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Shun Lu



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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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      JCSE01.10 - A Ph3 Study of Niraparib as Maintenance Therapy in 1L Platinum Responsive Extensive Disease Small Cell Lung Cancer Patients (ID 11679)

      10:25 - 10:35  |  Presenting Author(s): Shun Lu

      • Abstract
      • Presentation
      • Slides

      Background
      Small cell lung cancer (SCLC) accounts for 15% of lung cancer, characterized by early dissemination and rapid development of chemo-resistant disease after platinum response (60-80%). Less than 2% of extensive disease SCLC (ED-SCLC) patients survive 5 years. The bi-allelic loss or inactivation of TP53 and RB1 is common in SCLC, the poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA damage repair enzyme, is highly expressed in SCLC, and SCLC is sensitive to platinum based chemotherapy, suggesting that the defect in DNA damage repair pathways plays an important role in SCLC. ZL2306/ Niraparib is a highly selective PARP-1/2 inhibitor which was exclusively licensed for development in China by Zai Laboratory from TESARO. In SCLC PDX model, niraparib demonstrated anti-tumor activities as monotherapy. In addition, niraparib demonstrated promising tumor growth inhibition in maintenance post platinum treatment in platinum sensitive SCLC PDX models. Clinically, in phase III NOVA study, niraparib demonstrated clear clinical benefit as maintenance treatment by significantly extending progression free survival in all platinum-sensitive recurrent ovarian cancer patients regardless gBRCA or HRD status which led to the approval by FDA and EMA in ovarian cancer. It is suggested that niraparib maintenance therapy could provide potential clinical benefit in platinum responsive SCLC. ZL-2306-005 is a randomized double-blind multi-center phase 3 study to evaluate the efficacy and safety of niraparib versus placebo as maintenance therapy in ED-SCLC patients who have had responses to platinum based chemotherapy.Approximately 590 Chinese patients with histologically or cytologically confirmed ED-SCLC who have achieved either complete response or partial response to their platinum based chemotherapy to their newly diagnosed disease will be randomized (2:1) to 2 groups, receiving either ZL-2306 or placebo in ZL-2306-005 study. Patients need to complete 4 cycles of etoposide + cisplatin/ carboplatin. All patients will be stratified by gender, LDH level and history of prophylactic cranial irradiation. ZL-2306 will be started with 300mg PO QD for patients with a baseline body weight ≥77 kg and a baseline platelet count ≥150,000/μL, or 200 mg PO QD for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL based on RADAR analysis in NOVA study. Patients will remain on treatment until disease progression or intolerable toxicity. The co-primary endpoints are PFS assessed by independent central radiologic review and OS; the secondary endpoints are PFS assessed by investigator, CFI, QoL, safety and tolerability.

      Section not applicable

      Section not applicable

      a9ded1e5ce5d75814730bb4caaf49419

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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.06 - EGFR Clonality and Tumor Mutation Burden (TMB) by Circulating Tumor DNA (ctDNA) Sequencing in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 13146)

      14:05 - 14:10  |  Author(s): Shun Lu

      • Abstract
      • Presentation
      • Slides

      Background

      TKI has significantly improved survival time of NSCLC pts with sensitive mutation. However, pts present different outcome while receiving TKI treatment. We conduct a prospective multicenter clinical trial to determine whether clonality of sensitive mutation is related to the efficacy of TKI. We also evaluate the consistency of TMB between tissue and blood in this cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve pts with advanced NSCLC. DNA was sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR mutation was defined if EGFR mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR mutation. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3 % and ≥0.5 %, respectively. TMB-high pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).

      4c3880bb027f159e801041b1021e88e8 Result

      During February 2017 to April 2018, 127 advanced NSCLC pts were enrolled from 9 centers. A total of 653 somatic variations were detected in tissues. Mutations occurred most frequently in EGFR (57 %), TP53 (54 %), KRAS (9 %), ALK (8 %). In matched plasma, 405 (62 %) tumor-derived mutations were detected by pan-caner panel sequencing. A total of 90 EGFR mutations were detected in 73 pts, most of which occurred in tyrosine kinase domain (L858R, 41%; Ex19del, 33%). Most EGFR mutation were clonal in tissue and plasma, with a consistence of 83 % in paired samples. In addition, bTMB was significantly correlated to tTMB (Pearson r= 0.85, p-value= 1.8e-30), with a consistence of 89 %. Interestingly, high TMB was observed in a small fraction of patients (8 %) with driver mutations, such as mutations in EGFR, ALK fusion, ERBB2 and PIK3CA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Deep sequencing with the pan-cancer panel can effectively detect mutations and evaluate TMB in both tissue and blood with high consistence. EGFR mutations can be clonal or subclonal in both tissue and blood. Prospective multicenter study is ongoing to determine the EGFR clonality as a predictive factor for the TKI efficacy in NSCLC (TRACELib-NSCLC, NCT03059641).

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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.01 - Accumulation of Concomitant Mutations Involved in Drug Resistance in the Sequential ALK TKI Treatments of ALK-Positive NSCLC (ID 12550)

      13:30 - 13:35  |  Presenting Author(s): Shun Lu

      • Abstract
      • Presentation
      • Slides

      Background

      ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next-generation TKIs, have shown promising clinical outcomes for ALK-positive lung cancer patients. However, distinct resistant-mechanisms have been suggested for different ALK fusion variants in response to various TKIs. The genomic alterations associated with these heterogeneous resistant-mechanisms have not been adequately investigated, especially for patients received sequential ALK TKI treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The distribution of ALK fusion variants in 475 ALK-positive lung cancer patients (cohort I) out of 11842 lung cancer patients (4%) tested by next-generation sequencing were analyzed. In addition, mutation profiles of 416 cancer-relevant genes in the post-ALK TKI treatment tumor samples from 52 non-small cell lung cancer (NSCLC) patients (cohort II) who represent the similar distribution of ALK fusion variants as in cohort I were analyzed. Thirty-five patients received crizotinib treatment only (crizotinib group), whereas the other 17 patients were treated with multiple lines of ALK TKIs (multi-TKI group), including lorlatinib, alectinib, ceritinib and brigatinib.

      4c3880bb027f159e801041b1021e88e8 Result

      EML4-ALK v3 and v1 are the two most common ALK fusion variants in both cohorts. In cohort II, 18 different ALK activating mutations were found in 17 patients (49%) of the crizotinib group and 10 patients (59%) of the multi-TKI group, although with different mutation patterns. In the multi-TKI group, G1202R was the most frequent ALK activating mutation found in 35% of the patients, while L1196M (14%) and G1269A (11%) were more common in the crizotinib cohort. Of note, there was a significant enrichment of concomitant ALK activating mutations in the multi-TKI group (p=0.031), as well as a trend of increased number of patients carrying activation of ALK by-pass/downstream pathways (p=0.056) in this group compared with the crizotinib group, resulting in a significantly higher recurrence of dual activation of ALK and ALK by-pass/downstream pathways in the multi-TKI group (29%) than that in the crizotinib group (6%) (p=0.031). Patients with concomitant TP53 mutation had significantly shorter progression free survival (PFS) compared with TP53 wildtype patients upon crizotinib treatment (median PFS: 8 vs 13 months, HR 1.494, p=0.019) regardless of fusion variant types.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Significantly higher frequency of concomitant mutations, including concomitant ALK activating mutations, and dual activation of ALK and ALK by-pass/downstream pathways, was observed after multiple lines of ALK TKI treatments, indicating the diversity and complexity of resistance-mechanisms in response to next-generation ALK TKIs. Concomitant TP53 mutation might serve as a prognosis biomarker for worse clinical outcomes treated with crizotinib.

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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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      P1.01-62 - The Third Generation Irreversible EGFR Inhibitor HS-10296 in Advanced Non-Small Cell Lung Cancer Patients (ID 13138)

      16:45 - 18:00  |  Presenting Author(s): Shun Lu

      • Abstract
      • Slides

      Background

      The epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism of drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The third generation irreversible EGFR inhibitor HS-10296 has been shown to be safe and effective against both EGFR TKI-sensitizing and T790M resistance mutations in preclinical studies.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A Phase I, open-label, multi-center clinical trial was conducted in patients with locally advanced or distant metastatic NSCLC who have progressed following prior therapy with EGFR TKIs. The study was consisted of dose-escalation cohorts (55, 110, 220 and 260 mg) and dose-expansion cohorts (55, 110 and 220 mg) with once daily oral administration of HS-10296. In each expansion cohort, tumor biopsies were collected for central determination of EGFR T790M status. Patients were assessed for safety, tolerability, pharmacokinetics and efficacy of HS-10296.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 117 patients (median age 60) received at least one dose of HS-10296 across multiple sites in China (43 patients), Taiwan (69 patients) and the United States (5 patients). Maximum tolerated dose(MTD)has not been reached in this study. The most common adverse events were grade1/2 rash, pyrexia, upper respiratory tract infection, constipation, diarrhoea and blood creatine phosphokinase elevation. Drug-related serious adverse events were anemia (0.8%), blood creatinine elevation (0.8%), anemiarhabdomyolysis (0.8%) and blood creatine phosphokinase elevation (0.8%) occurred mainly in the cohorts with higher doses at 220 mg or 260 mg, respectively. These data demonstrated favorable tolerability and safety of HS-10296 in patients enrolled. The pharmacokinetics of HS-10296 was dose proportional and the plasma half-life was 30.7~37.5 hours. Among 82 evaluable patients (18 in escalation cohorts and 64 in expansion cohorts) with the EGFR T790M mutation, the overall objective response rate (ORR) was 52.4% (43/82; 95% CI, 41.6 to 63.3), while disease control rate (DCR) was 91.5% (75/82; 95% CI, 85.4 to 97.5). 110mg cohort showed better DCR (97.2% VS. 86.1%) than 55mg cohort. Phase II study is ongoing with the dose at 110 mg.

      8eea62084ca7e541d918e823422bd82e Conclusion

      HS-10296 has the potential to provide clinical benefit to locally advanced or distant metastatic NSCLC patients with EGFR T790M mutation who had disease progression following prior therapy with EGFR TKIs.

      (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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    P1.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 944)

    • 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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      P1.12-04 - A Ph3 Study of Niraparib as Maintenance Therapy in 1L Platinum Responsive Extensive Disease Small Cell Lung Cancer Patients (ID 12119)

      16:45 - 18:00  |  Presenting Author(s): Shun Lu

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) accounts for 15% of lung cancer, characterized by early dissemination and rapid development of chemo-resistant disease after platinum response (60-80%). Less than 2% of extensive disease SCLC (ED-SCLC) patients survive 5 years. The bi-allelic loss or inactivation of TP53 and RB1 is common in SCLC, the poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA damage repair enzyme, is highly expressed in SCLC, and SCLC is sensitive to platinum based chemotherapy, suggesting that the defect in DNA damage repair pathways plays an important role in SCLC. ZL2306/ Niraparib is a highly selective PARP-1/2 inhibitor which was exclusively licensed for development in China by Zai Laboratory from TESARO. In SCLC PDX model, niraparib demonstrated anti-tumor activities as monotherapy. In addition, niraparib demonstrated promising tumor growth inhibition in maintenance post platinum treatment in platinum sensitive SCLC PDX models. Clinically, in phase III NOVA study, niraparib demonstrated clear clinical benefit as maintenance treatment by significantly extending progression free survival in all platinum-sensitive recurrent ovarian cancer patients regardless gBRCA or HRD status which led to the approval by FDA and EMA in ovarian cancer. It is suggested that niraparib maintenance therapy could provide potential clinical benefit in platinum responsive SCLC. ZL-2306-005 is a randomized double-blind multi-center phase 3 study to evaluate the efficacy and safety of niraparib versus placebo as maintenance therapy in ED-SCLC patients who have had responses to platinum based chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Approximately 590 Chinese patients with histologically or cytologically confirmed ED-SCLC who have achieved either complete response or partial response to their platinum based chemotherapy to their newly diagnosed disease will be randomized (2:1) to 2 groups, receiving either ZL-2306 or placebo in ZL-2306-005 study. Patients need to complete 4 cycles of etoposide + cisplatin/ carboplatin. All patients will be stratified by gender, LDH level and history of prophylactic cranial irradiation. ZL-2306 will be started with 300mg PO QD for patients with a baseline body weight ≥77 kg and a baseline platelet count ≥150,000/μL, or 200 mg PO QD for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL based on RADAR analysis in NOVA study. Patients will remain on treatment until disease progression or intolerable toxicity. The co-primary endpoints are PFS assessed by independent central radiologic review and OS; the secondary endpoints are PFS assessed by investigator, CFI, QoL, safety and tolerability.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 947)

    • 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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      P1.15-19 - Treatment of Choice for First-Line Therapy of EGFR-Mutated Stage IIIB Lung Adenocarcinoma Based on the Real World Data (ID 13665)

      16:45 - 18:00  |  Presenting Author(s): Shun Lu

      • Abstract
      • Slides

      Background

      There is a lack of consensus on the choice of first-line therapy for stage IIIB EGFR-mutated lung adenocarcinoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A prospectively maintained database at the Shanghai Chest Hospital was used to identify patients who received therapy for stage IIIB EGFR-mutated lung adenocarcinoma between 2015 and 2017. Clinicopathological data were extracted from the database and analyzed. Patients were stratified into four groups based on the therapy they received; chemotherapy alone, chemoradiation (concurrent or sequential), first-generation EGFR-TKI, or surgical resection with or without chemoradiation. Log-rank test and Kaplan-Meier method were used to determine significant differences in the progression free survival (PFS) between treatment groups

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 114956 patients treated at the institution during the study period 85 (0.07%) were eligible for the study. 12 patients (14.1%) received chemotherapy, while 19 (22.4%), 30 (35.3%) and 24 (28.2%) received chemoradiation, EGFR-TKI and surgery respectively. The common mutations included Del19 (N=35, 41.18%), L858R (N=42, 49.41%), G719X (N=4, 4.71%) and S768I (N=2, 2.35%).

      The median PFS was shorter in patients who only received chemotherapy (8.5 months) as compared to those managed with chemoradiation (14.6 months), EGFR-TKI (16.2 months) or resection (18.6 months) (p=0.04,figure 1b). No statistically significant difference was observed in PFS between EGFR-TKI and chemoradiation (p=0.86), or EGFT-TKI and resection (p=0.90). A subgroup analysis of patients with N3 disease resulted in similar findings (figure1c).

      20180504143009.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In conclusion, when used as a first-line therapy chemoradiation, EGFR-TKI and resection with or without chemoradiation can achieve similar PFS, which is superior to that of patients receiving chemotherapy alone. Further studies are required to elucidate the efficacy of EGFR-TKI as a first-line or as maintenance therapy for these patients.

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    P2.03 - Biology (Not CME Accredited Session) (ID 952)

    • 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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      P2.03-12 - EGFR and ERBB2 Germline Mutations in Chinese Lung Cancer Patients and Their Roles in Genetic Susceptibility to Cancer (ID 12560)

      16:45 - 18:00  |  Presenting Author(s): Shun Lu

      • Abstract
      • Slides

      Background

      Inherited genetic determinants of lung cancer risk remains relatively elusive. Rare germline mutations in EGFR and ERBB2 have previously been reported in lung cancer patients, which may be associated with the genetic susceptibility to lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed the next-generation sequencing (NGS) results targeting 416 cancer-relevant genes, including the whole exons of EGFR and ERBB2, in a cohort of 9091 Chinese lung cancer patients.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 9091 Chinese lung cancer patients, nine germline mutations from 12 patients were identified within or adjacent to the kinase domain of EGFR: K757R (two patients), D1014N (two patients), I646S, G724S, V786M, T790M, L792F, R831H, and L844V, and one germline mutation was identified adjacent to the kinase domain of ERBB2: V1128I. The incidence of EGFR T790M germline mutation is much lower compared with the reported frequency in the Caucasian patients. Somatic mutations detected in the 12 patients carrying rare EGFR/ERBB2 germline mutations were most commonly EGFR exon19 deletion, L858R, and G719S mutations, and rare EGFR: S768I mutation and a novel D770delinsDNPH indel mutation. The superior response to afatinib of the patient carrying only EGFR L844V germline mutation suggests that this germline mutation might be sensitive to TKI treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Here we indentified eight novel EGFR germline mutations and the ERBB2: V1128I germline mutation were linked to the genetic susceptibility of lung cancer in Chinese population.

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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: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-19 - Correlation of Clinicopathological Characteristics with Tumor Mutation Burden in Chinese Patients with NSCLC (ID 13127)

      16:45 - 18:00  |  Presenting Author(s): Shun Lu

      • Abstract
      • Slides

      Background

      Higher tumor mutation burden(TMB) has been associated with improved immune checkpoint inhibitor objective response, progression-free survival and over survival in non-small cell lung cancer(NSCLC). But the correlation of clinicopathological characteristics with tumor mutation burden(TMB) in Chinese patients with NSCLC remains unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      266 lung adenocarcinoma (LUAD) and 66 lung squamous cell carcinoma (LUSC) patients from 18 hospitals across 11 provinces in China were recruited and the clinical whole exome of paired tumor/normal samples of each patient were sequenced.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 332 prospectively enrolled NSCLC patients, 81.3% patients were recommended at least one FDA approved targeted/immunotherapy drug and 88.5% were matched at least one ongoing clinical trials. The median TMB of Chinese NSCLC patients was 5.62 mutations/Mb and upper tertilewas 7.87 mutations/Mb. TMB in Chinese LUSC cohort was slightly higher than the TCGA cohort (median: 10.6 mutations/Mb vs.9.0 mutations/Mb).WhileTMB in Chinese LUAD patients was slightly lower than the Caucasian cohort (median: 5.14 mutations/Mb vs. 6.3 mutations/Mb).Chinese LUAD patients with EGFR-mutant status (122/266) had significantly lower TMB compared with patients with EGFR wild-type (median: 4.90 mutations/Mb vs. 5.53 mutations/Mb, P=0.0013). This may help to explain why in EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel in secondline setting. However LUAD patients with KRAS-mutant status (31/266) had significantly higher TMB compared with patients with KRAS wild-type (median: 9.94 mutations/Mb vs. 4.84 mutations/Mb, P=0.021).A small subset (8/266) of NSCLC patients with CDKN2A-mutant possessed high TMB, although it did not reach statistical significance (P=0.0588). Consistent with previous research, mutant POLE/POLD1 (LUAD: 15/266 and LUSC: 8/66)was significantly associated with increased TMB. For all NSCLC in our study, patients with mutant POLE/POLD1 had significantly higher TMB compared with patients with wild-type POLE/POLD1 (Median: 10.18 mutations/Mb vs. 5.59 mutations/Mb; P=5.16e-7).TP53 and PTEN mutations were not enriched in NSCLC patients with high TMB. One EGFR (p.L858R) mutant LUAD patient with CTNNB1 (p.S33F) co-mutation developed to be innate PD-1 and EGFR-TKI resistance. Increased β-catenin signaling led to poor T cells infiltration into tumors and promoted epithelial-mesenchymal transition (EMT) as well. This case represented a novel genomic predictor of de-novo resistance to immune checkpoint blockade in EGFR-mutant LUAD.

      8eea62084ca7e541d918e823422bd82e Conclusion

      High TMB caused by DNA repair deficiency such as POLE/POLD1 mutation is common in Chinese NSCLC patient, and clinical evidence ssuggest thatTMB status and cancer driver mutations can help to establish clinically available tool to identify patients who are most likely to benefit from immunotherapies or targeted therapies.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • 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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      P2.13-36 - Analysis of CDK4/6 Pathway Activity in Lung Adenocarcinoma Patients with Oncogenic Driver Mutations in China (ID 12944)

      16:45 - 18:00  |  Presenting Author(s): Shun Lu

      • Abstract
      • Slides

      Background

      Selective tyrosine kinase inhibitors (TKIs) targeting key driver mutations have significantly improved the outcomes of lung adenocarcinoma (ADC) patients. However, rapid emergence of drug resistance underlines the need for more sustainable treatment options, which mostly requires the combined use of multiple drugs. This study aims to establish the relationship between CDK4/6 pathway activity and oncogenic driver mutations in EGFR, ALK and KRAS in Chinese lung ADC patients. The results will provide a biomarker strategy for rational combination therapy involving TKIs and CDK4/6 inhibitors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Total of 108 stage I-III NSCLC ADC patients who have completed resection in Shanghai Chest Hospital, and whose oncogenic driver mutations including EGFR, ALK and KRAS have been determined, were selected for the current study. Paraffin-embedded tissue samples from these patients were analyzed by Immunohistochemistry (IHC) for expression level of various CDK4/6 pathway markers. Stained sections were examined using Aperio eSlide manager, and H score was calculated for each marker and used for expression comparison between patients.

      4c3880bb027f159e801041b1021e88e8 Result

      EGFR, ALK and KRAS mutations were examined in all the patients. EGFR L858R mutation was found in 30 patients (27.8%) and 27 patients (25%) showed EGFR Exon19 deletion. In addition, KRAS mutation was found in 5 patients (4.6%) and only one patient manifested EML4-ALK fusion positive. Preliminary IHC results show that EGFR L858R mutation seems to be associated with higher Rb and phospho-Rb levels. A trend of increased number of patients carrying EGFR L858R mutation was detected in Rb/ phospho-Rb positive samples (18/54, 33.3% & 17/50, 34%) compared with Rb/ phospho-Rb negative samples (12/54, 22.2% & 13/58, 22.4%), although the differences are not yet statistically significant (P= 0.28 & 0.2, Fisher’s exact test). And EGFR Exon 19 deletion was just the opposite. Higher percentage of patients with EGFR 19 exon deletion was found in Rb/ phospho-Rb negative group (17/54, 31.5% & 19/58, 32.8%) compared with Rb/ phospho-Rb positive group (10/54, 18.5% & 8/50, 16%) with P value of 0.18 and 0.049, respectively. KRAS mutation also appeared to be linked with higher Rb and phospho-Rb levels in tumor tissue.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The observed correlation between oncogenic driver mutations and Rb/phospho-Rb levels suggests that combined use of EGFR TKIs and CDK4/6 inhibitors may be beneficial to lung ADC patient with EGFR L858 mutation. Patients with KRAS mutations may also benefit from CDK4/6 inhibitors as a single therapeutic agent.

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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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      P3.01-63 - Baseline Biomarkers for Outcome of Advanced NSCLC Patients Receiving Anti-PD1/PD-L1 Treatment—Data from a Chinese Population (ID 12360)

      12:00 - 13:30  |  Presenting Author(s): Shun Lu

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitor therapy has shown optimal efficacy in advanced non-small-cell lung cancer (NSCLC). However, the biomarkers of immunotherapy response are not well established. In the present study, we aimed to determine baseline prognostic factors associated with progression-free survival (PFS) in anti-PD1/PD-L1 treatment and to identify a predictive biomarker for immunotherapy response.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data of 54 advanced NSCLC patients receiving anti-PD1/PD-L1 treatment were prospectively collected in Shanghai Chest Hospital from Dec. 2015 to May 2017. Clinical data included baseline routine blood examination and demographic characteristics of patients prior to immunotherapy. Systemic inflammatory biomarkers were obtained from routine blood tests to calculate leukocyte-to-lymphocyte ratio (LLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). Receiver operating characteristic (ROC) and area under the curve (AUC) were used to identify the optimal cut-off value of LLR, NLR, PLR, LMR and SII for survival analysis. Endpoints were PFS and objective response rate (ORR) following anti-PD1/PD-L1 treatment. Univariate survival analysis for PFS was used by Kaplan-Meier method and statistical differences were determined by Log rank test. The Cox proportional hazards model was used for multivariable analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 54 cases were analyzed, with 38 treated with Atezolizumab and 16 treated with Nivolumab. Median PFS was 2.8±0.18 and 1.8±1.2 months, respectively (P = 0.988). 44 patients received second-line anti-PD1/PD-L1 treatment and 10 patients underwent three-line or above. The median PFS of the two groups were 2.8±0.88 and 2.8±0.23 months, respectively, (P=0.851). ROC and AUC identified LLR=6.3, NLR=4.5, PLR=124.45, LMR=3.4 and SII=1066 as the best cut-off values. Univariate survival analysis showed that LLR, age, pathological type, neutrophil percentage, hemoglobin, platelet count, albumin, serum lactate dehydrogenase (LDH), NLR and SII were associated with PFS (P<0.05). Cox multivariate analysis showed that LLR (P=0.003;HR 2.99;95%CI:1.45-6.17), albumin (P=0.000;HR 8.11; 95%CI:2.63-25.06) and LDH (P=0.000;HR 4.55;95%CI:2.13-9.73) were independent prognostic factors for PFS . For patients with favorable (1 IN 3 factors), (2 IN 3 factors) and (3 IN 3 factors) biomarker profile median PFS were 0.94, 1.63 and 8.17 months, respectively (P =0.000) .

      8eea62084ca7e541d918e823422bd82e Conclusion

      Blood markers predict survival in advanced NSCLC treated with immune checkpoint blockade. Our findings show that baseline LLR≤6.3, normal serum levels of albumin and LDH were independently and advantageously associated with the PFS of patients receiving anti-PD1/PD-L1 treatment , and they may help identify patients with benefit from immune therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 982)

    • 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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      P3.16-02 - Phase III Study of Canakinumab (ACZ885) as Adjuvant Therapy in Patients with Surgically Resected NSCLC (ID 12069)

      12:00 - 13:30  |  Author(s): Shun Lu

      • Abstract

      Background

      Preclinical and clinical data suggest that cytokines such as interleukin (IL)-1β can promote angiogenesis and tumor growth, and are essential to tumor invasiveness. Canakinumab (ACZ885) is a high-affinity human IgGκ anti-IL-1β monoclonal antibody approved for patients with various IL-1–driven auto-inflammatory diseases. In the Phase III Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) in patients with atherosclerosis, canakinumab was associated with a significant reduction in the incidence of fatal and non-fatal lung cancer in patients with increased high-sensitivity C-reactive protein levels. ACZ885T2301 (NCT03447769) is evaluating the efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This Phase III, randomized, double-blind, placebo-controlled study is enrolling patients (≥18 years, Eastern Cooperative Oncology Group Performance Status ≤1) with completely resected (R0) American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) v.8 stages II−IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg every 3 weeks [Q3W], subcutaneous [s.c.]) or placebo (Q3W, s.c.) on Day 1 of 21-day cycles for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Following baseline screening, imaging assessment will be performed every 12 weeks for the first year (treatment phase) following Cycle 1 Day 1, then every 26 weeks during Years 2 and 3, and annually during Years 4 and 5 (post-treatment surveillance phase). Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region.

      The primary objective is to compare disease-free survival (DFS) in the canakinumab versus placebo arms, as determined by local investigator assessment. Secondary objectives include a comparison of the two treatment groups with respect to overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Exploratory objectives include assessment of the relationship between pharmacokinetics, pharmacodynamics, safety, and efficacy, and evaluation of correlation between cytokines/soluble markers and efficacy endpoints. Enrollment is ongoing.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PC04 - Targeted Therapy for NSCLC (ID 843)

    • Event: WCLC 2018
    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 106
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      PC04.03 - Adjuvant Targeted Therapy for pts with Genomic Alterations - Yes (ID 11616)

      15:39 - 15:51  |  Presenting Author(s): Shun Lu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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