PD-L1 ≥1% and < 25% 31 19.4% (7.5%, 37.5%) 3.1 (1.8, 4.9) 76.7% (57.2%, 88.2%) NR (NR, NR) PD-L1 ≥25% and < 50% 11 45.5% (16.7%, 76.6%) 6.0 (1.9, NR) 81.8% (44.7%, 95.1%) NR (2.9, NR) PD-L1 ≥50% (without EGFR mutation) 25 28.0% (12.1%, 49.4%) 7.6 (3.3, 11.4) 55.2% (32.3%, 73.2%) NR (8.6, NR) PD-L1 ≥50% (with EGFR mutation) 5 0 1.7 (1.2, NR) 40.0% (5.2%, 75.3%) 10.3 (1.2, NR) ITT 146 18.5% (12.6%, 25.8%) 3.2 (2.0, 3.4) 56.6% (47.3%, 64.9%) 19.4 (11.6, NR) Abbreviation: NR, Not Reached.
Conclusion
In Chinese patients with previously treated advanced/metastatic NSCLC, camrelizumab demonstrated improved ORR, PFS, and OS compared with historical data of the 2nd line chemotherapy. The efficacy in patients with PD-L1 <1% is similar as the 2nd line mono-chemotherapy, while patients with higher PD-L1 expression derived greater benefit from camrelizumab, the ORR, PFS and OS in patients with PD-L1 ≥25% was comparable to the 1st line doublet chemotherapy in advanced NSCLC. Camrelizumab was well tolerated. This phase 2 data warrant further clinical studies of camrelizumab in NSCLC.Only 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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JCSE01.16 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 3430)
07:00 - 11:15 | Author(s): Jin-Ji Yang
- Abstract
Abstract
Background
Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC).
Methods
We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs).
Results
290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs.
Conclusion
Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment. -
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JCSE01.22 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (ID 3436)
07:00 - 11:15 | Author(s): Jin-Ji Yang
- Abstract
Abstract
Background
Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.
Methods
A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells.
Results
In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor.
Conclusion
PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 4
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-104 - Survivals in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer Treated with First-Line Crizotinib (ID 1735)
09:45 - 18:00 | Author(s): Jin-Ji Yang
- Abstract
Background
The c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) can be treated effectively with crizotinib, a tyrosine kinase inhibitor (TKI) of anaplastic lymphoma kinase (ALK), ROS1, and mesenchymal-epithelial transition (MET). However, few studies have investigated on survivals in ROS1-rearranged advanced NSCLC patients treated with first-line crizotinib.
Method
We retrospectively analyzed clinicopathological and survival data of ROS1-rearranged patients with advanced NSCLC treated with crizotinib between August 2013 and January 2019 at the Guangdong Provincial People's Hospital. ROS1 rearrangements were detected by Reverse Transcription-Ploymerase Chain Reaction(RT/PCR),Fluorescence in situhybridization (FISH), or Next-generation Sequencing (NGS) . Overall survival (OS) and progression-free survival (PFS) were compared between first-line crizotinib, chemotherapy followed by crizotinib and first-line chemotherapy without any subsequent targeted therapy.
Result
Among totally 40 patients with ROS1-rearranged advanced NSCLC, 29 were treated with crizotinib (16 with first-line; 13 with second- or further-line), and 11 were not treated with crizotinib at data cutoff (April 4, 2019). Median OS was significantly prolonged in patients with first-line crizotinib (N=16) than those with first-line chemotherapy followed by subsequent crizotinib (N=9), not reached vs. 27.1 months, P=0.042. However, there was no significant difference in median PFS between the two groups, 16.3 vs. 5.7 months, P=0.054. Meanwhile, first-line crizotinib (N=16) was significantly superior to first-line chemotherapy without any subsequent targeted therapy (N=8) in both median OS (not reached vs. 9.1 months, P=0.024) and PFS (16.3 vs. 4.8 months, P=0.017).
Conclusion
First-line crizotinib prolongs survivals than chemotherapy for patients with ROS1-rearranged advanced NSCLC.
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P1.01-61 - A Phase II Umbrella Study of Camrelizumab in Different PD-L1 Expression Cohorts in Pre-Treated Advanced/Metastatic Non-Small Cell Lung Cancer (ID 1633)
09:45 - 18:00 | Author(s): Jin-Ji Yang
- Abstract
Background
The role of PD-L1 expression in 2nd line and beyond non-small cell lung cancer (NSCLC) remains controversial. Camrelizumab (SHR-1210) is a potent anti-PD-1 monoclonal antibody and has shown promising activity in NSCLC in Phase I studies. We report results from the SHR-1210-201 study (NCT03085069), a phase II umbrella study of camrelizumab monotherapy in different PD-L1 expression cohorts in Chinese patients with previously treated advanced or metastatic NSCLC.
Method
Patients who progressed during or following platinum-based doublet chemotherapy were enrolled and assigned to one of 4 cohorts based on PD-L1 expression. Patients with EGFR or ALK genomic alterations were eligible provided they had disease progression with at least one approved tyrosine kinase inhibitor and with ≥50% PD-L1 expression in tumor. All enrolled patients received camrelizumab at 200 mg IV Q2W until loss of clinical benefit. The primary endpoint was objective response rate (ORR), other endpoints included progression-free survival (PFS) and overall survival (OS).
Result
As of Aug 1st 2018, of all the 259 patients who underwent screen, 229 cases could be pathologically evaluated. PD-L1 expression were 47.6% (109/229) in PD-L1 < 1%, 27.1% (62/229) in PD-L1 ≥1-<25%, 8.7% (20/229) in ≥25-<50% and 16.6% (38/229) in ≥50%. A total of 63.8% (146/229) patients were enrolled. 89.0% of patients had stage IV NSCLC and 54.8% had non-squamous tumor histology. ORR was 18.5% (95%CI: 12.6%–25.8%) in ITT population. Subgroup analysis showed increased PD-L1 expression was associated with better response rate (Table 1). No response was observed in patients with EGFR mutation. The responders had durable response (median: 15.1 months; 95%CI: 5.5–not reached). Median PFS was 3.2 months (95%CI: 2.0–3.4) and median OS was 19.4 months (95%CI: 11.6–not reached) (Table 1). Treatment-related adverse events (AEs) occurred in 87.7% of patients (all Grade); 20.5% had ≥G3 related AE; and 15.8% had related SAE. 21.2% of AEs led to dose interruption and 7.5% led to treatment discontinuation.
Table 1 - Efficacy data in subgroups Population No of pts ORR, % (95%CI) PFS (month),
median (95%CI)
1YOS, % (95%CI) OS (month),
median (95%CI)
PD-L1<1% 74 12.2% (5.7%, 21.8%)
2.1 (1.9, 3.2) 47.1% (33.8%, 59.2%) 11.6 (7.8, NR) PD-L1 ≥1% and < 25% 31 19.4% (7.5%, 37.5%) 3.1 (1.8, 4.9) 76.7% (57.2%, 88.2%) NR (NR, NR) PD-L1 ≥25% and < 50% 11 45.5% (16.7%, 76.6%) 6.0 (1.9, NR) 81.8% (44.7%, 95.1%) NR (2.9, NR) PD-L1 ≥50% (without EGFR mutation) 25 28.0% (12.1%, 49.4%) 7.6 (3.3, 11.4) 55.2% (32.3%, 73.2%) NR (8.6, NR) PD-L1 ≥50% (with EGFR mutation) 5 0 1.7 (1.2, NR) 40.0% (5.2%, 75.3%) 10.3 (1.2, NR) ITT 146 18.5% (12.6%, 25.8%) 3.2 (2.0, 3.4) 56.6% (47.3%, 64.9%) 19.4 (11.6, NR) Abbreviation: NR, Not Reached.
Conclusion
In Chinese patients with previously treated advanced/metastatic NSCLC, camrelizumab demonstrated improved ORR, PFS, and OS compared with historical data of the 2nd line chemotherapy. The efficacy in patients with PD-L1 <1% is similar as the 2nd line mono-chemotherapy, while patients with higher PD-L1 expression derived greater benefit from camrelizumab, the ORR, PFS and OS in patients with PD-L1 ≥25% was comparable to the 1st line doublet chemotherapy in advanced NSCLC. Camrelizumab was well tolerated. This phase 2 data warrant further clinical studies of camrelizumab in NSCLC.
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P1.01-82 - The Different Frequencies and Genetic Profiles of Histologic Transformation After Different EGFR-TKIs in EGFR-Mutant Adenocarcinomas (ID 418)
09:45 - 18:00 | Author(s): Jin-Ji Yang
- Abstract
Background
Histologic transformation is a mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor(TKIs) in EGFR-mutant non-small cell lung cancers（NSCLCs）. Those adenocarcinomas with histologic transformation usually underwent poor prognosis. However, few studies have focused on the different occurrence rates and genetic profiles between EGFR-mutant adenocarcinomas treated with different generations of EGFR-TKIs.
Method
Pathology was confirmed in 345 EGFR-mutant patients at baseline and recurrence. Among these patients，235 patients were treated with gefitinib or erlotinib，54 with afatinib and 56 with osimertinib. But only 11 patients with sufficient tumor specimens could be evaluated for the genetic profiles by next-generation sequencing (NGS). Demographics, disease features, and outcomes of these patients were analyzed.
Result
The frequency of these EGFR-mutant adenocarcinomas with histologic transformation after the treatment of different generation TKIs were quite different. The frequency of gefitinib/erlotinib group was 7.2% (17/235)，while the others were 5.6%（3/54, afatinib group）and 17.9%（10/56, osimertinib group）. The median progression free survival （PFS）to EGFR-TKIs of those patients were 12.2 months（gefitinib/erlotinib group）, 5.3 months （afatinib group）and 7.7 months（osimertinib group） respectively. Four adenocarcinomas treated with gefitinib/erlotinib all harbored TP53 mutations at baseline. One adenocarcinoma treated with afatinib was founded to have acquired MET amplification and transformed to small-cell lung cancer meanwhile. Moreover, the PFS of one patient to afatinib was just 3 months and her genetic profile at baseline was characterized by Rb1, TP53, and PIK3CA mutations. There were 3 patients treated with osimertinib underwent histologic transformation from adenocarcinomas to squamous carcinoma. One patient after progressive disease of osimertinib did not have enough tissue to detect NGS，and her blood NGS result just showed EGFR L858R and T790M mutation. The tissue NGS result of the second patient showed EGFR p.Glu746-Ala750 deletion, EGFR T790M and C797S mutations, CDK4/ CCND1/ EGFR/ KRAS amplifications. The second patient received the chemotherapy of pemetrexed+ carboplatin + bevacizumab and the best response was partial response. The third patient take palbociclib and osimertinib meanwhile and his symptoms improved with the tissue NGS of EGFR T790M mutation and CDK4/ MDM2/ EGFR amplifications. They were characterized by EGFR amplification and CDK4 amplification. The others transform from adenocarcinomas to small cell cancers or neuroendocrine tumors were seem to harbor with TP53, Rb1 and PIK3CA mutations.
Conclusion
It seems more common in some subtypes that the EGFR-mutant adenocarcinomas treated with osimertinib undergo histologic transformation. The genetic profiles vary greatly between transformation to squamous carcinomas and transformation to small-cell cancers/neuroendocrine tumors in EGFR-mutant adenocarcinomas treated with osimertinib. Further verification is needed.
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P1.01-85 - Treatment for Advanced NSCLC with EGFR Mutations and De Novo MET Amplification/Overexpression (ID 2190)
09:45 - 18:00 | Author(s): Jin-Ji Yang
- Abstract
Background
Combination of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitors (TKIs) are effective in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation and acquired MET-amplification. However, there are few reports about treatments of patients with EGFR mutation and de novo MET amplification/ overexpression.
Method
We retrospectively screened 88 consecutive advanced NSCLC patients harboring EGFR mutation and de novo MET amplification/overexpression at Guangdong Provincial People's Hospital of China from January, 2014 to December, 2018. Among them, a total of 41 patients receiving first-line targeted therapy were included and stratified into EGFR-driven, MET-driven and EGFR/MET co-driven groups illustrated respectively in Table 1.
Table 1. Classification of advanced NSCLC with EGFR mutation and MET overexpression/amplification. Group EGFR mutation MET overexpression/amplification Response to first-line TKI EGFR-driven Exon 19 deletion or exon 21 L858R mutation (tested by next generation sequencing (NGS) or amplification refractory mutation system (ARMS) or polymerase chain reaction (PCR)). Overexpression: strong intensity staining was in more than 50% of tumor cells (tested by immunohistochemistry (IHC)).
Amplification: CNG≥5, or MET/centromeric portion of chormosome 7 ratio≥2.2, with an additional criterion of focal amplification was in more than 10% of tumor cells (tested by fluorescence in situ hybridization (FISH)).
PFS＞3 months, best response is complete response (CR)/partial response (PR)/stable disease (SD); not receiving MET-TKIs in later-line treatment, or had MET-TKIs but PFS≤3 months. MET-driven PFS≤3 months, receive MET-TKIs monotherapy or MET-TKIs plus EGFR-TKIs in later-line treatment and PFS＞3months, or PFS≤3 months，but with acquired mechanism to MET. EGFR/MET co-driven Response to EGFR-TKIs at least one time, receiving EGFR-TKIs plus MET-TKIs in later-line treatment and PFS＞3 months, or PFS≤3 months, but with acquired mechanism to MET.
Result
Among enrolled patients, 40 of them received first-line first-generation EGFR-TKIs while 1 treated with MET-TKI. Twenty-eight received targeted therapy in the later-line treatments after resistance. Thirty-one (75.6%), 5 (12.2%) and 5 (12.2%) patients were classified into EGFR-driven, MET-driven and EGFR/MET co-driven groups. Median progression-free survival (PFS) was 12.1, 1.0 and 5.3 months respectively in the first-line setting. Objective response rates were 58.1%, 0.0% and 20.0% (P=0.028) respectively. Among 28 patients receiving subsequent targeted therapies, 58.1% (18/31), 100.0% (5/5) and 100.0% (5/5) were EGFR-driven, MET-driven and EGFR/MET co-driven respectively. Median PFS was 7.0, 6.5 and 10.3 months for the EGFR-driven group receiving subsequent EGFR-TKIs, the MET-driven group receiving MET-TKIs with or without EGFR-TKIs, and the EGFR/MET co-driven group treating with EGFR-TKIs plus MET-TKIs respectively (P=0.399). Also, no significant difference was observed in overall survival for these 28 patients (33.8 vs. 11.8 vs. 27.9 months, P=0.098).
Conclusion
Subsequent individualized targeted therapy or co-targeted therapies might favor clinical outcomes for both MET-driven and EGFR/MET co-driven patients with advanced NSCLC after resistance to first-line EGFR-TKIs.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-42 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (Now Available) (ID 651)
09:45 - 18:00 | Author(s): Jin-Ji Yang
- Abstract
Background
Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.
Method
A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells.
Result
In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor.
Conclusion
PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.
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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
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-31 - Lack of Association Between BIM Deletion Polymorphism and Clinical Efficacy of EGFR-TKIs in NSCLC Based on NGS (Now Available) (ID 2154)
09:45 - 18:00 | Author(s): Jin-Ji Yang
- Abstract
Background
BIM deletion polymorphisms are most common in Asian population, with an incidence of 12-16% in lung cancer patients with EGFR mutations. Previous studies showed BIM deletion polymorphisms could predict poor treatment response to EGFR-TKIs, owing to loss function in mediating apoptosis of tumor cells. Recently, available data on BIM is inconsistent on its predictive role and we don’t know if NGS could bring us something new.
Method
Data were pooled from clinical trial CTONG0901 and local database in our hospital (GLCI). 194 and 117 EGFR mutant patients with IIIB-IV NSCLC are enrolled for survival analysis in the two cohorts, respectively. BIM status of all these patients were confirmed by NGS. 28 patients have baseline NGS results with 168 genes panel.
Result
The incidence of BIM deletion polymorphism in patients with EGFR mutation was 11.3% (22/194) and 17.6% (26/148) in CTONG0901 and GLCI, respectively. In CTONG0901, median PFS of patients treated with erlotinib or gefitinib between BIM deletion polymorphism and BIM wild type is 10.47m versus 11.17m (P=0.59). Median OS is 20.5m versus 20.47m (P=0.82). In GLCI, median PFS between BIM deletion polymorphism and BIM wild type is 10.13m versus 12.87m (P=0.33). Median OS is 58.5m versus 54.97m (P=0.82). No survival differences on PFS and OS present in the two cohorts. 28 patients with baseline NGS were analyzed from two cohorts. Three patients with MET amplification, ALK rearrangement and PD-L1 expression (20%+++) are lower than median PFS (8.63m). Two patients with MET amplification are around median PFS.
Conclusion
In our study, BIM deletion polymorphism has no relationship with the efficacy of EGFR-TKIs in CTONG0901. The result is confirmed in our local database. Outcomes of NGS showed that combined molecular variations, such as MET amplification, ALK rearrangement and PD-L1 expression seems more important to the prediction of EGFR-TKIs on NSCLC patients.
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P1.14-39 - Acquired ALK Rearrangement in EGFR-Mutant Lung Adenocarcinoma Treated with EGFR TKIs (ID 1784)
09:45 - 18:00 | Author(s): Jin-Ji Yang
- Abstract
Background
Few studies have been reported on acquired anaplastic lymphoma kinase (ALK) rearrangement in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients with EGFR tyrosine kinase inhibitors (TKIs).
Method
EGFR-mutant lung adenocarcinoma patients were screened after resistance to EGFR TKIs from September 2017 to December 2018 at the Guangdong Lung Cancer Institute. Both EGFR mutation and ALK rearrangement were tested by next-generation sequencing (NGS). Acquired ALK rearrangement was defined as positive ALK rearrangement after resistance to EGFR TKIs, but negative result detected by NGS at the baseline of EGFR TKI treatments.
Result
Totally 320 patients were tested by NGS after resistance to EGFR TKIs ( 175, 42 and 103 with first-, second- and third-generation EGFR-TKIs respectively). Frequency of acquired ALK rearrangement was 1.14% (2/175), 2.38% (1/42) and 1.94% (2/103) in patients treated with first-, second- and third-generation EGFR TKIs respectively. The fusion partners of ALK were EML4 in 2 patients, CLIP4 (1), NPM1 (1) and PIBF1 (1). Non-EML4-ALK fusion accounted for 60%. One with acquired EML4-ALK achieved minor response with osimertinib plus crizotinib. One with acquired NPM1-ALK achieved partial response with erlotinib plus crizotinib. Unfortunately, one with acquired CLIP4-ALK fusion and BRAF V600E mutation did not respond to ensartinib single agent. One with acquired PIBF1-ALK had no clinical benefit with osimertinib plus alectinib. Finally, one with acquired EML4-ALK died shortly without any treatment due to poor performance status.
Conclusion
The frequency of acquired ALK rearrangement is similar in EGFR-mutant lung adenocarcinomas after resistance to the first-, second-, or third-generation EGFR TKIs. The majority of acquired ALK-fusion partners are non-EML4. Combination of EGFR TKIs and ALK inhibitors might be a strategy to overcome such resistance.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 3
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-35 - Acquired MET-Aberrance Is a Mechanism of Resistance to ALK Inhibitors in ALK-Positive Advanced Non-Small-Cell Lung Cancer (Now Available) (ID 1739)
10:15 - 18:15 | Author(s): Jin-Ji Yang
- Abstract
Background
Anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI) is standard of care in ALK-positive advanced non-small-cell lung cancer (NSCLC). Unfortunately ALK-positive NSCLC patients treated with ALK TKIs inevitably develop resistance mediated by complex mechanisms including ALK mutations, ALK amplification, or activation of alternative signaling pathways. However, there are few reports about Mesenchymal-epithelial transition factor (MET) signal in NSCLC.
Method
Totally 136 ALK-positive advanced NSCLC patients were screened for ALK rearrangement detected by tumor tissue or plasma Next-generation sequencing(NGS) at the Guangdong Lung Cancer Institute from January 2016 to December 2018 .MET-aberrance was defined as c-Met overexpression performed by immunohistochemical(IHC) staining method with SP44 antibody and MET amplification assessed by tumor tissue or plasma Next-generation sequencing (NGS) or fluorescent in situ hybridization(FISH).
Result
Totally 5.89% (8/136) of patients were identified with MET-aberrance in 136 ALK-rearranged cases. Among the 8 patients，there were 6 with de novo MET-aberrance and 2 with acquired MET-aberrance.The median progression-free survival (PFS) in ALK-rearranged patients with de novo MET-aberrance was 9.6 months (95% CI 0.0 to 19.2months).The other 2 patients gained MET-aberrance after the treatment with alectinib. Both of them received lorlatinib, but the PFS only lasted for 2months. One achieved partial remission with crizotinib , which was originally developed as an inhibitor of the MET gene.
Conclusion
Acquired MET-aberrance maybe a mechanism of acquired resistance to the second-generation ALK-TKIs for ALK-rearranged advanced NSCLC patients.
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P2.01-80 - Clinical Outcomes in Advanced EGFR-Mutant NSCLC Patients Treated with First-Generation EGFR TKIs Followed by Subsequent Osimertinib (ID 1732)
10:15 - 18:15 | Author(s): Jin-Ji Yang
- Abstract
Background
Treatment with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) plus subsequent osimertinib is standard of care for advanced (EGFR)-mutant non-small cell lung cancer (NSCLC) harboring T790M mutation. However, few data are available that have assessed the cumulative survival benefit of sequential EGFR TKIs in patients with EGFR-mutant NSCLC with T790M mutations in ‘real-world’ clinical practice.
Method
We retrospectively identified advanced EGFR-mutant NSCLC patients treated with first-line EGFR TKIs plus subsequent osimertinib between January 27th, 2015 and December 1st, 2018 at our institute. Clinical outcomes were analyzed. Subsequent genetic profiling was performed at the time of progression by next-generation sequencing (NGS). The primary endpoint was overall survival (OS) calculated from first-line treatment start to death or the last follow-up, and the secondary endpoint was progression-free survival (PFS) with osimertinib defined as the time from the first dose of osimertinib to disease progression or death. Primary resistance to osimertinib was defined as PFS≤4 months for T790M-mutant patients treated with osimertinib. The last follow-up time was January 27th, 2019. Median follow-up time was 52.0 months (range, 9.0~108.0 months).
Result
Among 117 eligible patients treated with first-line EGFR TKIs plus subsequent osimertinib, 96 had T790M mutation and 21 showed negative T790M mutation or unknown status at the baseline of osimertinib treatment,. Median OS was significantly prolonged in T790M-mutant patients than those with negative/unknown T790M mutation (58.0 vs. 28.3 months, p＜0.001). However, there was no significant difference in median PFS with osimertinib between the two groups. Furthermore, there was no significant difference in both median OS and PFS with osimertinib between the non-brain metastatic and brain metastatic groups (median OS, 58.0 vs. 54.8 months, p=0.840; median PFS, 11.8 vs. 9.1 months, p=0.145). Median OS was significantly shortened in patients (N=20) with primary resistance to osimertinib than those (N=72) with PFS＞4 months (38.2 vs 54.8 months, p=0.027).
Conclusion
In real-world clinical practice, treatment with first-generation EGFR TKIs plus subsequent osimertinib for T790M-mutant patients can significantly prolong OS than those with negative/unknown T790M mutation. However, survivals are similar between the patients with and without brain metastases at the baseline of osimertinib. OS is significantly shorter in those with primary resistance to osimertinib.
Non-brain metastasis at the baseline
(n=55)
Brain metastasis at the baseline
(n=41)
P-value
Osimertinib PFS≤4m
(n=20)
Osimertinib PFS＞4m
(n=72)
P-value
Sex
Male
21 (38.2%)
20 (48.8%)
0.299
7 (35.0%)
32 (44.4%)
0.450
Femal
Age,years
≤55
＞55
34 (61.8%)
19(34.5%)
36(65.5%)
21 (51.2%)
18(43.9%)
23(56.1%)
0.357
13 (65.0%)
9 (45.0%)
11(55.0%)
40 (55.6%)
27(37.5%)
45(62.5%)
0.543
ECOG PS
0-1
54(98,2%)
38(92.7%)
0.000
20(100%)
68(94.4%)
0.281
2-4
1(1.8%)
3(7.3%)
0(0%)
4(5.6%)
Histology
adenocarcinoma
53 (96.4%)
41 (100%)
0.217
18 (90.0%)
72 (100%)
0.007
non-adenocarcinoma
2 (3.6%)
0 (0%)
2 (10.0%)
0 (0%)
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P2.01-88 - Molecular Alterations in Cerebrospinal Fluid Predict Clinical Outcomes of Central Nervous System Metastases in Lung Cancer (ID 1511)
10:15 - 18:15 | Author(s): Jin-Ji Yang
- Abstract
Background
Cerebrospinal fluid (CSF) has been proven as good media for genetic profiling of central nervous system (CNS) metastases. However, the association of genetic alterations in CSF and clinical outcomes remains elusive.
Method
A total of 94 lung cancer patients with CNS metastases underwent lumbar puncture. Circulating tumor DNA were extracted from CSF and profiled by next-generation sequencing. The effect of genetic alterations in CSF on survival and treatment outcomes were evaluated.
Result
The most common genes seen in CSF were EGFR, TP53, MET, CDKN2A, MYC, NTRK1 and CDK6. Kaplan-Meier survival analysis indicated that CDK4, CDK6, FGFR1, MET and MYC alterations, which were also characterized by more copy number changes, were associated with poor survival. Multivariate analysis found only MET (HR, 2.01; 95% CI, 1.15 to 3.52) and MYC alterations (HR, 2.31; 95% CI, 1.27 to 4.21) were correlated to poor OS. Forty-two patients harbored high n-CNVs (defined as the number of genes with copy number variations >2) while 50 patients carried low n-CNVs (defined as the number of genes with copy number variations <=2). Median overall survival (OS) of patients with high n-CNVs in CSF was 14.9 months (95% CI, 9.2 to 25.8 months), significantly shorter than those with low n-CNVs (21.6 months, 95% CI, 17.9 months to not reached (NR); HR, 1.9; 95% CI, 1.11 to 3.24; P=0.016). Patients with high n-CNVs and MET and MYC CNVs (copy number variations) were associated with the poorest OS. Osimertinib significantly prolonged OS only among patients with high n-CNVs (with vs. without osimertinib, 25.8 vs. 9.2 months; P=0.004). Among T790M negative patients, high n-CNVs seemed to positively associate with better response to osimertinib (OS with vs. without osimertinib, 23 vs. 7.8 months; P=0.058). Further analysis indicated that EGFR and FGFR1 CNV were the most significant factors associated with OS benefit from osimertinib among the high n-CNVs group (P=0.014; P=0.02). TP53_LOH and Wnt pathway alterations were significantly more prevalent in the high n-CNVs group than in the low n-CNVs group (P=0.016, P=0.006). With regard to clinical characteristics, higher performance status score (HR, 2.06; 95% CI, 1.38 to 3.07; P=0.0004) and occurrence of extracranial metastases (HR, 3.21; 95% CI, 1.25 to 8.24; P=0.015) suggested poor OS.
Conclusion
While genetic profiles in CSF, like high n-CNVs as well as MET and MYC CNV were related to poor prognosis, patients with high n-CNVs, especially those with EGFR or FGFR1 CNV might benefit more from osimertinib, further supporting CSF as liquid biopsy of CNS metastases in lung cancer.
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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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P2.04-38 - Tumor-Associated Neutrophils as a Potential Predictor for Early Recurrence in Resectable I-IIIA Lung Adenocarcinoma (Now Available) (ID 1509)
10:15 - 18:15 | Author(s): Jin-Ji Yang
- Abstract
Background
A recurrence of the early-stage non-small cell lung cancer (NSCLC) is usually unpredictable by clinical features alone. It has been appreciated that the high degree of infiltrated neutrophils is significantly associated with poor patient outcome in NSCLC.
Method
Transcriptional profiles and clinical information of 484 primary lung adenocarcinoma (ADC) subjects were retrieved from Gene Expression Omnibus (GEO). An additional cohort of mRNA expression, somatic mutations, and clinical data of 398 ADC were obtained from The Cancer Genome Atlas (TCGA). CIBERSORT algorithm was employed to infer the relative proportions of 22 sorts of leukocytes in each tumor using gene-expression profiles. Patients were stratified into two groups by the fraction of neutrophils using an optimal cutoff value (0.01) obtained with the "survminer" algorithm in R. We further investigated comprehensively the molecular differences between the high- and low-neutrophils patients.
Result
A significantly higher rate of 1-year recurrence was found in the high-neutrophils compared with the low-neutrophils group in both training (GEO,19.5% vs 6.1%) and validation (TCGA, 27.3% vs 19.0%) cohorts. However only in training cohort the patients with high neutrophils experienced a poorer recurrence-free survival (HR 1.95, 95% CI 1.47-2.51, P< 0.0001). The two groups were not only distinguished by clinical behaviors, but presented characteristic mutation genes and mutation patterns. EGFR and BRAF were more frequently mutated in low-neutrophils patients, whereas in high-neutrophils patients the most common mutation was found in STK11. Yet such molecular distinction was more pronounced in ADC with high tumor mutation load (TMB >=10). Gene Set Enrichment Analysis (GSEA) suggested that the common mutant genes in high-neutrophils patients were involved in the TP53 signaling, cell cycle pathways or associated with molecular functions including chemokine production and CD4 activation, while the common mutant genes in low-neutrophils patients were linked to RAS signaling pathway. Interestingly, we observed immune scene accompanied with good prognosis of ADC and concordant with limited infiltration of neutrophils, for instance high infiltration of B memory cells, resting memory CD4+T cells, resting mast cells and CD8+T cells.
Conclusion
Our findings suggested that local neutrophils are one of important components which are determinant for early recurrence of ADC, and it might serve as a simple predictor. Further research is warranted to identify the molecular mechanisms that neutrophils employed to exert, directly or indirectly, the regulatory effect on ADC progression.
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P2.17 - Treatment of Early Stage/Localized Disease (ID 189)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.17-16 - Genomic Heterogeneity and Evolutionary Trajectory in Multifocal Synchronous Lung Cancer (ID 2082)
10:15 - 18:15 | Author(s): Jin-Ji Yang
- Abstract
Background
Multifocal synchronous lung cancer (MSLC) presented as coexistence of multiple tumor lesions that share an identical germline genetic background and environmental exposure in individual patients. Along with the improved resolution of cross-sectional imaging, multiple types of ground glass opacities (GGOs) have been detected in increasing frequency as well as solid nodules even in an unique patient. However the molecular origins and relationships among the synchronous lesions remain unclear.
Method
10 treatment-naive MSLC patients were retrospectively collected while 25 tissue samples were performed whole exosome sequencing. In addition, we constructed phylogenetic trees to estimate the ancestral relationships of individual foci.
Result
79 somatic mutations in average were identified in MSLC tissues. The most significant mutated gene EGFR has been detected in 10 samples from 7 patients in our cohort. Tumor mutation burden as was significantly higher in IAC lesions than AIS/MIA ones. The mutation spectra of single-nucleotide variations (SNVs) were fairly consistent across the same histologic type even from different patients. Compared to AIS/MIA, IAC samples displayed a preponderance of A>T/T>A transition (Ti) while less frequency of A>C/T>G transversion (Tv). However few share mutations were located by pair of lesions in individual patients. Distinct genomic profiles suggested all were primary tumours. WNT pathway was enriched in AIS/MIA lesions exclusively while IAC appeared TGFβ/TP53 pathway mutation associated with cell proliferation and apoptosis.
Conclusion
Even in the same individual patient different lung cancer lesions may be driven by distinct genomic profiles so that each presented its own evolutionary trajectory. A deeper understanding of tumorigenesis is still in need to improve the diagnosis and treatment of MSLC.
