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Giulio Metro



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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-65 - Immune Gene Expression, Bayesian Network and Genetic Mutation Analysis in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 1361)

      09:45 - 18:00  |  Author(s): Giulio Metro

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have dramatically revoluzionized the therapeutic paradigm for NSCLC, but only a small subset of patients achieves durable benefit. The only adopted predictive biomarker, PD-L1 IHC testing, suffers from some limitations. A better understanding of biomarkers associated with response to ICIs is needed. Here, we studied immune gene-expression and genetic mutation profiles and association with clinical response to immunotherapy in advanced NSCLC patients treated with ICI.

      Method

      A total of 37 Formalin-fixed, paraffin-embedded (FFPE) samples from advanced NSCLCs were analyzed by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) (ThermoFisher Scientific) on Ion Torrent PGM and Transcriptome Analysis Console (TAC) 4.0 Software. This panel measures the expression level of 395 genes associated with 36 functional groups including checkpoint pathways, lymphocyte regulation and cytokine interactions. Gene network analysis based on Bayesian algorithm was performed by GeneMANIA database querying with the genes selected through mRNA expression analysis. Cancer somatic mutation analysis were performed using Ion NGS Panel on PGM Instrument.

      Result

      Among 37 FFPE samples only 18 showed more than 300 OIRRA detectable target genes. In this subgroup, gene expression analysis revealed 7 genes (CCR2, CRTAM, FASLG, SELL, TIGIT, TNFRSF4, and TP63) up-regulated and one gene (CXCL8) down-regulated (p-value < 0.05) in ICI-responders compare to ICI-no responders. Bayesian enrichment computational analysis of eight gene expression signature showed a more complex network which involves other 10 genes (SIRPG, GZMK, XCL2, CD8A, CD2, IFNG, SIT1, TAGAP, PTPRC and GZMH), correlated with different functional groups. Three main immune-pathways were identified (p < 0.01) (T cell activation, leucocyte activation and migration) involving TIGIT, TNFRSF4, CCR2 and CXCL8 genes among the gene expression signature identified. Gene mutational analysis was feasible for 28 samples. KRAS mutation was detected in 41% of ICI-responders respect to 12.5% of ICI-no responders. Conversely, no STK11 mutation was found in ICI-responders, consistent with previous reports.

      Conclusion

      Our results revealed an immune response gene expression signature of 8 genes differentially expressed between ICI and ICI-no responders. Cancer systems biology analysis approach strengthen our findings identifying an immune molecular network and confirm the correlation of the gene expression signature with relevant immune regulatory functions. If validated, our results may have an important role for the development of a robust test to select patients properly and predict immune response to enable precision immunotherapy. Furthermore, TMB assessment in such subset of patients is under investigation and more data will be available for the meeting.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-09 - Post-Progression Outcomes After Pembrolizumab in Patients with NSCLC and High PD-L1 Expression: Real-World Data from a European Cohort (ID 2749)

      09:45 - 18:00  |  Author(s): Giulio Metro

      • Abstract

      Background

      Real-world data regarding treatment patterns and clinical outcomes after progression on first-line pembrolizumab (pembro) monotherapy among NSCLC patients are lacking.

      Method

      A comprehensive clinicopathological database of 173 consecutive patients with NSCLC and PD-L1>50% treated with first-line pembro in 14 centers in Italy, Spain, Greece and Switzerland was retrospectively created and post-progression patterns and outcomes were recorded. Analysis was performed using the SAS 9.3 software.

      Result

      Main clinicopathological features are summarized in Table 1. Median TPS score for PD-L1 expression was 70%. Median duration of pembro treatment was 6.1 months (range: 0.2-20.8). Thirty patients (17.4%) received pembro despite having non-metastatic disease (stage I-IIIC), as deemed medically inoperable or ineligible for definite chemo-radiotherapy. At data cut-off (10th April 2019), 100 patients (58%) had stopped treatment due to disease progression, 9 (5%) due to toxicity, 3 (2%) for other reasons and 61 (35%) were still on treatment. Best response to pembro was CR, PR, SD and PD in 2%, 34%, 20% and 24% respectively, while in 11.6% death occurred in the absence of documented PD. Among patients who progressed (N=100), in 18 cases pembro was continued beyond progression, as considered to confer clinical benefit. Among patients who discontinued pembro (N=94), 47% received any second-line chemotherapy and 53% received no further treatment. Main chemotherapy regimens were carboplatin with either pemetrexed (16%) or gemcitabine (9%) or paclitaxel (7%), cisplatin-pemetrexed (7%) and gemcitabine monotherapy (9%). Best response to chemotherapy was CR, PR, SD and PD in 2%, 30%, 11% and 32% respectively. After a median follow-up of 11.2 months, median OS was 13.5 months (range: 0.16-25.8+).

      Table 1: Main clinicopathological characteristics of the patient cohort.

      N=173

      %

      COUNTRY OF ORIGIN

      Italy

      98

      56.7

      Greece

      32

      18.5

      Switzerland

      27

      15.6

      Spain

      16

      9.2

      SEX

      Male

      112

      64.7

      Female

      61

      35.3

      AGE Median (Range) yrs

      68 (19-86)

      SMOKING STATUS

      Current

      66

      38.2

      Former

      86

      49.7

      Never

      18

      10.4

      Unknown

      3

      1,7

      PERFORMANCE STATUS

      0

      50

      28.9

      1

      80

      46.2

      2

      41

      23.7

      3

      2

      1.2

      HISTOLOGY

      Adeno

      116

      67.1

      Squamous

      37

      21.4

      Large Cell

      2

      1.2

      Pleiomorphic

      3

      1.7

      Sarcomatoid

      7

      4.0

      Poorly differentiated/

      Undifferentiated

      8

      4.6

      SITE OF METASTASIS

      Bone

      74

      49.7

      Intrapulmonary/Contralateral Lung

      72

      48.3

      Adrenal

      43

      28.9

      Brain

      30

      20.1

      Liver

      23

      15.4

      Other

      63

      36.4

      TNM STAGE AT DIAGNOSIS (AJCCC v.8)

      I

      2

      1.2

      II

      2

      1.2

      III

      26

      15.0

      IV

      142

      82.1

      Unknown

      1

      0.5

      STEROID USE

      Yes

      48

      27.7

      No

      105

      60.7

      Unknown

      20

      11.6

      Conclusion

      Real-world data in a large retrospective cohort, indirectly compared to Keynote 024, suggest that: 1) Due to it’s favorable toxicity profile, pembro is also an option in earlier stages in frail (PS=2 or medically inoperable stage I-III) patients, 2) One in five patients continues pembro beyond progression due to clinical benefit and 3) More than half of patients who progress do not receive any second-line treatment, mainly due to clinical deterioration.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-84 - NSCLC Survival Expectancy for Patients Treated with Docetaxel/Nintedanib in the SENECA Trial and Previous Immunotherapy (ID 807)

      10:15 - 18:15  |  Author(s): Giulio Metro

      • Abstract
      • Slides

      Background

      The phase IIb SENECA trial was an Italian real-world experience recently ended, which demonstrated similar progression free survival (PFS) and overall survival (OS) in non-squamous non-small cell lung cancer (nsNSCLC) patients treated with second-line docetaxel/nintedanib, regardless the relapsing-time from end of first-line chemotherapy and the docetaxel schedule employed (weekly or q3wks), with a slightly higher toxicity-trend in the q3wks arm. During accrual period (January 2016-April 2018), no therapeutic alternative to the use of docetaxel was available for patients with recurrent nsNSCLC until April 2017, when the first immune-checkpoint inhibitor was approved and reimbursed in Italy in this setting. At that point, the study was amended allowing enrolment of patients previously treated with immunotherapy (IT). Because of the lack of data about the optimal therapeutic algorithm in this context, aim of the present evaluation is to investigate if survival expectancy of patients treated with docetaxel/nintedanib could positively influenced when previously treated with IT.

      Method

      In the SENECA trial, 212 nsNSCLC patients, progressing after first-line chemotherapy, were treated with docetaxel plus continuous oral nintedanib, with the possibility of maintenance in case of stabilization or response. This evaluation focus on 16 patients previously treated with IT and compares them to the rest of patient population. Survival analysis is performed using Kaplan Meier curves; Hazard Ratios (HR) with 95% Confidence Interval (95%CI) are reported to compare the two groups.

      Result

      Patients treated with IT (2 combined with first-line chemotherapy, 14 alone) correspond to 7.5% of the entire study population; they were 9 males and 7 females, with a median age of 62.5 years, mainly current or former-smokers, with an ECOG-performance status 0 in 93.7% of cases. At the cut-off date (December 25th, 2018), after a median follow-up of 35.5 months, no significant differences appear between patients previously treated with IT and the other ones in terms of PFS (5.84 vs 4.31 months, respectively; HR 0.564 [95% CI 0.283-1.122], p-value=0.1029), and OS (9.37 vs 9.02 months, respectively; HR 1.108 [95% CI 0.393-3.123], p-value=0.8456). No significant differences have been observed also in disease-control rates (80.0% vs 66.7%, p-value=0.5436).

      Conclusion

      Despite this report does not show a greater survival expectancy for patients treated with docetaxel/nintedanib and previous IT, it's likely that the small sample size may affect this result. The longer PFS and greater disease-control rate are attractive hints for future evaluations with larger sample sizes, supposing a new therapeutic algorithm for recurrent nsNSCLC patients.

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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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      P2.14-58 - A Phase IIIb, Open-Label Study of Afatinib in Caucasian EGFR TKI-Naïve Patients with EGFRm+ NSCLC: An Interim Analysis (ID 1371)

      10:15 - 18:15  |  Author(s): Giulio Metro

      • Abstract
      • Slides

      Background

      First-line afatinib demonstrated significantly improved median PFS in patients with EGFR mutation-positive (EGFRm+) NSCLC versus chemotherapy in LUX-Lung 3/6 (HR [95% CI]: 0.58 [0.43–0.78]/0.28 [0.20–0.39]), and versus gefitinib in LUX-Lung 7 (0.73 [0.57–0.95]). Since these trials had strict inclusion criteria, it is important to support these findings with real-world studies of broader patient populations. We report interim results of a Phase IIIb study of afatinib treatment for EGFRm+ NSCLC in a patient population similar to real-world practice.

      Method

      EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC, and ECOG PS 0–2, received afatinib 40 mg/day. Dose reduction was permitted (minimum 20 mg/day). Primary endpoint: adverse events (AEs; descriptive fashion). Efficacy was also assessed.

      Result

      At data cut-off (30-April-2018), 479 patients were enrolled and treated (Caucasian/Asian/other: 97%/2%/<1%; ECOG PS 0–1/2: 92%/8%; 1st/2nd/≥3rd-line therapy: 78%/17%/5%; common/uncommon mutations: 87%/13%; brain metastases: 17%). Median time on afatinib: 359 days. Objective response and disease control rates were 46% and 86%, respectively. Other efficacy outcomes are in the Table. The most common grade ≥3 afatinib-related AEs were diarrhoea (16%) and rash (11%). 258 (54%) patients had AEs leading to dose reduction (most frequently diarrhoea [25%]/rash [11%]), and 37 (8%) had TRAEs leading to discontinuation (most frequently diarrhoea [3%]; all others [<1%]). Serious afatinib-related AEs occurred in 39 (8%) patients.

      Median TTSP, months

      (95% CI)

      Median PFS, months

      (95% CI)

      All pts (n=479)

      14.9

      (13.8–17.6)

      13.4

      (11.8–14.5)

      Line of therapy

      1st (n=374)

      15.6

      (14.1–18.5)

      13.8

      (12.6–15.2)

      2nd (n=81)

      14.7

      (11.3–20.6)

      13.2

      (8.3–17.7)

      ≥3rd (n=24)

      8.1

      (3.7–14.4)

      6.6

      (3.2–12.6)

      Baseline brain metastases*

      No (n=395)

      15.8

      (14.1–18.8)

      13.9

      (12.7–15.5)

      Yes (n=83)

      13.7

      (9.7–17.2)

      10.1

      (8.2–13.9)

      Baseline mutation type*

      Common (n=416)

      15.9

      (14.5–19.1)

      14.1

      (13.0–15.7)

      Uncommon (n=62)

      6.7

      (5.4–8.3)

      5.9

      (4.0–7.4)

      Baseline ECOG PS*, including age

      01 (n=442)

      15.8
      (14.4–18.8)

      13.8
      (12.8–15.2)

      <65 years (n=221)

      14.7
      (12.7–17.6)

      13.4
      (11.6–15.5)

      65 years (n=221)

      18.9
      (14.7–21.7)

      14.1
      (12.6–16.4)

      2 (n=36)

      8.9
      (5.7–13.2)

      6.2
      (2.5–11.6)

      <65 years (n=16)

      6.0
      (2.4–13.2)

      3.2
      (1.5–9.1)

      65 years (n=20)

      9.9
      (7.6–13.9)

      7.7
      (5.7–13.9)

      *Missing (n=1); Del 19 and/or L858R with or without uncommon mutation; Includes, n (%, of those with uncommon mutations): ex 20 ins: 37 (60), T790M: 12 (19), G719S/A/C: 12 (19), L861Q: 10 (16), S768I: 9 (15). TTSP, time to symptomatic progression; PFS, progression-free survival

      Conclusion

      This interim analysis indicated predictable and manageable safety, and encouraging efficacy, with afatinib in a broad patient population. The high proportion of patients with tumours harbouring exon 20 insertions may account for the differences in TTSP/PFS by common/uncommon mutation subgroup. Independent of treatment line, median TTSP/PFS in patients with ECOG PS 0–1 (LUX-Lung trials’ inclusion criteria) was 15.8/13.8 months, and, notably, was 18.9/14.1 months in those also aged ≥65 years. These findings by ECOG PS/age are consistent with those of the LUX-Lung trials.

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