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Sara Pilotto



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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.02 - Upfront or Sequential Strategy for New Generation Anaplastic Lymphoma Kinase (ALK) Inhibitors: An Italian Retrospective Study.  (ID 12790)

      13:35 - 13:40  |  Author(s): Sara Pilotto

      • Abstract
      • Presentation
      • Slides

      Background

      Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected 242 ALK-positive advanced NSCLC diagnosed between 2010 and 2018 in 23 Italian institutions (expanded data collection from Gobbini et al. Lung Cancer 2017). 138 patients received exclusively crizotinib as ALKi (not considered for this analysis). 78 patients received crizotinib and a new (second or third) generation ALKis as further treatments (group A). 26 patients performed a new generation ALKi as upfront agent (group B). These groups are larger than those considered in a previous analysis (15 and 8 patients, respectively).

      4c3880bb027f159e801041b1021e88e8 Result

      Study population clinical features and treatments received are summarized in Table 1.

      Group A

      Crizotinib followed by new generation ALKis

      N= 78

      Group B

      Upfront new generation ALKis

      N=26

      Treatments per line n(%)

      Crizotinib

      28(36)

      50(64)

      -

      -

      -

      -

      2(8)

      -

      Alectinib

      -

      11(14)

      18(23)

      5(17)

      7(27)

      -

      -

      -

      Ceritinib

      -

      9(12)

      23(30)

      3(4)

      8(31)

      8(31)

      1(4)

      -

      Brigatinib

      -

      6(8)

      6(8)

      2(3)

      -

      2(8)

      -

      2(8)

      Lorlatinib

      -

      -

      4(5)

      5(6)

      -

      -

      1(4)

      -

      Chemotherapy

      50(64)

      2(3)

      10(13)

      na

      11(42)

      6(23)

      1(4)

      Na

      Clinical features n(%)

      Age (range)

      58 (27-83)

      55 (24-82)

      Male

      37(47)

      10(38)

      p= 0.42

      Female

      41(53)

      16(62)

      Current smoker

      8(10)

      5(19)

      p= 0.23

      Never/former smoker

      70(90)

      21(81)

      ALKi beyond PD

      27(34)

      4(15)

      p= 0.06

      With a median follow-up of 22.6 months (CI 95% 20.09-25.10), 33 patients had died (32%). In group B, the median progression free survival (PFS) for new generation ALKis administered as first (14.0 months, CI 95% 9.52-18.471), second (12.7 months, CI95% 7.22-18.17) or third-line (12.8 months, CI95% 6.24-19.35) was not statistically different (p= 0.522). The median time from the start of crizotinib to the disease progression after the new generation ALKi sequentially performed (group A) was longer than that one detected in group B for the upfront new generation ALKis (29 vs 14 months, HR 2.47 [CI95% 1.35-4.50], p=0.003). This result was confirmed even considering the time lost between the two treatments in group A. The median overall survival (OS) was not reached. The 12-months OS rate was 97% in group A and 84% in group B.

      8eea62084ca7e541d918e823422bd82e Conclusion

      New generation ALKis maintain their efficacy regardless of the treatment setting considered. The sequential strategy seems to provide a substantial benefit, but a longer follow-up and larger samples are needed to clarify the survival impact.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-15 - ROS1-Rearranged Non-Small Cell Lung Cancer Is Associated with High Rate of Venous Thromboembolism: Analysis of The METROS Trial (ID 12287)

      16:45 - 18:00  |  Author(s): Sara Pilotto

      • Abstract
      • Slides

      Background

      Patients with lung cancer are at increased risk for venous thromboembolism (VTE) and 8% to 15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE event during the course of their disease. The incidence of VTE in molecularly defined NSCLC is still unknown. However, emerging data suggests that patients harbouring ALKrearrangements are at increased risk of VTE. In light of the high amino-acid sequence and structural homology with ALK protein, we undertook this study to determine the incidence of VTE in patients with ROS1-rearranged NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The METROS trial is a multicentre prospective phase II study designed to assess efficacy, safety and tolerability of Crizotinib in pre-treated metastatic NSCLC with METamplification or METexon 14 mutation or ROS1rearrangement. ROS1-rearranged patients enrolled within cohort A and expansion cohort of the trial were evaluated in this analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 48 patients with ROS1-rearranged lung adenocarcinomas (median [range] age 50 [28-82]); 17 males [35.4%] and 31 females [64.5%]; PS 0-1 [95.8%], 2 [4.2%]; 21 current/former smokers [43.75], 27 never smokers [56.25]) , 20 (41.6%) had at least one VTE event. VTE events consisted in pulmonary embolism (PE) in 11 patients (55%), deep vein thrombosis (DVT) in 11 patients (55%), renal vein thrombosis in 2 patients (10%). Seven patients (35%) had ≥ 1 VTE event. Patients with VTE were more likely to be older than 65 years (P = 0.029). No other associations between clinical characteristics and development of VTE were observed. The occurrence of VTE was not associated with overall survival.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The incidence of VET is 3- to 5-fold higher in patients harbouring ROS1-rearrangment than previously observed for the general NSCLC population. Whether molecular profile of NSCLC should be incorporated into a risk-stratification tool and decision-making algorithm for VTE diagnosis, prophylaxis and treatment remains to be determined prospectively.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-12 - A Genomic Signature [JAK2, JAK3, PIAS4, PTPN2, STAT3, IFNAR2] Predicts Baseline Resistance to Nivolumab in Advanced NSCLC. (ID 13459)

      16:45 - 18:00  |  Presenting Author(s): Sara Pilotto

      • Abstract
      • Slides

      Background

      With the exception of PD-L1 expression for pembrolizumab, no biomarkers allow to maximize the benefit of immunotherapy in advanced pretreated non-small-cell lung cancer (AP-NSCLC). The genomic abnormalities of genes involved in immune-escape/editing are suggested as baseline mechanisms of resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective series of AP-NSCLC patients (pts) undergone Nivolumab (NIVO) was collected. FFPE-tumor blocks were analyzed to identity somatic mutations (SMs)/ copy number variations (CNVs) with a Ampliseq CGS panel (17 genes: APLNR, B2M, IFNAR1, IFNAR2, IFNGR1, IFNGR2, IRF9, JAK1, JAK2, JAK3, PIAS4, PTPN2, SOCS1, STAT1, STAT2, STAT3 and TYK2). End-points were overall-, progression-free-survival (OS/PFS) and objective response rate (ORR).

      4c3880bb027f159e801041b1021e88e8 Result

      Data from 24 consecutive AP-NSCLC pts who received NIVO were gathered (median age 69.5 yrs, median number of previous lines 3 [2-5], 2nd line NIVO [70.8%], median follow-up 6.8 months [range 1-23], deaths 14 [58.3%], male/female 79.2/20.8%, squamous/non-squamous 41.7/58.3%, EGFR mutant 5 [20.8%]). ORR (partial) was obtained in 4 pts (16.6%, 95% CI 1.7-31.6%), with stable- and progressive-disease in 5 (20.8%, 95% CI 4.5-37.1%) and 15 (62.5, 95% CI 43.1-81.8%) pts, respectively. JAK3/JAK2 (6/3 pts, 25/12.5%) CNVs, and IFNAR2/STAT3 SMs (2 pts, 8.3%) were the most frequent (>1 pts) abnormalities. The 12 pts with JAK3, PIAS4, PTPN2, STAT3, IFNAR2 and JAK2/3 SMs/CNVs had a significantly lower median OS (4 months, 95% CI 1-8) and PFS (3 months, 95% CI 2-3.5) than the other 12 pts wild-type/other alterations (median OS 13 months, n.e.; median PFS 6 months 95% CI 5-9) [p=0.046 for OS, p=0.002 for PFS]. No objective responses were observed in the pts’ subgroup harboring the gene signature (p=0.09). At multivariate analysis, the genomic signature was independently associated with shorter OS (HR 2.20 95% CI 1.21-4.06, p=0.01) and PFS (HR 6.1 95% CI 2-18.7, p=0.001). No significant correlation between EGFR mutations and outcome was found.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Despite the small sample, the customized gene sequencing of few genes involved in immune-escape/editing is able to identify a pts’ subgroup of AP-NSCLC who appears to derive a lower benefit from NIVO, supporting intrinsic resistance. A larger prospective validation is planned.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.08 - Oligometastatic NSCLC (Not CME Accredited Session) (ID 974)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.08-04 - OMEGA, A Randomized Trial of Local Ablative Therapy Vs. Conventional Treatment in Oligometastatic NSCLC – Trial in Progress (ID 13971)

      12:00 - 13:30  |  Author(s): Sara Pilotto

      • Abstract
      • Slides

      Background

      A recent randomized phase 2 study has shown that local ablative therapy in addition to systemic treatment was superior to maintenance therapy in prolonging disease-free survival in NSCLC patients harboring up to three metastatic sites.

      Oligometastatic lung cancer (OM-NSCLC) seems thus to be associated with a better prognosis than usual Stage IV non-small cell lung cancer when radical local therapy of all metastatic sites is administered but the impact of such an approach on overall survival and quality of life remains unclear

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A consortium of tertiary referral centres involved in Lung Cancer management at the national level was established with the aim of setting up a randomized trial addressing this issue

      4c3880bb027f159e801041b1021e88e8 Result

      A randomized trial of local ablative therapy in OM-NSCLC patients with potentially resectable or locally controlled primary tumors has been designed and 7 tertiary referral centers agreed to participate

      Patients with synchronous or metachronous oligometastatic lung cancer (1-3 metastatic lesions) will be randomized to local ablative therapy + standard treatment Vs. standard treatment.

      Balancing between study arms will be performed according to synchronous vs. metachronous presentation, Number of oligometastases, Nodal status and Oncogene-addiction or PDL-1 expression.

      Primary outcome will be Overall Survival (OS) from randomization. The sample size is set to 195 patients.

      Inclusion criteria include adequate performance status, primary tumor controlled or controllable staging with whole-body FDG PET scan and brain MRI, fit to receive at least 3 cycles of platinum-based doublet chemotherapy, or immunotherapy or targeted agents according to molecular profile.

      Exclusion criteria include cerebral oligometastasis alone (will receive local therapy in any case),

      metastasis in sites where normal radiotherapy constraints cannot be met, multiple subsolid nodules in the absence of extrapulmonary metastasis, prior malignant tumor with some exceptions, relevant co-morbidities that would significantly reduce life expectancy on their own,

      Disease state and life status assessed on a 2-monthly basis by physical examination, whole-body CT scan plus repeat PET-scan if needed and Brain MRI if brain metastasis at enrolment. Toxicity and adverse events will be assessed according to NCI-Common Terminology Criteria. Quality of life will be assessed at randomization and after six months by the SF36/LCSS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is a clear need for randomized controlled trials with overall survival as their main endpoint to confirm whether local ablative therapy indeed has a role in the management of oligometastatic lung cancer. The Omega trial will try to respond to such a need.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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