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Andrea Ardizzoni



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    Lunch & Poster Display session (ID 58)

    • Event: ELCC 2019
    • Type: Poster Display session
    • Track:
    • Presentations: 3
    • Moderators:
    • Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1
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      146P - Clinical significance of ROS1 5’ deletions detected by FISH and response to crizotinib (ID 399)

      12:30 - 13:00  |  Author(s): Andrea Ardizzoni

      • Abstract

      Background

      ROS1-rearranged non-small cell lung cancer (NSCLC) patients (pts) are eligible for crizotinib therapy. Diagnosis is based on break-apart fluorescence in situ hybridization (FISH), as for ALKrearrangements, and include 5’ deletions. We report assessment of ROS15’ deletion by FISH and next-generation sequencing (NGS) and outcome of crizotinib treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      We included all consecutive NSCLC pts treated at our Institution with: i) diagnosis of 5’ ROS1 gene fusion by break-apart FISH (≥15% of tumor cells with any 5’ deletion pattern); ii) availability in the samples of at least 50 ng of extracted RNA with at least 50% tumor cell enrichment; iii) treatment with crizotinib for at least 4 weeks following the diagnosis of ROS1fusion; iv) availability of clinical and radiological response data after therapy. FISH assay was performed using the Zytolight SPEC ROS1 Dual Color Break Apart Probe (ZytoVision, Germany). NGS was performed on Ion Torrent Personal Genome Machine (Thermo Fisher Scientific). The RNA panel identified rearrangements in 23 genes including ROS1 rearrangements with EZR, CD74 and SCD4.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      Eight patients were included. No patient had brain metastasis at diagnosis. Five pts were never-smoker, 2 light former smoker and 1 (case #1) a current heavy smoker (50 pack-year). Crizotinib therapy lasted for a mean of 11.0 months (range 2-31). The median overall survival was not reached at a median follow-up of 11.1 months (15.7 months for censored only). In 4 of the 8 cases (cases #2, 3, 7, 8; 50%), NGS confirmed a ROS1 fusion: 3 of them with the partner EZR and 1 with SCD4. All of these pts showed an objective response to crizotinib, 2 of them being complete responses according to RECIST v1.1 criteria. All these pts were alive at the time of last follow-up. In the other 4 pts (cases # 1, 4 ,5 ,6), NGS analysis did not detect ROS1 fusions. Of these, objective response to crizotinib was observed in only 2 pts, including one (case #5) with a concomitant EML4-ALKrearrangement, confirmed by FISH. The two other patients experienced rapid progressive disease.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      FISH-detected ROS15’ deletion is associated with a high response probability to crizotinib, similarly to classical ROS1 gene rearrangement. However, confirmation with at least one other method, e.g. NGS, is recommended, in order to exclude possible false positive results.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      This work was in part supported by the Pallotti fund to Michelangelo Fiorentino.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

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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): Andrea Ardizzoni

      • 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): Andrea Ardizzoni

      • 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.

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