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Marcello Tiseo



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    Lunch & Poster Display session (ID 58)

    • Event: ELCC 2019
    • Type: Poster Display session
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1
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      148P - KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic non-squamous NSCLC (ID 368)

      12:30 - 13:00  |  Author(s): Marcello Tiseo

      • Abstract
      • Slides

      Background

      Programmed cell death -1 (PD-1) PD-ligand 1 (PD-L1) inhibitors represent a novel therapeutic option for advanced chemotherapy-pretreated non-small cell lung cancer (NSCLC) patients, leading to a significant improvement in median and long-term survival. However, about 50% patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression and tumor mutational burden (TBM) have been proposed as biomarker of benefit to anti-PD-1/PD-L1 therapy. However, PD-L1 is not an ideal biomarker and TMB calculation is hardly obtainable for all patients. Here, we planned to test specific NSCLC genetic alterations as potential predictive factors of response to immunotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      Tumor DNA was obtained from advanced NSCLC patients treated with anti PD-1 monoclonal antibody nivolumab (N = 44) or pembrolizumab (N = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing using Oncomine™ Solid Tumour DNA assay (Thermo Fisher).

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11(9%), ERBB4 (6%), EGFR (6%), BRAF (6%) and MET (6%). We observed that KRASmut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRASwt patients. Additionally, we observed that patients with ERBB-family, including EGFR, ERBB2 and ERBB4, mutations all failed to respond to PD-1 blockers, independently from KRAS status.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      These results suggest that the analysis of the mutational status of KRAS and ERBB-family genes is a potential molecular biomarker of response to PD-1 inhibitors that could be used in clinical practice.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Associazione Italiana per la Ricerca sul Cancro (AIRC).

      682889d0a1d3b50267a69346a750433d Disclosure

      M. Tiseo: Advisory boards, speakers’ fee: BMS, MSD. A. Ardizzoni: Grants, personal fees: BMS; Grants: Celgene; Personal fees: MSD, Eli Lilly, Boehringer Ingelheim, Pfizer, outside the submitted work. All other authors have declared no conflicts of interest.

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      186TiP - An open-label, randomized phase III study of early switch maintenance vs delayed second-line nivolumab in advanced stage squamous non-small cell lung cancer (NSCLC) patients after standard first-line platinum-based chemotherapy: EDEN trial (ID 569)

      12:30 - 13:00  |  Author(s): Marcello Tiseo

      • Abstract

      Background

      Squamous non-small cell lung cancer (Sq-NSCLC) represents 20-30% of all NSCLC with a disappointing median overall survival (OS). In the last decades, first-line chemotherapy (Ctx) for advanced Sq-NSCLC has not changed and the standard of care remains a platinum-based regimen (cisplatin or carboplatin) combined with gemcitabine, vinorelbine or taxanes for up to 4-6 cycles. In non-squamous NSCLC, maintenance therapy (MTx) by continuing pemetrexed as single-agent after induction treatment has led to a 3-months improvement in OS. On the contrary, no randomized study has shown a significant benefit from MTx in Sq-NSCLC patients (pts), yet. More recently, nivolumab has become the standard of care as second line therapy. Unfortunately, 30-40% of Sq-NSCLC pts do not have access to second-line therapy because of rapid progression and decline of performance status (PS). Nivolumab as switch MTx would represent a strategy to anticipate its use, allowing more patients to benefit from immune check-points inhibitors.

      a9ded1e5ce5d75814730bb4caaf49419 Trial design

      Eligible pts: age ≥18, stage IIIB/IV or recurrent Sq-NSCLC, no disease progression (PD) after 4-6 cycles of first-line platinum-based Ctx, ECOG PS ≤ 2, no symptomatic and/or progressive treated brain metastases, good bone marrow, liver and renal functions. 388 pts will be randomized 1:1 to Nivolumab flat dose 240 mg i.v (Arm A) every 2 weeks or best supportive care (BSC) followed by Nivolumab 240 mg i.v at PD (Arm B), and stratified by centre and tumor response to first-line induction Ctx (complete response and partial response vs stable disease). Pts enrolled into Arm A will receive Nivolumab until PD or intolerable toxicity; at PD, they will be treated with Ctx according to local policy. Patients enrolled into Arm B will receive Nivolumab only after radiologic evidence of PD. Nivolumab treatment beyond initial PD will be allowed in both arms. Primary endpoint: OS. Secondary end-points: progression-free survival (PFS), PFS from induction (PFS-ind), time to treatment failure (TTF) and OS from induction (OS-ind). At January 5th 2019, 49 pts were enrolled.

      d9b324a48b043b3d87bc9b3fe620f260 Clinical trial identification

      NCT03542461.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Legal entity responsible for the study

      Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), Parma, Italy.

      213f68309caaa4ccc14d5f99789640ad Funding

      BMS.

      682889d0a1d3b50267a69346a750433d Disclosure

      L. Cavanna: Personal fees for serving in a consultant and/or advisory role: Astrazeneca, Merck; Honoraria: Celgene, Pfizer, Ipsen. A. Ardizzoni: Research grant support: BMS, Celgene; Personal fees for serving in a consultant and/or advisory role: BMS, MSD, Boehringer Ingelheim; Honoraria: Eli Lilly, Pfizer. All other authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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    Mini Oral session III (ID 65)

    • Event: ELCC 2019
    • Type: Mini Oral session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/12/2019, 17:45 - 18:45, Room C
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      2O - Differentially regulated high-throughput CT imaging features correlate to distinct tumor immune contextures portraying a radiomic signature with prognostic impact on surgically resected NSCLC (ID 507)

      17:45 - 18:45  |  Author(s): Marcello Tiseo

      • Abstract
      • Presentation
      • Slides

      Background

      The ground-breaking advent of immunotherapy in the oncologic arena still leaves uncovered the identification of valid prognostic and predictive biomarkers. To this aim, we advanced the hypothesis that intersecting the tumor immune microenvironment (TIME) with high-throughput extracted radiomic features may identify NSCLC patients with distinct clinical outcome.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We enrolled 60 surgically resected NSCLC patients. TIME was assessed by the quantitative evaluation of PD-L1 levels and an extensive morphometric analysis of Tumor Infiltrating Lymphocytes (TILs). From each CT scan, in addition to semantic characteristics, 841 radiomic features were extracted through an open-source (3d Slicer) software. Radiomic variables were subjected to statistical analysis to test their correlation with tissue immune profiles and survival outcome.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      A cluster of 3 patients (A) displaying oppositely regulated radiomic features was identified by an unsupervised hierarchical model. Compared to the remaining cases, cluster A had a significantly reduced (p < 0.01) OS (13 vs 33 mos.) and DFS (11 vs 25 mos.) and shared similar semantic imaging characteristics (no effect on parenchyma and subsolid texture) and a desertic TIME (PD-L1low and TILslow). Radiomic variables from cluster A were then compared to those extracted from patients matched for both desertic TIME and qualitative CT parameters but with favorable survival outcome (cluster B). By applying signal-to-noise ratio and T-test, the most significant oppositely regulated wavelet features (p < 0.0001) in the two clusters were Large Dependence Emphasis, Busyness, Cluster-Tendency and Gray Level Variance. The detailed analysis of corresponding TIME revealed that PD-1-to-CD8 ratio was the only immunophenotypic parameter differentially expressed by the two prognostic classes.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      Higher order radiomic features associated with specific TILs phenotype may enclose a radiologic signature with prognostic impact on NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      University Hospital of Parma.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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    Proffered Paper session III (ID 64)

    • Event: ELCC 2019
    • Type: Proffered Paper session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/12/2019, 08:30 - 10:00, Room A
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      106O - Brigatinib (BRG) vs crizotinib (CRZ) in the phase III ALTA-1L trial (ID 166)

      08:30 - 10:00  |  Author(s): Marcello Tiseo

      • Abstract
      • Presentation
      • Slides

      Background

      We report results of the first interim analysis (IA) from the ALTA-1L study of BRG vs CRZ in anaplastic lymphoma kinase (ALK) inhibitor–naive, ALK-positive non–small cell lung cancer (ALK+ NSCLC; NCT02737501).

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      This open-label, multicenter study enrolled patients (pts) with advanced ALK+ NSCLC. Eligible pts had ≤1 prior systemic therapy for advanced NSCLC. Asymptomatic central nervous system (CNS) metastases were allowed. Pts were randomized 1:1 to BRG 180 mg QD with 7-day lead-in at 90 mg or CRZ 250 mg BID. Primary endpoint was blinded independent review committee (BIRC)-assessed progression-free survival (PFS; RECIST v1.1); secondary efficacy endpoints included BIRC-assessed objective response rate (ORR), intracranial ORR (iORR), and intracranial PFS (iPFS). IAs were planned at 50% and 75% of 198 expected PFS events.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      275 pts were randomized (BRG/CRZ, n = 137/138); median age (years) 58/60. 26%/27% received prior chemotherapy for advanced disease, and 29%/30% had baseline brain metastases. At data cutoff (19 Feb 2018), with a median follow-up of 11.0/9.3 months (BRG/CRZ) and 99 PFS events, BRG met the prespecified threshold for statistical superiority vs CRZ in the primary endpoint of BIRC-assessed PFS (HR 0.49; 95% CI, 0.33–0.74; log-rank P = 0.0007); BRG median PFS was not reached (NR; 95% CI, NR) vs CRZ 9.8 months (95% CI, 9.0–12.9). Investigator-assessed PFS HR 0.45 (95% CI, 0.30–0.68); log-rank P = 0.0001. Table shows additional efficacy data. Most common grade ≥3 treatment-emergent adverse events (AEs): BRG: increased blood creatine phosphokinase (16.2%) and lipase (13.2%), hypertension (9.6%); CRZ: increased alanine aminotransferase (9.5%), aspartate aminotransferase (5.8%), and lipase (5.1%). Any grade interstitial lung disease/pneumonitis: BRG, 3.7%; CRZ, 2.2%. Discontinuations due to AE (BRG/CRZ): 11.8%/8.8%.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      BRG showed a statistically and clinically significant improvement in PFS vs CRZ in ALK inhibitor–naive ALK+ NSCLC.

      b651e8a99c4375feb982b7c2cad376e9 Clinical trial identification

      NCT02737501.

      7a6a3ffa2dadc03a6151ee2c4d6fa383 Editorial acknowledgement

      Professional medical writing assistance was provided by Lauren Gallagher, PhD, (Peloton Advantage, Parsippany, NJ) and funded by Millennium Pharmaceuticals, Inc.

      934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study

      ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

      213f68309caaa4ccc14d5f99789640ad Funding

      ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

      682889d0a1d3b50267a69346a750433d Disclosure

      R. Califano: Honoraria, consulting/advisory role: AstraZeneca, BMS, Roche, MSD, Boehringer Ingelheim, Takeda, Novartis, Pfizer, Lilly Oncology. C. Gridelli: Speakers bureau, advisory role: Pfizer, Roche. A. Delmonte: Consulting/advisory role: AstraZeneca, Boehringer Ingelheim. M.R. Garcia Campelo: Honoraria: ARIAD, AstraZeneca, Roche, Pfizer, BMS, Boehringer Ingelheim; Speakers bureau, advisory role: ARIAD, AstraZeneca, Roche, Pfizer, BMS, Boehringer Ingelheim. A. Bearz: Speakers bureau, advisory role: AstraZeneca, Pfizer, Eli Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Takeda. F. Griesinger: Research funding to institution: AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Siemens; Consulting or advisory role: ARIAD, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, ARIAD, AbbVie, Siemens. E. Felip: Consulting/advisory role: AbbVie, AstraZeneca, Blue Print Medicines, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Guardant Health, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda; Speakers bureau: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda. S. Popat: Research funding to institution: Boehringer Ingelheim, Epizyme, BMS, Clovis Oncology, Roche, Lilly, Takeda; Honoraria: Boehringer Ingelheim, AstraZeneca, Roche, Takeda, Chugai Pharma; Consulting or advisory role: Boehringer Ingelheim, Roche, Novartis, Pfizer, AstraZeneca, BMS, MSD, Guardant Health, AbbVie; Travel, accommodations, expenses: Boehringer Ingelheim, BMS, Merck Sharp & Dohme. A. Morabito: Honoraria: AstraZeneca, Roche, Boehringer Ingelheim, Pfizer, MSD, BMS. S. Ghosh: Honoraria/speakers bureau: Pfizer. M. Tiseo: Speakers bureau, advisory role: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Roche. J. Haney, D. Kerstein: Employment, stock and other ownership interests: Arîad. D.R. Camidge: Honoraria: AstraZeneca, Takeda, Arrys/Kyn, Genoptix, G1 Therapeutics (DSMB), Mersana Therapeutics, Roche/Genentech, Ignyta, Daichii Sankyo (ILD adjudication committee), Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med, Orion, Clovis, Celgene, Novartis); Research funding (ARIAD/Takeda). All other authors have declared no conflicts of interest.

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