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Lucio Crinò



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    ES 09 - Recent Progress in the Management of Small Cell Lung Cancer (ID 518)

    • Event: WCLC 2017
    • Type: Educational Session
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      ES 09.05 - Management of Paraneoplastic Syndromes in SCLC (ID 7623)

      14:30 - 16:15  |  Presenting Author(s): Lucio Crinò

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Small cell lung cancer (S.C.L.C.) represents approximately 15% of lung cancers and offers a unique profile of clinical and biological features) S.C.C.L. is a fast growing tumor with are estimated doubling time of 10 days, high propensity to metastatic diffusion since the early beginning of the disease, high sensitivity to chemoradiotherapy but early and common development of pleiotropic drug resistance. Unfortunately in the past 30 years very few advances have been realized in the treatment of S.C.L.C. which in most of the patients is a fatal disease with a median survival of 16-18 months in limited thoracic and 11 months in extensive disease. S.C.L.C. is the most common cancer associated with paraneoplastic syndromes because of it’s propensity to release endocrine peptides, ectopic hormones and neoantigens that can develop the para neoplastic syndromes.Paraneoplastic syndromes constitutes different and heterogeneous clinical conditions associated with cancer development, affecting various tissues at remote locations from theprimary tumour , with an unpredictable clinical behavior. In SCLC, a large number of paraneoplastic syndromes have been reported, involving different organ functions and complicating the clinical course of the disease, including endocrine, neurological and miscellaneous less frequent manifestations. The most common paraneoplastic syndromes in SCLC, can be divided in ectopic hormone-associated syndromes, and immunomediated neurologic syndromes. According to the S.C.L.C. produced hormones we can recognized among the ectopic hormone-associated syndromes, the Hyponatremia (10%) of S.C.L.C., the ectropic Cushing syndrome (5%) Hypertension reninrelated (1%), galactorrhea (1%) and hyperamylasemia (1%). S.C.L.C. has the unique feature to be often heralded or accompanied by a number of immune-mediated neurologic syndromes, the Lambert-Eaton myastemic syndrome 1%, the limbic encephalopaty and the encephalomyelitis, the sensory polyneuropathy, the cerebellar degeneration the opsoclonus myoclonus, all accounting for less than 1%. In most of the cases the neurological symptoms develop before the onset of clinical overt S.C.L.C manifestation and the stage seems not to be related to the presence of paraneoplastic neurological syndrome, whose evolution usually mirrors the behavior and the clinical manifestation. In most of the cases the starting of systemic chemoterapy can induce a dramatic improvement of neurological symptoms in advance to clinical response, and viceversa the worsening of the neurological condition can indicate progressive disease and resistance to the treatment.The study and the improved understanding of pathophisiolgy mechanisms of paraneoplasic syndromes in SCLC can contribute to elucidate the natural history of a fascinating and still largely unknown disease which was erroneously predicted to be a potential curable disease in the eighty years. From that time the treatment strategies and the therapeutic results have been only marginally improved and the undersanding and resolution of paraneoplastic syndromes can contribute substantially to the cure improvement of SCLC.

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    MA 10 - Immunotherapy I (ID 664)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 10.06 - Real-World Results in Non-Squamous Non-Small Cell Lung Cancer Patients: Italian Nivolumab Expanded Access Programme (ID 9580)

      11:00 - 12:30  |  Author(s): Lucio Crinò

      • Abstract
      • Presentation
      • Slides

      Background:
      Nivolumab monotherapy has shown survival benefit in patients (pts) with different tumors, including melanoma, lung cancer, renal cell carcinoma, head and neck cancer and Hodgkin lymphoma. Controlled clinical trial setting differs from what experienced by pts and physicians in routine clinical practice. Here, we report efficacy and safety results of nivolumab in pts with non-squamous non-small cell lung cancer (Non-Sq-NSCLC) treated in the Expanded Access Programme in Italy.

      Method:
      Nivolumab was available upon physician request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Squamous NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months. Pts included in the analysis had received at least one dose of nivolumab and were monitored for adverse events (AE) using Common Terminology Criteria for Adverse Events.

      Result:
      Overall, 1588 pts were enrolled in the EAP across 168 Italian centers. Baseline characteristics of pts were representative of Non-Sq-NSCLC population, in the advanced disease setting. As of March 2017, median overall survival (OS) was 11 months (10.0-12.0), with a median follow-up of 7.8 months (1-21.9) and a median of 7 doses (1-46). The best overall response rate (BORR) was 18%, including 10 pts (<1%) with complete response and 280 pts (17.6%) with partial response. Stable disease has been defined for 414 pts (26.0%) and totally 274 (17.2%) patients were treated beyond progression. Response rates and survival were comparable among pts regardless age (< and ≥ 75 years), presence of brain metastasis and number of prior therapies. Overall, among 1588 pts, 1254 discontinued treatment for any reason, with only 93 (7%) pts who discontinued treatment due to adverse events, in line with what observed in previous studies.

      Conclusion:
      To date, this is the largest clinical experience with nivolumab in a real-world setting and these EAP data are in line with what reported in the registrative phase 3 clinical trial. According to these results, nivolumab seems to be an effective and safe therapy for pre-treated patients with non-squamous NCSLC, supporting its use in current clinical practice.

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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P1.01-015 - Crizotinib in ROS1 Rearranged or MET Deregulated Non-Small-Cell Lung Cancer (NSCLC): Final Results of the METROS Trial (ID 9454)

      09:30 - 16:00  |  Author(s): Lucio Crinò

      • Abstract

      Background:
      Crizotinib is the standard of care in NSCLC with ALK rearrangement. Recent data showed that the drug is dramatically effective in patients with ROS1 rearrangement (ROS1[+]), with promising activity also in individuals with MET exon 14 mutations (MET[Ex14]) or MET amplification (MET[FISH+]).

      Method:
      The METROS is an Italian multicenter prospective phase II trial designed to assess the efficacy and safety of crizotinib in ROS1[+ ]or MET[Ex1][4 ]or MET[FISH][+ ]advanced NSCLC patients who failed at least 1 standard chemotherapy regimen. The co-primary end-point was response rate (RR) in cohort A (ROS1+: centrally confirmed ROS1 rearrangement) and cohort B (MET+: centrally confirmed MET[FISH][+ ]defined as ratio MET/CEP7 >2.2 or locally confirmed MET[Ex1][4]). Eligible patients received crizotinib at the standard dose of 250 mg BID orally.

      Result:
      At the data cut-off of April 30[th], 2017, both cohorts completed accrual. Among 498 screened patients, 52 accounted for the intent-to-treat population (ITT) and received at least 1 dose of crizotinib. Among them, 26 resulted ROS1[+], 16 MET[FISH][+] and 10 MET[Ex1][4]. Notably, 3 MET[Ex1][4] cases had concurrent KRAS mutation and 1 had concurrent MET gene amplification. No concomitant driver event was detected in the ROS1 cohort. Cohort A included individuals with adenocarcinoma, median age of 55 years (range 29-86), predominantly female (61%) and never smokers (54%). Cohort B included older subjects (median age 68, range 39-78), predominantly male (65%), current/former smokers (77%) and with adenocarcinoma (92%). In both cohorts, the vast majority of patients (85%) presented > 2 metastatic sites and crizotinib was mainly offered as second line treatment (74%). Time from end of first line therapy to crizotinib was 4.1 and 1.6 months for cohort A and B, respectively. In ITT population RR, median progression free-survival (PFS) and overall survival (OS) were 61.5%, 17.2 months and not reached in cohort A and 26.9%, 3.1 months and 5.3 months in cohort B, respectively. For cohort B, responses were observed in both MET[FISH][+] and MET[Ex1][4] (25% and 30%, respectively), with evidence of rapid progression in patients carrying MET[Ex1][4][/KRAS]. At present, for 2 MET+ patients assessment is pending. Therapy was generally well tolerated with no unexpected adverse event.

      Conclusion:
      The METROS is the first prospective trial specifically conducted in ROS1+ or MET+ deregulated NSCLC. The study confirms remarkable efficacy of crizotinib in ROS1[+] NSCLC. Responses observed in the MET cohort were of short duration confirming aggressiveness of the disease and the urgent needs for innovative therapies.

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      P1.01-053 - Italian Nivolumab Expanded Access Programme (EAP): Data from Patients with Advanced Non-Squamous NSCLC and Brain Metastases (ID 10056)

      09:30 - 16:00  |  Presenting Author(s): Lucio Crinò

      • Abstract

      Background:
      Among patients (pts) affected by non-squamous non-small cell lung cancer (non-Sq-NSCLC), those with secondary brain metastases are very common and are characterized by a poor prognosis. As they are usually excluded from clinical trials, the EAP offered an opportunity to evaluate nivolumab efficacy and safety in these patients outside of a controlled clinical trial in Italy.

      Method:
      Nivolumab was available upon physician request for pts aged ≥18 years with a diagnosis of non-Sq-NSCLC who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months. Pts included in the analysis had received ≥ 1 dose of nivolumab and were monitored for adverse events using Common Terminology Criteria for Adverse Events. Pts with brain metastasis were eligible if asymptomatic, neurologically stable and either off corticosteroids or on a stable dose or decreasing dose of ≤ 10 mg daily prednisone.

      Result:
      Out of 1588 patients with non-Sq-NSCLC participating in the EAP in Italy, 409 (26%) had asymptomatic and controlled secondary brain metastases. Pts received a median number of 7 doses (1-45) and had a median follow-up of 6.1 months (0.1-21.9). The disease control rate was 40%, including 3 pts with a complete response, 65 pts with a partial response and 96 with stable disease. Among these pts, 118 were receiving steroid therapy at baseline and 74 received concomitant radiotherapy. As of March 2017, median overall survival of this subpopulation was 8.1 months (6.2-10.1). Overall, among pts with brain metastasis, 337 discontinued treatment for any reason, with only 23 (7%) pts who discontinued treatment due to adverse events, in line with what observed in the general population and in previous studies.

      Conclusion:
      These data confirmed the activity of nivolumab in patients with non-Sq-NSCLC and brain metastases, supporting the use of nivolumab in this population with poor prognosis. Moreover, as already observed in other tumor types, safety results were consistent to what already reported and confirmed the favorable safety profile.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-007 - Circulating miRNAs as Prognostic Biomarkers in Resected Early-Stages Non-Small-Cell Lung Cancer  (ID 8965)

      09:30 - 16:00  |  Presenting Author(s): Lucio Crinò

      • Abstract

      Background:
      Non small cell lung cancer (NSCLC) is the primary cause of cancer-related death, and 5-years survival rate remains below 16% mainly because of disseminated disease, also in fully resected early stages. Biomarkers identifying patients with a higher risk of relapse could be very useful. Circulating microRNAs (miRNAs), represent promising markers in this setting.

      Method:
      A case series of 182 resected early stage (IA-IIIA) NSCLC, of which 99 adenocarcinoma (ADC) and 83 squamous cell carcinoma (SCC), was analyzed. Peripheral blood samples were collected from each patient before surgical resection and serum was obtained after centrifugation and stored at -80°C until miRNA extraction. A panel of 84 circulating miRNAs was analyzed by Real Time PCR. Data were normalized by means of an external spike in, cel-miR-39, and the mean of two most stable endogenous housekeeping chosen separately for ADC and SCC samples. miRNA expression was analyzed in relation to disease-free survival (DFS) through Cox regression model. Results are reported as hazard ratios (HRs) and 95% confidence intervals (CIs).

      Result:
      Of the 99 ADC, 45 (45.5%) had a relapse during the follow-up whereas among the 83 SCC patients, 50 relapses (60.2%) were observed. The minimum follow-up time was three years for both groups of patients. In the group of ADC patients, stage was significantly associated with DFS (HR stage II-IIIA vs stage I = 4.94 , 95% CI [2.71 - 9.02]). Multiple statistical analysis methods were used to analyze miRNA expression data. At univariate analysis, two miRNAs (miR-222-3p and miR-22-3p) were significantly associated with time to relapse (p = 0.033 and p = 0.041, respectively). The significance was not maintained after adjustment for multiple testing. In the group of SCC patients, stage of disease was significantly associated with DFS (HR stage II-IIIA vs stage I = 3.31, 95% CI [1.74 - 6.33]). Five miRNAs (let-7a-5p, miR-126-3p, miR-26a-5p, miR-130b-3p, miR-21-5p) were found significantly associated with DFS even after adjustment for multiple testing false discovery rate q-value <0.001.

      Conclusion:
      Pre-surgery circulating levels of let-7a-5p, miR-126-3p, miR-26a-5p, miR-130b-3p and miR-21-5p seem to be significantly correlated with prognosis in resected early stage SCC patients.

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    P3.07 - Immunology and Immunotherapy (ID 723)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P3.07-012 - Nivolumab Versus Docetaxel in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer and Liver Metastases (ID 8484)

      09:30 - 16:00  |  Presenting Author(s): Lucio Crinò

      • Abstract
      • Slides

      Background:
      Patients with non-small cell lung cancer (NSCLC) who have metastasis to the liver have poor prognosis. The phase 3 trials CheckMate 017 and 057 demonstrated improved overall survival (OS) and a favorable safety profile with nivolumab, an anti-programmed death-1 antibody, versus docetaxel in patients with previously treated advanced squamous and non-squamous NSCLC, respectively. A prior subgroup analysis from these trials evaluated and demonstrated efficacy and safety with nivolumab in patients with asymptomatic central nervous system metastases (Goldman J. ASCO 2016). Here we report subgroup analyses from these trials of patients with baseline liver metastases.

      Method:
      In both trials, patients were randomized 1:1 to nivolumab 3 mg/kg every 2 weeks or docetaxel 75 mg/m[2] every 3 weeks until progression or discontinuation. The primary endpoint of each study was OS. Patients from CheckMate 017 and 057 with baseline liver metastases reported as either target or non-target lesions were identified and pooled across studies by treatment.

      Result:
      Baseline characteristics were generally similar between patients with liver metastases randomized to nivolumab (n=99) and docetaxel (n=94). In the nivolumab group, 26% of patients had squamous and 74% had non-squamous NSCLC; in the docetaxel group, 36% had squamous and 64% had non-squamous NSCLC. The minimum follow-up was 24.2 months (Feb 2016 database locks). Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio [HR]=0.68; 95% confidence interval [CI]: 0.50, 0.91), similar to findings from the ITT group (HR=0.72; 95% CI: 0.62, 0.84). Median OS in patients with liver metastases was 6.83 months with nivolumab versus 5.93 months with docetaxel, both of which were lower than those observed in the overall pooled intent-to-treat (ITT) population (11.14 months vs 8.11 months). Two-year OS rates were 18% with nivolumab versus 6% with docetaxel in patients with liver metastases. Rates of grade 3−4 treatment-related adverse events in patients with liver metastases were lower with nivolumab compared with docetaxel (7% vs 53%), and similar to those in the ITT population (10% vs 55%).

      Conclusion:
      The lower median OS observed in this subgroup of patients with previously treated advanced NSCLC and baseline liver metastases corroborates previous findings that metastasis to the liver is an unfavorable prognostic factor. However, nivolumab demonstrated sustained OS benefit versus docetaxel in these patients, similar to the ITT population. The safety profile of nivolumab was favorable versus docetaxel in this subgroup, with no new safety concerns identified.

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