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Koichi Azuma



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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.11 - A Multicenter Phase II Study of Low-Dose Erlotinib in Frail Patients with EGFR Mutation-Positive, Non-Small Cell Lung Cancer: TORG1425 (Now Available) (ID 633)

      14:30 - 16:00  |  Author(s): Koichi Azuma

      • Abstract
      • Presentation
      • Slides

      Background

      We conducted a multicenter phase II trial evaluating the efficacy of low-dose erlotinib (ERL) in frail patients with EGFR-mt non-small cell lung cancer (NSCLC). The primary endpoint was met, with the objective response rate (ORR) of 60%. Here we present the final overall survival (OS) results. Furthermore, we investigated the effect of ABCB1 genetic polymorphisms on the ERL plasma concentration pharmacokinetics (PK) and pharmacodynamics (PD).

      Method

      Chemotherapy-naïve NSCLC patients with EGFR mt who had frailty were enrolled and received ERL 50 mg/d. Patient’s frailty was defined as follows: (Group 1) 20 to 74 years of age with Eastern Cooperative Oncology Group performance status (PS) ≥2 or Charlson Comorbidity Index (CCI) ≥6 points; (Group 2) 75 to 80 years of age with PS ≥1 or CCI ≥6 points; (Group 3) ≥81 years of age with any PS and CCI. ABCB1 gene polymorphism analysis were using the i-densyTM genetic testing platform, and blood samples for the ABCB1 genetic testing were collected prior to treatment. Steady-state trough plasma ERL concentration was measured with a high-performance liquid chromatograph-tandem mass spectrometry at 15 days (±7 days) after initiating ERL administration.

      Result

      From December 2014 and April 2017, 80 patients were enrolled: males/females 26/54; median age 80 (range 49-90); Group 1/2/3 15/28/37; Ad/Sq/Others 76/1/3. EGFR mt types were: exon 19/21 42/38. All 80 patients were included in efficacy and safety analysis. Median progression-free survival and OS were 9.3 (95%CI: 7.2-11.4), 26.1 (95%CI: 21.9-30.4) months respectively. The trough of ERL could be measured in 48 patients, and 45 of these patients were analyzed for ABCB1 genetic polymorphism. The ORR for the 48 patients was 62.5%, and their median trough of ERL was 685 ng/ml (range 153-1950) , which surpassed the reported “effective” level (500ng/ml). Nine (60%) of 15 the patients who failed to achieve the level responded. Genetic polymorphisms were not correlated with ERL PK, nor were they associated with efficacy and adverse events.

      Conclusion

      This is the first prospective study evaluating low-dose ERL for frail patients with EGFR mt NSCLC. This treatment was safe and effective, and the ABCB1 genetic polymorphisms did not affect ERL PK/PD. Clinical trial information: UMIN 000015949.

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.06 - The Sequential Therapy of Crizotinib Followed by Alectinib: Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L) (Now Available) (ID 2145)

      10:30 - 12:00  |  Author(s): Koichi Azuma

      • Abstract
      • Presentation
      • Slides

      Background

      Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of CRZ followed by other ALK-inhibitorcan provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries.

      Method

      We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of CRZ followed by ALEC, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the TTF of CRZ plus the TTF of ALEC if patients were treated with ALEC followed by CRZ. In the ALEC group, the TTF of ALEC was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group.

      Result

      Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P=0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P=0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P<0.0001.

      Conclusion

      The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown.

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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-14 - Early Changes in Plasma CXCL2 and MMP2 Levels Predicts the Response to Anti-PD-1 Therapy in Non-Small-Cell Lung Cancer (ID 1675)

      09:45 - 18:00  |  Author(s): Koichi Azuma

      • Abstract

      Background

      Previously we reported that changes in the plasma levels of CXCL2 and MMP2, measured by a bead-based multiplex assay: Bio-Plex 200 system, were significantly associated with the clinical outcomes of anti-PD-1 therapy (Matsuo, et al. IJC. 2018). Here we attempted to validate CXCL2 and MMP2, measured by ELISA, as a marker of the effectiveness of anti-PD-1 therapy in expanded patient cohort.

      Method

      Peripheral blood samples were taken from 97 patients with non-small cell lung cancer before nivolumab or pembrolizumab treatment and after 4-10 weeks from the patients who continued these drugs. The levels of CXCL2 and MMP2 were examined before and after anti-PD-1 therapy. We employed Cox regression analysis for CXCL2 and MMP2 as a single explanatory carriable. In comparing the fitness of CXCL2 and MMP2 Cox models, discrimination was assessed by the Harrell’s C-statistic for survival data. Bootstrap methods with 10000 resamplings were used to assess the stability of the regression analysis predictors. The optimal cutoff point was determined as the point at which the Youden index was maximized by ROC curve. Survival curves were generated using the Kaplan–Meier method and comparisons made using the log-rank test.

      Result

      The changes in the plasma levels of CXCL2 after treatment were significantly correlated with PFS (HR 1.003, 95%CI: 1-1.005, P=0.026) and OS (HR 1.004, 95%CI: 1.001-1.007, P=0.003). The C-statistic of the CXCL2 model for PFS and OS were 0.652 (95% CI: 0.437-0.727) and 0.626 (95% CI: 0.528-0.722), respectively. The decreasing revels of CXCL2 tended to be related to better DCR (P=0.134). The changes in the plasma levels of CXCL2 < 29.1 pg/ml was associated with better PFS (HR 2.872, 95%CI: 1.785-4.618, P<0.001) and OS (HR 2.800, 95%CI: 1.633-4.801, P<0.001). The changes in the plasma levels of MMP2 after treatment were also significantly correlated with PFS (HR 0.998, 95%CI: 0.996-0.999, P=0.003) and OS (HR 0.998, 95%CI: 0.996-0.999, P=0.001). The C-statistic of the MMP2 model for PFS and OS were 0.599 (95% CI: 0.515-0.673) and 0.614 (95% CI: 0.523-0.703). The increasing revels of MMP2 was significantly related to better DCR (P=0.020). The changes in the plasma levels of MMP2 > 0.847 ng/ml was associated with better PFS (HR 0.614, 95%CI: 0.388-0.971, P=0.037) and OS (HR 0.501, 95%CI: 0.295-0.852, P=0.011).

      Conclusion

      The early change of CXCL2 and MMP2 were significantly associated with the clinical outcomes of anti-PD-1 therapy. Since these factors in plasma can be easily measured by minimally invasive method, they could be clinically applicable as biomarkers for predicting the clinical benefit of anti-PD-1 therapy for NSCLC patients.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-30 - Phase I Study of Afatinib Plus Bevacizumab in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations (ID 1580)

      09:45 - 18:00  |  Author(s): Koichi Azuma

      • Abstract

      Background

      Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is one of the standard therapies for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. The first-generation EGFR-TKIs in combination with bevacizumab have been reported to improve progression-free survival (PFS). However, data on afatinib plus bevacizumab are limited.

      Method

      In this phase I study, we examined the safety and the efficacy of afatinib plus bevacizumab in patients with advanced non-squamous NSCLC harboring EGFR mutations. This study comprised two cohorts. In the dose-finding cohort, eligible patients received afatinib 20, 30, or 40 mg/day (days 1–21) plus bevacizumab 15 mg/kg (day 1) in 21-day cycles. This cohort was designed and conducted in a 3 + 3 manner. In the expansion cohort, the patients were treated with the recommended dose (RD) based on the findings in the dose-finding cohort, and we evaluated the preliminary efficacy of this combination therapy. The serum trough concentration of afatinib was assessed at the steady state.

      Result

      Sixteen patients were enrolled in this study (5 patients in the dose-finding cohort and 11 patients in the expansion cohort). No dose-limiting toxicities (DLTs) occurred with afatinib 30 mg/day. With afatinib 40 mg/day, 2 out of 2 patients had DLTs (grade 3 diarrhea) in cycle 1. From these results, afatinib 30 mg/day plus bevacizumab 15 mg/kg was decided as the RD. Additionally, 11 patients in the expansion cohort were treated with RD. Common treatment-emergent adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs and interstitial lung disease. The response rates and median PFS were 56% and 16.8 months in EGFR-TKI naïve patients, and 0% and 4.9 months in patients pretreated with EGFR-TKIs. The median serum concentration at the steady state was 13.7 ng/mL (range: 8.1–38.1 ng/mL) in the patients treated with the RD. Rebiopsy was conducted in eight patients after disease progression with afatinib plus bevacizumab, and three patients acquired an exon 20 T790M mutation.

      Conclusion

      Afatinib 30 mg/day plus bevacizumab 15 mg/kg was well tolerated. Large-scale studies are warranted to evaluate the efficacy of this combination therapy.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-01 - Changes of BCR Repertoire Are Predictive Biomarker for the Efficacy of Immune Checkpoint Inhibitor in NSCLC (ID 1688)

      10:15 - 18:15  |  Presenting Author(s): Koichi Azuma

      • Abstract

      Background

      Clonal diversity of T cell receptor (TCR) and/or B cell receptor (BCR) repertoires might play a major role in antitumor immunity in cancer patients. Assessment of TCR and BCR repertoires might enable us to predict the efficacy of immune checkpoint inhibitors (ICI).

      Method

      The study population comprised 30 patients with non-small-cell lung cancer (NSCLC), who started treatment with nivolumab (3mg/kg, every two weeks) or pembrolizumab (200mg, every three weeks) between February 2016 and August 2017. Patient blood samples were collected before and four to six weeks after the initiation of treatment. TCR and BCR chain sequences were determined by using the unbiased gene amplification method with Adaptor-Ligation PCR. The diversity of TCR and BCR repertoires was evaluated with inverse Shannon-Weaver index (iSWI).

      Result

      We compared the iSWI between before and after treatment. The fold changes of iSWI in BCR repertoire after treatment in patients with PR were significantly higher than those with SD or PD. In contrast, the fold changes of iSWI in TCR repertoire after treatment were not associated with tumor responses. When the cut-off value of fold change of iSWI in BCR repertoire after treatment was determined as 0.85, 25 (83%) and 5 (17%) patients were considered as high and low fold change group, respectively. Progression free survival in the high fold change group was significantly longer compared with that in the low fold change group (182 vs 49 days; 95% confidence interval (CI);99-N.R. vs 31-168 days, respectively; P=0.01).

      Conclusion

      Our findings suggest that reduced repertoire diversity in BCR, but not in TCR, might be associated with better clinical outcomes in advanced NSCLC patients treated with ICI. Assessment of the changes of BCR repertoire after treatment might be useful for predicting the efficacy of ICI. The present results require confirmation in a large-scale prospective study.

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      P2.04-85 - Clinical Significance of the PD-L2 Expression in Patients with NSCLC Receiving Anti-PD-1 Inhibitors (ID 1611)

      10:15 - 18:15  |  Author(s): Koichi Azuma

      • Abstract
      • Slides

      Background

      The programmed cell death 1 (PD-1) receptor–ligand interaction is a major pathway often hijacked by tumors to suppress immune control. Programmed cell death-ligand 1 (PD-L1), a ligand of PD-1, can potentially predict the response to anti-PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer (NSCLC); however, the role of PD-L2, another ligand of PD-1, remains unclear in patients receiving anti-PD-1 inhibitors. This retrospective study aims to determine the significance of the PD-L2 expression in anti-PD-1 inhibitors–treated patients with NSCLC.

      Method

      We enrolled 82 patients with advanced or recurrent NSCLC who received anti-PD-1 inhibitors. The PD-L2 expression was assessed by immunohistochemical analysis staining with an antibody of PD-L2 (1:200, clone 176611), and cases with >1% tumor staining of PD-L2 were considered positive. Furthermore, we analyzed correlations between PD-L2 expression and patients’ characteristics, efficacy, and immune-related adverse events (irAEs) of anti-PD-1 inhibitors.

      Result

      In this study, 59 (72.0%) and 56 (68.3) patients with NSCLC exhibited positive tumor PD-L2 and PD-L1 staining, respectively. Overall, 39 irAEs developed in 36 patients. The PD-L2 expression markedly correlated with the development of irAEs; however, we observed no correlation between PD-L2 expression and the efficacy of anti-PD-1 inhibitors. Other factors, including the PD-L1 expression, age, sex, smoking status, histology, did not correlate with the development of irAEs.

      Conclusion

      This study suggests that the PD-L2 expression could be accountable for the development of irAEs in anti-PD-1 inhibitors–treated patients with NSCLC.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-52 - The Results from Plasma EGFR Mutation Analysis in NEJ026 Study (ID 602)

      10:15 - 18:15  |  Author(s): Koichi Azuma

      • Abstract

      Background

      EGFR mutation analysis of plasma circulating tumor DNA (ctDNA) has been reported to be useful to detect resistant mutations and to predict the efficacy of treatment. In NEJ026 study, we demonstrated the PFS of erlotinib plus bevacizumab (BE) treatment was significantly superior to the erlotinib alone (E) in NSCLC patients harboring EGFR mutation. Evaluation of plasma EGFR mutations included in NEJ026 study as preplanned analysis.

      Method

      At the time points of pretreated (P0), 6 weeks after study treatment started (P1), and confirmed progressive disease (P2), the plasma samples were collected from the patients enrolled to NEJ026 study. The number of enrolled patients were 112 in BE and 114 in E. Plasma ctDNA analysis for detection of the activating EGFR mutation and T790M mutation were performed by modified PNA-LNA PCR clamp method.

      Result

      The total numbers of collected plasma samples in BE and E were 108 (96.4%) and 107 (95.5%) at P0, 95 (84.8%) and 97 (86.6%) at P1, and 42 (37.5%) and 53 (47.3%) at P2, respectively. In eligible patients having EGFR activating mutation detected by cytohistological specimens, detection rate of plasma EGFR mutation at P0 was 68% (147/215). The detection ratio of T790M mutation at P2 were similar in both arms: 8 (19.0%) in BE and 11 (20.8%) in E. By detection pattern of activating EGFR mutation, PFS was evaluated among three groups: type A (P0 (-),P1 (-)), type B (P0 (+), P1(-)), and type C (P0 (+), P1(+)). Type A achieved the best response to both TKI [Type A BE: 18.1 M (n = 32, 95% CI, 11.5 to upper limit not reached(NR)), E: 16.7 M (n = 26, 95% CI, 11.2 to NR )]. Type B also had better PFS to TKI and BE is more favorable effect than E compared to other types [type B BE: 15.5 M (n = 48, 95% CI, 12.4 to 23.3), E: 11.1 M (n = 57, 95% CI, 8.5 to 13.7)]. Type C showed worse response to both treatment [type C BE: 6.0M. (n = 12, 95% CI 2.6 to NR), E: 4.3 M (n = 10, 95% CI, 2.8 to 20.2)]. BE had better PFS in all types.

      Conclusion

      Frequency of T790M in P2 was similar among BE and E. When patients still had detectable activating EGFR mutation in plasma ctDNA after treatment for 6 weeks, you should consider that they might have poor response to both BE and E.