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Yongfeng Yu



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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  |  Author(s): Yongfeng Yu

      • 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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    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  |  Author(s): Yongfeng Yu

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 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  |  Author(s): Yongfeng Yu

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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  |  Author(s): Yongfeng Yu

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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