Virtual Library

Start Your Search

Alfredo Addeo



Author of

  • +

    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
    • +

      EP1.01-66 - Detection of Genomic Mutations in Blood and Urine ctDNA in Lung Adenocarcinoma with EGFR Mutation on Tissue – An Interim Progress Report (Now Available) (ID 2766)

      08:00 - 18:00  |  Author(s): Alfredo Addeo

      • Abstract
      • Slides

      Background

      Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective therapy for stage IIIB/IV EGFR-mutation positive (EGFRm+) NSCLC. Despite initial response, clinical progression occurs, often with development of a second TK mutation.

      Mutation analysis is performed at time of diagnosis usually on single tissue biopsy. Samples can be difficult to obtain and may not represent neoplastic tissue at other sites due to heterogeneity. On progression, patients rarely undergo repeat tissue biopsy. Therapy is no longer truly personalised.

      CtDNA may be an alternative to tissue biopsy for mutation analysis. It may be more representative, and provide real time assessment of disease status, maintaining individualised therapy.

      Published retrospective data are available on detection of EGFR mutations in plasma ctDNA, and evidence that urine can be used is emerging. Clinical use has been limited by lack of evidence for detection methods and concordance with tissue.

      Retrospective data suggest that on response to TKI, TK mutation load reduces, and on progression, mutation load increases and/or a new mutation emerges. This has not been validated prospectively.

      Method

      A prospective pilot study: 20 patients, 2 UK sites; with stage IIIB/IV EGFRm+ NSCLC on tissue sample, TKI-treatment naïve. Plasma and urine collected prior to TKI treatment and monthly on treatment. CtDNA is extracted from plasma and urine using Quigen kit, and analysed using digital droplet PCR for the 3 most common EGFR mutations – del19, L858R and T790M.

      Objective: To investigate if urine/plasma ctDNA may be used to prospectively detect and monitor EGFR mutational status at baseline and during TKI therapy

      Primary Endpoint: To assess if ctDNA from urine/plasma could be a reliable source of EGFR testing

      Secondary Endpoint: To assess if changes in levels of baseline mutation or development of new mutations in ctDNA correlates with disease response/progression during TKI therapy

      Outcome: To inform development of a larger study to further investigate and validate the role of liquid biopsy in treatment of EGFRm+ NSCLC

      Result

      CtDNA analysis performed on samples from 14patients to date. On baseline tissue, 8 (57%) had del19 mutation, 5 (36%) had L858R mutation, and 1 (7%) had L861Q mutation. Representative of population distribution of EGFR mutations.

      In those with tissue del19 mutation, del19 mutation was identified on baseline ctDNA in 8/8 (100%) plasma samples and 6/7 (86%) urine samples (one patient did not provide baseline urine sample). None had L858R mutation in plasma/urine. In one plasma ctDNA sample, very low levels of T790M mutation were identified, but no T790M mutations were found in urine ctDNA.

      In those with tissue L858R mutation, L858R mutation was identified on baseline ctDNA in 3/5 (60%) plasma samples and 4/5 (80%) urine samples. All were found to have del19 mutation on baseline plasma ctDNA, 3/5 had del19 mutation in urine ctDNA. None had T790M mutations in plasma/urine ctDNA.

      Conclusion

      Sensitivity is high for identifying baseline EGFR mutations in plasma/urine ctDNA.

      Very hard to comment on specificity. It's known that del19 and L858R mutations can co-exist. It's possible that mutation analysis performed on DNA extracted away from primary tumour site may carry additional mutations due to heterogeneity.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 1
    • Now Available
    • +

      JCSE01.05 - Biomarker in Immunotherapy: Myth or Reality? (Now Available) (ID 3418)

      07:00 - 11:15  |  Presenting Author(s): Alfredo Addeo

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background: NSCLC treatment landscape has rapidly evolved with several immune checkpoint inhibitors (ICIs) approved initially in second line as monotherapy and subsequently in first line as either monotherapy or in combination with chemotherapy. The recent presentation at the ASCO 2019 of the 5 years overall survival (OS) of the Keynote 001 has further strengthened the importance and impact of ICIs on patients with NSCLC, showing unprecedented 5 years overall OS. However up to 50-60% of NSCLC patient does not benefit from such a treatment. The need to validate and find out new effective biomarker (BM) remains crucial.

      Discussion: PD-L1 expression is the only approved BM in NSCLC that proved to be predictive of better OS for anti-PD1 (Pembrolizumab). Despite several advantages such as short turnaround time (TAT), relatively simple IHC assay (gone through an harmonized process in the blueprint2) there are several limitations: PD-L1 non expresser could still be responders and benefit form ICIs or in driven mutated NSCLC the PD-L1 level might be very high, generally mediates by the JAK3 pathway, but not being responsive to ICIs for the rarity of T cell infiltrations.

      A new promising BM is the tumour mutation burden (TMB). The prevalence of somatic mutation varies between 0.01 mut/Mb to 400 mutations/Mb. Some of these mutations led to the translation of novel peptide epitopes or neoantigens that should enhance the immunogenicity of the tumour by eliciting T cell repertoire. The hypothesis then is that in case of high TMB ICIs should work better than chemo. So far this has been partially seen in some studies in term of response rate (RR) an progression free survival (PFS) but no study has been designed yet as having primary endpoint better OS in High TMB patients. Furthermore there are several aspects to consider about TMB: TAT is at least 2 week (it the first studies were conducted by using whole exome sequencing), high cost, no clear cut-off, unclear if it should be performed on cancer tissue or circulating tumour DNA (ctDNA) and the most important one the prospective trial has ever validated TMB as predictive of better OS compared to chemotherapy.

      There are several new BM in embryonic phase: role and importance of TILs, immune gene signature, INFgamma relatedmRNAbased signatures, myeloid-derived suppressor cells(MDSCs) or the neutrophil-to-lymphocyte ratio (NLR) at baseline. None of them is ready for prime time but there are ongoing studies that hopefully will validate useful BM to adopt in clinical practice

      Conclusion: are BMs reality? Yes we already have a reliable predictive BM which remains PD-L1 expression. TMB might represent a possible alternative to identify a different subgroup of NSCLC patients. PD-L1 high and high TMB might partially overlap but they highly likely correspond to 2 different patients populations. There is indeed room for improvement and more BMs are needed: possibly simple to adopt in clinical practice, with short TAT and most important showing OS benefit, to definitively move from the myth to the reality.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    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
    • +

      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): Alfredo Addeo

      • 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.

  • +

    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.01-67 - Are KRAS Mutations Predictive of Response to Immunotherapy in Non Small-Cell Lung Cancer? A Single Center Experience (Now Available) (ID 1994)

      10:15 - 18:15  |  Author(s): Alfredo Addeo

      • Abstract
      • Slides

      Background

      Lung cancer is the leading cause of cancer-related mortality. In the last decade, the treatment landscape has evolved for non-small-cell lung cancer (NSCLC), in large part thanks to two therapeutic advances: targeted therapy for oncogene driven tumours and immune checkpoint-inhibitors (ICI). The latter can lead to very long survival, but only in a limited number of patients. Post-hoc analyses and preclinical data suggest KRAS mutated NSCLC may respond better to ICI.

      Method

      We retrospectively analysed all stage IV NSCLC patients treated in our center with immunotherapy from January 2016 to December 2017 and compared KRAS mutated to wildtype patients. The clinical outcomes analysed were disease control rate (DCR), partial response (PR), progression free survival (PFS) and overall survival (OS). We performed an exploratory analysis on the impact of KRAS mutation type and concurrent mutations.

      Result

      45 patients treated with ICI. 7 were excluded due to insufficient data. 38 were included. 27 patients (71%) with nivolumab, 9 patients (24%) with pembrolizumab and 2 patients (5%) with atezolizumab. 22 patients (58%) were male and 16 (42%) female. The median age was 63.

      21 patients (55%) presented KRAS mutations, of which 4 (19%) had concurrent p53 mutations and 1 (5%) an EGFR mutation. 17 patients (45%) were KRAS wild-type, of which 4 (24%) had EGFR mutations and 1 (6%) had a BRAF V600E mutation. In the KRAS mutated subgroup 59% were male and 41% were female, the median age was 61 years and all patients had PS 0-1. All patients received second line immunotherapy except for 2, one in third line, one fifth line.

      In the intention to treat population (ITT) the DCR was 71% with 55% PR, PFS was 11.3 months, and OS 17.7 month. In the KRAS wild-type subgroup DCR was 59% with 49% PR, the PFS was 8.4 months and OS 16.8 months. In the KRAS mutated subgroup, DCR was 81%, with 62% PR, PFS was 13.6 months and OS 18.5 months.

      An exploratory analysis based on KRAS mutation types or co-mutations was performed. The average PFS for G12C, G13C, G12V, G61H and other mutations was 19.1, 7.8, 9.4, 2.2, 13.9 months respectively. PFS for p53 co-mutated KRAS NSCLC was 23.5 months. Further analyses for STK11 co-mutations are ongoing, as these confer resistance to ICI.

      At the time of analysis 7 patients were still receiving immunotherapy.

      .

      Conclusion

      In our retrospective study, KRAS mutations in NSCLC were predictive of numerically superior response to ICI compared to wildtype patients. Currently, the data is conflicting and larger clinical trials are needed to clarify this hypothesis and ascertain whether and how KRAS should be part of the treatment algorithm for the selection of ICI patients. Furthermore, more research is needed to confirm the potential role of mutation types and clinical impact of co-mutations in KRAS.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    P2.12 - Small Cell Lung Cancer/NET (ID 180)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.12-21 - Outcomes with Immune Checkpoint Inhibitors (ICI) for Relapsed Small Cell Lung Cancer (SCLC) in a Swiss Cohort (ID 1026)

      10:15 - 18:15  |  Author(s): Alfredo Addeo

      • Abstract

      Background

      Chemotherapy for relapsed small-cell lung cancer (SCLC) has limited activity. Results from early clinical trials showed promising outcomes in a subset of patients with relapsed SCLC receiving ICI. Therefore, nivolumab +/- ipilimumab, pembrolizumab or atezolizumab have been used off-label in Switzerland.

      Method

      9 cancer centers in Switzerland contributed data to this retrospective cohort of patients who received off-label ICI for relapsed SCLC. Patient characteristics including age, smoking status, stage at diagnosis and previous treatments were collected. Outcomes of ICI were assessed by the local investigators using standard RECIST v1.1 criteria. Tumor tissues were assessed centrally for PD-L1 expression, tumor mutational burden and immune-related gene expression signatures.

      Result

      45 patients were included between November 2016 and January 2019. Median age was 63 years. 73% were males, 4% never smokers and 18% had a performance status (PS) ≥2. ICIs were given as second line treatment in 24 patients (53%). 24 patients (53%) received combination immunotherapy with ipiliumumab and nivolumab. 28 patients (62%) had undergone tumor irradiation (RT) prior to or during ICI. In the entire population, the overall response rate was 31%, while 49% had progressive disease as best response. Median progression-free survival was 2.5 months and median overall survival 6.5 months. There was no significant association between type of ICI (mono vs. combo) or prior RT vs. no RT with survival outcomes in a multivariate analysis. There were no new safety signals. One patient died of immune-related pneumonitis.

      Conclusion

      This is the first report of “real-world” data on ICI in relapsed SCLC also including patients with poor PS. We confirm the efficacy and safety of ICI in relapsed SCLC as previously shown in clinical trials. No clinical prognostic marker could be identified. Results on the prognostic value of tissue-based biomarkers will be presented at the meeting.