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Silvia Novello



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    GR 01 - What to Do at the Time of Progression on Targeted Therapy (ID 520)

    • Event: WCLC 2017
    • Type: Grand Rounds
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      GR 01.05 - First-Line Management of ALK Mutant NSCLC (ID 8119)

      11:00 - 12:30  |  Presenting Author(s): Silvia Novello

      • Abstract
      • Presentation

      Abstract:
      The identification of anaplastic lymphoma kinase (ALK) gene rearrangements as an oncogenic driver in NSCLC has radically changed the treatment of a subset of patients harboring this molecular alteration. [1] ALK mutations occur in 3-7% of NSCLCs and are more frequently associated with never/light smoker, younger age and adenocarcinoma histology. Crizotinib, an oral small-molecule multitargeted ALK/c-MET /ROS1 tyrosine kinase inhibitors, was the first-in-class agent approved from FDA for advanced, ALK-rearranged NSCLC. The accelerated approval in 2011 was granted on the basis of pronounced activity observed in early phase I and II clinical studies, coupled with a favorable toxicity-profile and concurrent development of a diagnostic test for ALK rearrangement. [2] More recently, the results from a front-line phase III trial in ALK-positive NSCLC, PROFILE 1014, revealed the superiority, in terms of progression free survival (PFS) and overall response rate (ORR), of crizotinib versus standard pemetrexed-platinum chemotherapy.[3] Based on these data, crizotinib represents standard fist- line therapy in patients with advanced ALK mutant NSCLC. [4] Despite marked and durable initial responses to crizotinib, most patients develop progressive disease after a median of 11 months, with the brain as a common site of relapse. This can be explained by pharmacokinetic limitations rather than a biologic resistance. Several acquired resistance mechanisms have been characterized, including secondary mutations in the ALK kinase domain and/or ALK copy number alterations. ALK-independent resistance mechanisms can also occur through activation of alternative bypass signaling pathways, such as EGFR activation, KIT amplification, KRAS mutation and IGF-R1 activation.[5] This evidence has prompted the development of increasingly potent, selective and brain-penetrant ALK inhibitors, with differential spectrum of activity against the most common resistance mutations. [6] Several next-generation ALK inhibitors, such as ceritinib, alectinib, brigatinib have demonstrated clinical benefit in patients with crizotinib-refractory NSCLC patients also at the central nervous system (CNS) level. This observation has supported the assessment of these drugs as frontline therapy in patients crizotinb-naïve with advanced ALK+ NSCLC.[7] Soria and colleagues have published the results of the ASCEND-4 trial, randomizing ALK+ treatment naïve patients to ceritinib or chemotherapy. Ceritinib treatment significantly has improved median PFS compared to chemotherapy (16.6 vs 8.1 months; hazard ratio [HR] 0.55,P<0.00001). This molecule was also associated with a better control of the disease in the brain (PFS 10.7 vs 6.7 months, HR 0.70, 95% CI: 0.44–1.12). Dose-limiting gastrointestinal adverse events were common with ceritinib at the starting dose of 750 mg daily and 80% of cases required dose reduction or interruption. Although ceritinib has not been compared head-to-head with crizotinib, data confirm ALK inhibitor superior efficacy compared to standard chemotherapy in the ALK-rearranged NSCLC and suggest ceritinib as another option for the front line management. [8] First Line Head to Head trials are ongoing or recently completed. Findings from J-ALEX trial, involving untreated Japanese patients with ALK-rearranged advanced NSCLC, have shown that alectinib induces longer durations of response compared to crizotinib. Median PFS exceeded 2 years in the alectinib group, compared with just over 10 months in the crizotinib group. [9] Recently, Peters et al. have presented the results of global ALEX study. Data are consistent with previous Japanese analysis: PFS was significantly improved with alectinib as compared to crizotinib (25,7 5% vs 10,4%, HR 0.5, p<0.0001). In addition, 12% of patients in alectinib arm vs 45% in crizotinib arm has experienced brain progression (cause specific HR 0.16; 95% CI, 0.10 to 0.28; P<0.001). Alectinib appeared to be better tolerated than crizotinib with grade 3 to 5 adverse events occurring in 41% vs 50% of patients, respectively.[10] Other studies with next-generation ALK inhibitors versus crizotinib—such as lorlatinib, brigatinib, are ongoing and they will help define optimal sequencing therapy for patients with ALK-rearranged NSCLC. To improve outcomes in this patient population, some studies are also currently investigating several combination strategies, including immunotherapy, anti-angiogenetic agents or radiotherapy approach in association with ALK inhibitors as shown in Table 1. Table 1

      DRUGS (dose) Clinical trial (phase) Patient Number Comparator ORR (%) PFS (mo)
      Crizotinib (250 mg twice/day) PROFILE 1014 (III) 343 Pemetrexed+platinum 74 vs45 10.9 vs 7.0
      Ceritinib (750 mg/die) ASCEND 4 (III) 376 Pemetrexed+platinum pemetrexed±maintenance 72.7vs27.3 16.6 vs 8.1*
      Alectinib (300 mg twice/day) J-ALEX (III) 207 crizotinib (250 mg twice/day) 85vs70 NEvs10.2
      Alectinib (600 mg twice/day) ALEX (III) 303 crizotinib (250 mg twice/day) 82.9vs75.5 25.7vs10.4*
      Brigatinib (90 mg/die for 7 days, 180 mg/die) ALTA 1L (III) ongoing Crizotinib (250 mg twice/day) -
      Lorlatinib (150 mg/die) NCT03052608 (III) ongoing Crizotinib (250 mg twice/day) -
      Crizotinib+Bevacizumab (250 mg twice/day; 7.5 mg/kg every 3 wks) CAMAR01 (II) ongoing _ _ _
      Crizotinib+Pembrolizumab NCT02511184 (I) ongoing _ _ _
      ORR: overall response Rate, PFS Progression free survival, NE not evaluable, *independent review committee
      Treatment paradigms continue to evolve for patients with advanced ALK-positive NSCLC subsequently to rapid development of ALK inhibitors history. It is expected that one of the next generation of ALK inhibitors will be used as first-line. In this landscape it is necessary to define the impact of first-line choice on patterns of progression and mechanisms of resistance. [11] It is uncertain if a specific sequence of therapeutic agents influences the biology of the cancer and therefore the clinical course of the patient. The spectrum of ALK resistance mutations varies according to ALK inhibitor and it is unclear if the mechanisms of resistance to these agents as the first ALK inhibitor will be similar to the mechanisms of resistance identified when they are used after crizotinib. Future efforts should be focused on determining the best treatment sequence to maximize clinical outcomes. Key factors to guide the selection of therapies could be include: molecular characteristics of the patient's tumor, different toxicity profile of different ALK inhibitors, availability of combinations/ multimodal therapy. References 1. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Soda M et al. Nature 2007; 448:561–567 2. The continuum of care for ALK-positive NSCLC: from diagnosis to new treatment options-an overview Solomon & Soria, Ann Oncol Vol 27 Supp 3 2016 3. First-line crizotinib versus chemotherapy in ALK-positive lung cancer Solomon et al N Engl J Med 2014 Dec 4;371(23):2167-77 4. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Novello S et al. Annals of Oncology 27 (Supplement 5): v1–v27, 2016 5. Crizotinib resistance: implications for therapeutic strategies. Dagogo-Jack & Shaw Ann Oncol Supp 3 2016 6. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged LungCancer. Gainor et al Cancer Discov2016Oct;6(10): 1118-1133. 7. Ascending role of next-generation ALK inhibitors. Costa. Lancet Oncol.2017 Jul; 18(7):837-839. 8. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomized, open-label, phase 3 study. Soria et al Lancet 2017; 389: 917–29 9. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomized phase 3 trial Hida et al. Lancet 2017; 390: 29–39 10. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer Peters et al for for the ALEX Trial Investigators NEJM N Engl J Med. 2017 Jun 6. 11. First-line treatment options for ALK-rearranged lung cancer. Solomon. Lancet Oncology 2017 Mar 4; 389(10072): 884-886

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    MA 19 - Mesothelioma: Bench to Bedside (ID 680)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Mesothelioma
    • Presentations: 1
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      MA 19.03 - Nintedanib + Pemetrexed/Cisplatin in Malignant Pleural Mesothelioma (MPM): Phase II Biomarker Data from the LUME‑Meso Study (ID 8111)

      11:00 - 12:30  |  Author(s): Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Background:
      Nintedanib is a triple angiokinase inhibitor. LUME-Meso (NCT01907100) is a randomised, Phase II/III study of ≤6 cycles of nintedanib+pemetrexed/cisplatin versus placebo+pemetrexed/cisplatin, followed by nintedanib or placebo maintenance, in chemo-naïve patients with MPM. In Phase II results, nintedanib+pemetrexed/cisplatin improved progression-free survival (PFS) versus control (hazard ratio [HR]=0.54; p=0.010), with a trend for prolonged overall survival (OS; HR=0.77; p=0.319). Benefit was most pronounced in patients with epithelioid tumours. Since no pharmacodynamic/predictive biomarkers are validated for anti-angiogenic therapies, exploratory analyses were conducted to investigate potential associations of plasma-derived angiogenic factors and genomic markers with treatment outcome in the LUME-Meso Phase II epithelioid population.

      Method:
      Blood samples were collected at baseline and, for patients receiving maintenance, at monotherapy Cycle 3 (C3mono) and end of monotherapy (EoTmono). Analyses focused on 58 angiogenic factors (Human AngiogenesisMAP[®] panel, Myriad RBM) and single-nucleotide polymorphisms (SNPs) in genes implicated in mesothelioma and/or associated with response to anti-angiogenic therapies in other tumour types (VEGFR1, VEGFR3 and mesothelin). Associations of biomarkers with treatment effect were evaluated by Cox regression and tested for interaction with false discovery rate (FDR) adjustment. Adjusted mean changes in angiogenic factor levels were compared between arms by ANCOVA. Analyses were exploratory, limited by small sample size, and considered hypothesis generating.

      Result:
      Of 77 patients with epithelioid tumours, angiogenic factor and genomic data were available for 71 and 67 patients, respectively. PFS/OS benefit of nintedanib appeared potentially more pronounced in patients with baseline plasma endoglin level below the median. There were possible weak associations between major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A), and OS benefit and between VEGFR1 SNP rs9582036 A/A genotype and PFS benefit. Biomarker treatment associations were limited by small subgroup size, especially for low-frequency SNPs, and interaction tests were not significant after FDR adjustment. Regarding pharmacodynamic effects, adjusted mean change in interleukin-8 levels with nintedanib was greater from baseline to C3mono and lower from C3mono until EoTmono, compared with placebo. Nintedanib showed lower adjusted mean changes versus placebo for VEGFR2 from baseline to C3mono, and for VEGFR2 and VEGFR3 from baseline to EoTmono.

      Conclusion:
      These analyses represent the first biomarker results for nintedanib-treated MPM. While there seemed to be signals for greater PFS and OS improvement in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, no biomarkers showed clear significant association with treatment benefit. These findings warrant further evaluation in the Phase III study.

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    OA 02 - Mesothelioma: Challenges For New Treatment (ID 653)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Mesothelioma
    • Presentations: 1
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      OA 02.01 - Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Malignant Pleural Mesothelioma (ID 9377)

      11:00 - 12:30  |  Author(s): Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Background:
      Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4. We report the results of a randomized phase II trial of anetumab ravtansine compared to vinorelbine in patients with advanced malignant pleural mesothelioma (MPM) who have high mesothelin expression and have progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).

      Method:
      Patients (≥18 years) with locally advanced or metastatic MPM with progressive disease following first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab, were eligible. Patients were pre-screened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. The primary efficacy endpoint was progression-free survival (PFS) per central radiologic review using modified RECIST criteria for MPM. Secondary objectives included overall survival, tumor response, and safety. Patients were randomized in a 2:1 ratio to anetumab ravtansine 6.5 mg/kg Q3W IV or vinorelbine 30 mg/m[2] QW IV.

      Result:
      A total of 166 patients were randomized to anetumab ravtansine and 82 to vinorelbine; 3 and 10 patients, respectively, not receiving treatment were included for efficacy but not safety assessments. The treatment arms were evenly balanced, with 73% male, 64% ECOG performance status 1, 96% epithelioid histology, and a mean 2.5 (±2.4) months since last progression. The median duration of treatment (anetumab vs vinorelbine) was 12.6 weeks (range 3-61) vs 13.0 weeks (range 1-43). Treatment-emergent grade (G) ≥3 adverse events (AEs) were seen in 85 (52.1%) and 53 (73.6%) of patients, respectively. G3/G4 neutropenia (22.2%/16.7%) occurred in the vinorelbine arm whereas corneal epitheliopathy (39.3% all grade, 1.8% G3) was distinct for the anetumab ravtansine arm. Serious AEs (any grade) were similar; 52 (31.9%) vs 25 (34.7%). Treatment-emergent AEs leading to dose modification were 42.9% in the anetumab ravtansine arm and 80.6% in the vinorelbine arm. There was one treatment-related G5 event in each arm. Median PFS was 4.3 months (95% CI:4.1, 5.2) for anetumab ravtansine vs 4.5 months (4.1, 5.8) for vinorelbine; hazard ratio 1.22 (0.85, 1.74), p=0.859. Fourteen (8.4%) patients in the anetumab ravtansine arm had an objective response vs 5 (6.1%) in the vinorelbine arm, with no complete responses. Interim median overall survival was 10.1 mo (7.6, -) vs 11.6 mo (7.7, 12.5), respectively, p-value 0.721.

      Conclusion:
      In relapsed MPM, anetumab ravtansine was not superior to vinorelbine with respect to PFS.

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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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      P1.01-013 - Patient-Reported Outcomes and Safety from the Phase III ALUR Study of Alectinib vs Chemotherapy in Pre-Treated ALK+ NSCLC (ID 9007)

      09:30 - 16:00  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background:
      Alectinib demonstrated superior efficacy versus chemotherapy in ALK+ NSCLC after crizotinib failure (ALUR; NCT02604342). We present PROs and safety in the ITT population and in patients with baseline CNS disease (C-ITT).

      Method:
      Patients (n=107) with pre-treated ALK+ NSCLC (randomised 2:1) received alectinib (600mg BID) or chemotherapy (pemetrexed 500mg/m[2] or docetaxel 75mg/m[2] q3w) until PD/death/withdrawal. Primary endpoint: investigator-assessed PFS. Secondary endpoints: safety and PROs. Symptoms, functioning, and HRQoL were reported using questionnaires: EORTC QLQ-C30; lung module QLQ-LC13; BN-20 (3 items, CNS symptoms). Pre-specified endpoints included time-to-deterioration (TTD) in lung cancer symptoms, longitudinal analyses of mean score changes from baseline, proportion of patients with clinically meaningful change (≥10-point change from baseline) during treatment.

      Result:
      High compliance with assessment completion (alectinib 91.7%, chemotherapy 88.6% at baseline); compliance remained ≥70% with alectinib, and decreased with chemotherapy (64.3%, Week 6; ≤70% thereafter). Deterioration of patient-reported fatigue (median TTD 2.7 vs 1.4 months) and arm/shoulder pain (median TTD 8.1 vs 1.9 months) was delayed with alectinib versus chemotherapy. Median TTD in composite symptom endpoint (cough, dyspnoea, chest-pain) was similar between arms. Alectinib patients reported improvement in lung cancer symptoms from baseline (least square [LS] mean) during treatment: fatigue (-6.2), single-item dyspnoea (-6.0), multi-item dyspnoea scale (-2.3), coughing (-4.9), chest pain (-4.2), pain in other parts (-5.3). More patients reported improvement in baseline symptoms (nausea/vomiting, diarrhoea, peripheral neuropathy) with alectinib versus chemotherapy, except constipation. More alectinib patients reported improvements in cognitive function versus chemotherapy (ITT 19% vs 3%; C-ITT 24% vs 4%); average change from baseline in cognitive function favoured alectinib (LS means difference 10.0, 95% CI 2.2–17.7). Median treatment duration: 20.1 weeks alectinib (95% CI 0.4–8.2), 6 weeks chemotherapy (95% CI 1.9–47.1). For alectinib versus chemotherapy: AEs leading to discontinuation, 5.7% vs 8.8%; dose reductions, 4.3% vs 11.8%; dose interruptions due to AEs, 18.3% vs 8.8%. AEs: 77.1% alectinib (grade 3–5, 27.1%); 85.3% chemotherapy (grade 3–5, 41.2%); one fatal AE (chemotherapy); grade ≥3 AEs: 41.2% chemotherapy versus 27.1% alectinib. TEAEs occurring in ≥10% patients: constipation (alectinib 18.6%, all grade 1–2; chemotherapy 8.8% [grade ≥3 2.9%]), nausea (alectinib 1.4%, all grade 1–2; chemotherapy 17.6% [grade ≥3 2.9%]) and fatigue (alectinib 5.7%, all grade 1–2; chemotherapy 26.5% [grade ≥3 8.8%]).

      Conclusion:
      Alectinib improved HRQoL, functioning, and symptom burden versus chemotherapy (except constipation). Safety of alectinib compared favourably to chemotherapy. Alectinib patients (ITT and C-ITT populations) derived benefit versus chemotherapy.

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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): Silvia Novello

      • 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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    P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P1.04-002 - Tolerability of Osimertinib and Its Impact on Quality of Life in Advanced Non-Small Cell Lung Cancer Patients: The ARPA Study (ID 8081)

      09:30 - 16:00  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background:
      Osimertinib is a potent Epidermal Growth Factor Receptor (EGFR) inhibitor, conferring a longer survival if compared to platinum-pemetrexed chemotherapy in Non-Small Cell Lung Cancer (NSCLC) EGFR mutated patients who have progressed after first-line Tyrosine Kinase Inhibitor (TKI), with the aquired resistance mutation T790M. The ARPA study is a phase II, single institution observational study aiming to evaluate the tolerability of Osimertinib in a real world population of EGFR-T790M+ NSCLC patients, with special attention to patients' perception of symptomatic Adverse Events (AEs), their impact on health-related quality of life (HRQoL) and psychological issues.

      Method:
      Before entry into the study, patients have been requested to perform a new tissue or liquid biopsy to confirm the T790M+ status of their tumours. Multiple previous oncologic treatments and asymptomatic brain metastases at baseline were allowed. Patients' perception of symptomatic AEs and the matched medical evaluation were performed every 21 days under continuous treatment with dedicated questionnaires which mainly evaluated the HRQoL, until discontinuation. The psychological assessments include changes in domains related to physical, mental, emotional and social functioning, depression, sleep quality and distress. In case of documented clinical benefit, the study allows to patients to remain on treatment beyond progression.

      Result:
      From February 2016, a total of 34 patients have been evaluated: 2 of them were registered as screening failures for symptomatic brain metastases and lack of compliance, respectively. The 32 patients enrolled have a median age of 67,6 years (range 40-84 years), are predominantly female (65,6%), with ECOG performance status 0 (68,7%) and a non-smoking history (75,0%). Activating EGFR mutation at diagnosis have been described on exon 19 and 21 in 62,5% and 28,1% of cases, respectively. Only four patients had brain metastases at study entry. Osimertinib has been used as second-line treatment, after failure of first-line TKI, in 78,1% of cases. On the date of 1 June 2017, ten patients have interrupted the treatment for disease progression, with a median duration of therapy equal to 6,69 months (range 2,80-11,20 months).

      Conclusion:
      Data concerning the tolerability of treatment with Osimertinib in EGFR-T790M+ NSCLC patients, their perception of symptomatic AEs together with the psychological issues evaluated in the ARPA study, are not mature. Great expectations come from this study which reflects a real world population, and the hope of the investigators is to highlight the critical aspects for patients in order to better manage their treatment and the psychological issues.

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    P2.03 - Chemotherapy/Targeted Therapy (ID 704)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P2.03-058 - Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC) (ID 8395)

      09:30 - 16:00  |  Author(s): Silvia Novello

      • Abstract

      Background:
      Rociletinib, an oral, irreversible tyrosine kinase inhibitor (TKI), selectively targets activating mutations in EGFR and the acquired resistance mutation T790M and demonstrated antitumor activity in the phase 1/2 TIGER-X study (NCT01526928). Initial results are reported from the TIGER-3 study (NCT02322281) of rociletinib vs chemotherapy in EGFR TKI-resistant patients with EGFR-mutated NSCLC.

      Method:
      Eligibility criteria included: metastatic or unresectable, locally advanced, EGFR-mutated NSCLC; radiological progression on most recent TKI therapy; ≥1 line of platinum doublet chemotherapy. Patients were not selected based on T790M status. Patients (N=900) were to be randomized (1:1:1) to rociletinib 500 or 625 mg BID or investigator’s choice of chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). The primary endpoint was investigator-assessed progression-free survival (PFS) (RECIST v1.1); objective response rate (ORR) was a secondary endpoint. The rociletinib dosing groups were combined and compared with chemotherapy in a step-down procedure (patients with a centrally confirmed T790M mutation, followed by all randomized patients).

      Result:
      TIGER-3 enrollment was halted upon discontinuation of rociletinib development in NSCLC in 2016; therefore, target enrollment was not achieved. TIGER-3 enrolled 75 patients in the rociletinib groups [500 mg BID, n=53; 625 mg BID, n=22] and 74 in the chemotherapy group. Median age was 62 years, 69.1% had ECOG Performance Status of 1, 39.6% were Asian, 58.4% were female, and median number of prior therapies was 3. PFS and ORR data are presented in the Table. The most common adverse events (all grade; grade ≥3) in the rociletinib group were diarrhea (62.7%; 2.7%), hyperglycemia (58.7%; 24.0%), nausea (37.3%; 4.0%), fatigue (37.3%; 8.0%), and decreased appetite (37.3%; 0%) and in the chemotherapy group were nausea (27.4%; 5.5%), anemia (24.7%; 2.7%), and fatigue (24.7%; 9.6%).

      Outcome Centrally Confirmed T790MPositive Centrally Confirmed T790MNegative Intent-to-Treat Population*
      Rociletinib[†] (n=25) Chemotherapy (n=20) Rociletinib[†] (n=36) Chemotherapy (n=41) Rociletinib[†] (n=75) Chemotherapy (n=73)
      Median PFS, mo (95% CI) 6.8 (3.7–12.2) 2.7 (1.3–7.0) 4.1 (2.5–4.6) 1.4 (1.3–2.7) 4.1 (2.8–5.5) 2.5 (1.4–2.9)
      HR (95% CI) 0.570 (0.285–1.140); P=0.105 0.532 (0.322–0.878); P=0.011 0.609 (0.423–0.875); P=0.006
      Confirmed ORR, n (%) [95% CI] 9 (36.0) [18.0%–57.5%] 3 (15.0) [3.2%–37.9%] 3 (8.3) [1.8%–22.5%] 2 (4.9) [0.6%–16.5%] 13 (17.3) [9.6%–27.8%] 6 (8.2) [3.1%–17.0%]
      *Includes patients with undetermined T790M mutation status. [†]Rociletinib 500 mg BID and 625 mg BID dose groups were pooled for the analysis. CI, confidence interval; HR, hazard ratio.


      Conclusion:
      Incomplete enrollment precluded hypothesis testing. However, the data show a trend toward longer PFS and higher ORR with rociletinib.

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    P2.09 - Mesothelioma (ID 710)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
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      P2.09-003 - Dissecting the Immune Environment in Malignant Pleural Mesothelioma: Results from a Prospective Assessment (ID 8256)

      09:30 - 16:00  |  Presenting Author(s): Silvia Novello

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) cells grow in the context of immune cells, either infiltrating the tumor or present in the associated pleural effusion. Specific immune cell subsets and immune-checkpoints on T-lymphocytes infiltrating the tumor have been proposed as possible prognostic factors (Uiije, DOI:10.1080/2162402X.2015.1009285; Awad, DOI:10.1158/2326-6066.CIR-16-0171) and therapeutic targets (Marcq, DOI:10.1080/2162402X.2016.1261241; Khanna, DOI: 10.1016/j.jtho.2016.07.033). The immune cells infiltrating MPM are however dynamically exchanged with those present in the pleural fluid (Lievense, DOI: 10.1016/j.lungcan.2016.04.015). The heterogeneity of tumor bulk, ranging from terminally differentiated cells to tumor-initiating cells (TIC), makes the interactions between tumor and immune cells even more jeopardized. Our study is the first that analyzes at the same time the immune-phenotype of MPM cells, immune cells infiltrating the tumor and present in the matched pleural fluid, to obtain a comprehensive signature of MPM immune-environment and precise indications for personalized immunotherapy-based interventions.

      Method:
      From June 2015 to June 2017, we collected 120 pleural fluids and biopsies from patients that undergone diagnostic thoracoscopy: 34 samples were diagnosed as MPM (25 epithelioid, 5 sarcomatoid, 4 biphasic MPM), 56 samples were reactive non neoplastic pleuritis, 30 samples were pleural localization of lung adenocarcinoma or other tumors. Cells of pleural fluids were analyzed by cell sorting and flow cytometry. Biopsies were cut and digested, and cell populations were analyzed as well. We isolated, expanded and analyzed the TIC-component from 5 epithelioid and 5 sarcomatoid MPM.

      Result:
      MPM significantly differed from non neoplastic pleuritis for the increased number of CD3[+]CD8[+]T-lymphocytes in pleural essudate coupled with the reduction of this population within the tumor (p<0.001). M2/M1-macrophages ratio was also higher (p<0.02). The increased number of T-regulatory cells and granulocytic/monocytic myeloid-derived suppressor cells in both pleural fluid and tumor significantly (p<0.005) differentiated MPM from non neoplastic pleuritis and other malignancies. Either CD3[+]CD8[+]or CD3[+]CD4[+]T-lymphocytes present in pleural fluid and infiltrating the tumor had higher expression of PD-1, LAG-3, TIM-3 immune-checkpoints (p< 0.02), coupled with increased expression of PD-1L, LAG-3, TIM-3 and GAL-9 on matched MPM (p<0.05) compared to non neoplastic pleuritis. Interestingly, immune-checkpoints were down-regulated in TIC, suggesting that immune-checkpoint inhibitors may be poorly effective against this MPM component.

      Conclusion:
      Our study identified an immune-signature that discriminates MPM from pleuritis secondary to other tumors or non malignant diseases. Such immune-signature will help to refine prognostic factors and define a precision immunotherapy for MPM.

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    P3.06 - Epidemiology/Primary Prevention/Tobacco Control and Cessation (ID 722)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
    • Presentations: 1
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      P3.06-003 - What Do the Children Think about Smoking and How Are They Helped in Prevention? (ID 8815)

      09:30 - 16:00  |  Author(s): Silvia Novello

      • Abstract

      Background:
      Despite a lot of reports on the harmful effects of smoking on health, according to DOXA (Italian Institute of Health survey, 2016), most of people smoke the first cigarette between age 15 and age 17 (56.8%). The aim of this study was to evaluate the attitudes and knowledge of school-age children about cigarette smoking

      Method:
      Within the national primary prevention campaign “Questa non me la fumo” supported and promoted by WALCE we asked to teachers to administer a dedicated questionnaire to pupils. 724 questionnaires were analyzed between September 2016 and May 2017: 365 from 9 years-old primary-school pupils and 359 from 10 years-old Primary-school pupils ( 357 male: 49.3%).

      Result:
      66% of pupils believes that a program of intervention might be useful as prevention action; however, the perception about smoke is that harms only those who smoke, improves sports performances and can help to lose weight in 28%, 1.8% and 5.1 % of cases, respectively. Among the smoking disadvantages, pupils describe bad breath (74.3%) and yellow teeth (70.1%), without reporting hair and muscle damage. 82.2% of students declare "I will never smoke", but 7.8% of them "the curiosity to try". Considering the living environment, it resulted that 44% of parents, 20% of grandparents, 21% of teachers, and 8% of peers smoke; however, most parents talk of smoking damage to their children (72%). Answers to “In your opinion, is it possible to quit smoking?” are encouraging: 76.2% responded “Yes” while “No” in 23.8% of cases. According to age, the reason "to be cool" why starting smoking was reported in 48.2% and 55%, in the fourth and firth grade of Primary school, respectively. Other reasons frequently reported were: “to imitate adults” and “to try”. When asked, “What do you think is more dangerous for you?”, “smoking a cigarette” was the most frequent (78%) among heterogeneous responses such as to travel by hitchhiking or skydiving .

      Conclusion:
      These results highlight the awareness of children about the deleterious effect of smoke on health, but areas of greatest vulnerability emerged, such as poor knowledge about the smoking effects on some parts of the body or the consequences of passive smoking. Notably, children live with adults (family and school educators) but also with peers who smoke and this is worrying if we consider that the main reason for adolescent to start smoking attitude is emulation. These data emphasize the need to implement specific prevention programs also in primary school.

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    YI 01 - Young Investigator and First Time Attendee Session (ID 588)

    • Event: WCLC 2017
    • Type: Young Investigator
    • Track: Education/Publication/Career Development
    • Presentations: 1
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      YI 01.01 - Introduction to IASLC: What It Can Do For You (ID 7845)

      08:00 - 11:30  |  Presenting Author(s): Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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