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Paolo Bironzo



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    MS13 - Immunotherapy for Mesothelioma (ID 76)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MS13.06 - Role of Second Line Chemotherapy and New Target Treatment in Recurrent Mesothelioma (Now Available) (ID 3517)

      11:30 - 13:00  |  Author(s): Paolo Bironzo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant pleural mesothelioma (MPM) is a highly lethal disease, with a median overall survival (OS) between 12 and 18 months. Following first-line treatment, neither chemotherapy nor target treatments have clearly shown to increase overall survival (OS), to date. Historically, second-line cytoxic drugs, such as gemcitabine and vinorelbine have been the backbone in pre-treated patients, with response rates ranging from 7% to 16% [Zucali PA, Perrino M, Lorenzi E, et al. Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Lung Cancer 2014; 84:265-270; Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009; 63:94-97; van Meerbeck JP, Baas P, Debruyne C, et al. A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organisation for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 1999;85(12):2577-2582]. Pemetrexed rechallenge was assessed in small retrospective studies, suggesting its role, especially when combined with platinum compounds, in selected patients with a pemetrexed-free interval of at least 3 to 6 months [Zucali PA, Simonelli M, Michetti G, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung cancer 2012; 75: 360-367]. “Omics” studies have enlarged our knowledge of MPM, describing high prevalence of TP53, NF2, BAP1 and cyclin dependent kinase inhibitor 2A (CDKN2A) mutations, along with the lack of tyrosine receptor kinase (TRK) activating mutations [Lo Iacono M, Monica V, Righi L, et al. Targeted next-generation sequencing of cancer genes in advanced malignant pleural mesothelioma: a retrospective study.J Thorac Oncol 2015;10(3):492-9]. For this reason, the development of target treatment approaches in MPM has been more difficult and slower as compared to non-small-cell lung cancer (NSCLC), for example. However, many drugs have been tested, while others are currently under evaluation. Among the first studied agents, mTOR inhibitors failed to show activity in pre-treated MPM patients [Ou SH, Moon J, Garland LL, et al.SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). J Thorac Oncol 2015;10(2):387-91]. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is upregulated in MPM with BAP1 inactivation and its inhibition showed to be syntethic lethal in BAP1-negative tumors. The EZH2 inhibitor tazemetostat demonstrated a 51% disease control rate (DCR) in 74 MPM patients (95% with BAP1 inactivation) enrolled in a phase 2 study [Zauderer MG, Szlosarek P, Le Moulec S, et al. Phase 2, multicenter study of the EZH2 inhibitor tazemetostat as monotherapy in adults with relapsed or refrectory (R/R) malignant mesothelioma (MM) with BAP1 inactivation. J Clin Oncol 36, 2018 (suppl.abstr 8515)]. As BAP1 loss leads to homologous repair deficiency, PARP inhibitors are currently being tested in this subgroup [NCT03531840; NCT03207347; NCT03654833]. Neurofibromin 2 (NF2) inactivation, which encodes for merlin, has been proposed to be synthetic lethal to focal adhesion kinase (FAK) inhibition. However, the COMMAND trial, exploring the use of the FAK inhibitor defactinib as a maintenance treatment after first-line chemotherapy in MPM patients stratified for merlin expression, failed to show any improvement as compared to placebo [Fennell DA, Baas P, Taylor P, et al. Maintenance defactinib versus placebo after first-line chemotherapy in patients with merlin-stratified pleural mesothelioma: COMMAND-a double-blind, randomized, phase II study. J Clin Oncol 2019;37(10):790-798]. Defactinib is currently under investigation in combination with anti programmed-death 1 (PD-1) monoclonal antibody pembrolizumab in a phase I/IIA clinical trial enrolling pretreated MPM patients along with pancreatic cancer and NSCLC ones [NCT02758587]. The identification of argininosuccinate synthetase 1 (ASS1) loss in MPM, leading to arginine auxotrophy, paved the way to the use of the arginine depletor pegylated adenosine deiminase ADI-PEG20 in a phase 2 randomized trial in 70 ASS1-deficient patients [Szlosarek PW, Steele JP, Nolan L, et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol 2017;3(1):58-66]. Among the 68 treated patients, the drug improved progression free survival (PFS) as compared to best supportive care (BSC) (HR 0.56, 95% CI, 0-33-0.96), although by only 1.2 months (median PFS 3.2 vs 2.0 months for ADI-PEG20 and BSC, respectively; p=0.03). Currently, ADA-PEG20 is being explored in combination with first-line chemotherapy in biphasic and sarcomatous MPM only [NCT02709512]. Recent studies described novel prognostic MPM subsets with specific genomic characteristics that could further shape personalized treatment approaches, especially when looking at immunotherapic approaches [Hmljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov 2018;8(12):1548-1565]. Indeed, the high expression of V-domain immunoglobulin suppressor of T-cell activation (VISTA) negative immune-checkpoint in epithelioid MPM reported in this study, suggests a possible of role of specific inhibitors alone or in combination with other agents in advanced MPM.

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA07.07 - Quality of Life (QoL) Analysis in Lung Cancer: A Systematic Review of Phase III Trials Published Between 2012 and 2018 (Now Available) (ID 1958)

      11:00 - 12:30  |  Author(s): Paolo Bironzo

      • Abstract
      • Presentation
      • Slides

      Background

      We previously reported that QoL is not included among endpoints and QoL results are underreported in a high proportion of phase III trials in oncology. Here we describe QoL prevalence and heterogeneity in QoL reporting in lung cancer phase III trials.

      Method

      We selected all primary publications of lung cancer phase III trials evaluating anticancer drugs published between 2012 and 2018 by 11 major journals. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis.

      Result

      122 publications were identified. In 39 (32.0%) publications, QoL was not listed among endpoints: 10/17 (58.8%) early stage/locally advanced NSCLC, 15/54 (27.8%) first-line of advanced NSCLC; 10/41 (24.4%) second and further lines of advanced NSCLC, 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. QoL was not listed among endpoints in primary publication in 16/80 (20.0%) for-profit trials vs. 23/42 (54.8%) no-profit trials. Out of 83 trials including QoL among endpoints, QoL results were not reported in 36 primary publications (43.4%). Proportion of trials not reporting QoL results in primary publication significantly increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p=0.005). Overall, QoL data were not available in 65/122 (61.5%) primary publications, due to the absence as endpoint or unpublished results. QoL data were not available in primary publication in 48/80 (60.0%) for-profit trials vs. 27/42 (64.3%) no-profit trials. QoL data were lacking in 48/78 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement in time to publication comparing 2012-2015 vs. 2016-2018. Out of 83 trials including QoL, most common tools were EORTC QLQ-C30 (42, 50.6%); EORTC LC13 (39, 47.0%); EQ-5D (37, 44.6%); LCSS (19, 22.9%); FACT-L (15, 18.1%). Out of 58 trials with available results, common methods of analysis were mean scores or changes (45, 77.6%), time to deterioration (31, 53.4%) and proportion of responders (19, 32.8%). Availability of a secondary QoL publication allowed a higher number of methods of QoL analysis (p<0.001).

      Conclusion

      QoL is not assessed in a high proportion of phase III trials evaluating lung cancer patients, a setting where attention to QoL should be particularly high, due to symptoms and limited life expectancy. Furthermore, the timely inclusion of QoL results in primary publications is worsening in recent years. Secondary publications allow a more complete description of QoL results, but imply a delay in their availability.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-74 - Clinical-Pathological Features and Outcome of Patients with Oral Metastases from Lung Cancer: A Multicenter Retrospective Study (ID 2701)

      10:15 - 18:15  |  Author(s): Paolo Bironzo

      • Abstract
      • Slides

      Background

      Oral metastases are a rare event, accounting to less than 1% of all oral malignancies, sometimes being the first manifestation of a wide-spread disease. Regardless of the site of the primary tumor, patients with oral metastases have a poor prognosis, with a reported median overall survival (mOS) of 6 months. Lung cancer, particularly small cell lung cancer (SCLC) and poorly differentiated carcinoma, represents the main source of oral metastases, even if large datasets still lack. We conducted a multicenter retrospective study investigating incidence, clinical-pathological features and outcome of patients with oral metastases from lung cancer.

      Method

      Between January 2014 and December 2018 we collected data from all consecutive patients diagnosed with lung cancer in four oncological Italian centers. Clinical-pathological features of those patients with oral metastases involving jaw or/and soft tissues were described.

      Result

      Among 4,082 consecutive lung cancer patients, the incidence of oral cavity metastases was 0.15% (6 out of 4,082 patients,). Patients were more frequently male (5 out of 6, 83%), current or former smokers (5 out of 6, 83%), with a median age at diagnosis of 61 years (range 53-69) [table 1]. Four different histotypes of lung cancer were detected. Five patients (83%) were stage IV ab initio, with synchronous histologically confirmed oral metastases. All these patients had distant metastases other than in the oral cavity (median of 5 different metastatic sites). The mOS since the diagnosis of oral metastases was 67 days (range 36-166).

      Table 1. Patient characteristics

      Gender

      Age (years)

      Smoke

      Histotype

      N° metastatic sites

      Site of oral lesion

      Time between stage IV diagnosis and oral lesion occurrence

      Local radiotherapy

      Median OS from oral lesion occurrence (days)

      M

      69

      Current

      Poorly differentiated

      4

      Jaw

      Syncronous

      Yes

      57

      M

      61

      Current

      Sarcomatoid

      5

      Jaw

      Syncronous

      Yes

      107

      M

      61

      Former

      Adenocarcinoma

      3

      Gum

      11 months

      Yes

      77

      M

      53

      Former

      Poorly differentiated

      4

      Gum

      Syncronous

      No

      44

      M

      59

      Current

      SCLC

      5

      Gum

      Syncronous

      No

      36

      F

      66

      Unknown

      Squamous (mut ex 19 EGFR)

      5

      Gum

      Syncronous

      No

      166

      Conclusion

      To our knowledge, this is the largest study assessing the incidence of oral metastases in lung cancer patients. Oral involvement, usually diagnosed at an advanced stage, seems to be associated with a very poor prognosis, with a mOS of about 2 months. Further confirmatory datasets are warranted.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-15 - Association Between Opioids and Outcome of 1st Line Immunotherapy in Advanced NSCLC Patients: A Retrospective Evaluation (Now Available) (ID 2428)

      10:15 - 18:15  |  Author(s): Paolo Bironzo

      • Abstract
      • Slides

      Background

      Opioids represent the pharmacological backbone of cancer-related pain treatment. However, preclinical studies suggest that opioids can cause immunosuppression. Recently, immune checkpoint inhibitors (ICIs) have become available for treatment of patients with advanced NSCLC. With this study we aimed at retrospectively evaluate the impact of chronic opioid treatment on the outcome of advanced NSCLC (aNSCLC) patients treated with first-line ICIs.

      Method

      We retrospectively reviewed the records of aNSCLC patients treated with anti-programmed-death-1 (PD-1) or its ligand (PD-L1) single-agent ICIs in 2 Italian institutions. We included all patients with enough follow-up to have at least one radiological evaluation during ICIs treatment. Patients with rapid clinical progression were included in the analysis. We analyzed response rate (RR), progression-free survival (PFS), and overall survival (OS). Response was evaluated using RECIST v1.1 criteria.

      Result

      75 patients were found, 64 included in the analysis. Mean age at diagnosis was 66.5 years (range 37-84), 65% were male. Histological type were: 76.5% adenocarcinoma, 14% squamous, 9.5% others, most with high PD-L1 expression (90.5% with ≥50% TPS). 58 patients (90.6%) were stage IV at ICIs start, with mean number of metastatic sites 1.8. Most patients were current/former smokers (87.5%); ECOG performance status (PS) at ICI start was: 0 in 34 pts (53.1%), 1 in 25 (39%), 2 in 5 (7.9%). 20 patients were receiving opioids at ICIs start (31.3%), with a mean daily dose equal to 59 mg of oral controlled-release morphine. With a median follow-up of 10.9 months, the median number of ICIs cycles was 7.5 (range 1-26). RR, mPFS and mOS in the whole series were 40.6%, 9.4 months and 17.1 months, respectively. Compared to the others, patients receiving opioids had numerically lower RR (30% vs 45.5%, p=0.24), a shorter PFS (median 12.7 vs 1.7 months, Hazard Ratio [HR] 4.16, 95%CI 2.15-8.05, p<0.001) and OS (median not reached vs 3.2 months, HR 4.68, 95%CI 2.09-10.52, p<0.001). At the multivariate analysis, opioid use continued to be significantly associated with worst PFS (HR 3.19, 95%CI 1.45-7.01, p=0.004) and OS (HR 4.16, 95%CI 1.61-10.76, p=0.003), even when accounting for PS, disease stage and number of metastatic sites.

      Conclusion

      Our results suggest a possible detrimental effect of opioids in aNSCLC patients treated with first line single-agent ICIs, even when correcting for other prognostic factors. However, due to the short follow-up, the small number of patients, and the lack of a control group, our results should be considered exploratory.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-18 - Lymphocyte Infiltration Pattern and STING Expression Identify Different Prognostic Groups in Early Stage NSCLC (ID 2536)

      10:15 - 18:15  |  Author(s): Paolo Bironzo

      • Abstract
      • Slides

      Background

      Lymphocyte infiltration has been described has a potential biomarker of lung cancer patients’ survival. Different studies de-convoluted immune cell compartment (i.e. stromal CD8 density) trying to identify clinically relevant immune patterns.

      Method

      A series of 178 early-stage (IB-IIIA) NSCLC has been retrospectively collected at Department of Oncology, San Luigi Hospital (Orbassano, Italy). From Formalin-Fixed and Paraffine-Embedeed (FFPE) tumor blocks, Tissue Microarrays (TMA) were constructed (4 cores were selected for each case). Lymphocyte infiltration pattern was determined by light-microscopy on Hemathoxylin-Eosin (HE) whole slides. Immunohistochemistry was performed as follow: CD8 (SP57) and STING (D2P2F) antibodies were tested with Ventana Benchmark and PD-L1 (22C3) with Dako Autostainer. Infiltration pattern has been clustered in 4 different categories: brisk-diffuse, non-brisk multifocal, non-brisk focal and none. CD8 was quantified as positivity percentage, PD-L1 through TPS (<1%, 1-49% and ≥50%) and STING taking advantage of H-score. Overall survival (OS) and Progression Free Survival (PFS) were estimated using the Kaplan-Meier method and compared using log-rank test.

      Result

      Most represented patients had following features: male (119-71%), current or previous smokers (145-82%), stage II (94-53%) and adenocarcinoma histology (119-67%). Distribution of lymphocyte infiltration pattern was: 110 cases with brisk-diffuse (62%), 56 with non-brisk (multi-focal and focal) (31%) and 12 with none pattern (7%). CD8 positivity was distributed in 3 categories: high (66 - 37%), intermediate (75 - 42%) and low (37 -21%) density. For PD-L1 TPS analyses 111 cases (62%) had <1%, 39 cases (22%) 1-49% and 28 cases (16%) >50%. STING high-expressors were 88 (49%) and low-expressors 90 cases (51%). Lastly, were identified 81 samples (45%) with STING positivity at high-density on immune cells (IC) and 97 samples (55%) with low-density. As expected, Brisk-infiltrated samples presented an higher CD8 density (p=0.015). At PFS analyses, STING IC resulted associated (p=0.05) with a worse PFS for high-density patients. At OS analyses, brisk lymphocyte infiltration pattern appeared to have a negative impact (p=0.05) and STING higher-expressors on tumor cells had a worse prognosis (p=0.04).

      Conclusion

      NSCLC with wider lymphocyte infiltration and expression of immune activation markers (as STING) appeared to be associated with a worse prognosis (PFS and OS). These date need further validation at multivariate analyses.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-17 - Correlation Between Clinic-Pathological Data and T790M Detection in EGFR Mutated NSCLC Patients Progressing on 1st/2nd Generation TKIs (Now Available) (ID 2442)

      10:15 - 18:15  |  Author(s): Paolo Bironzo

      • Abstract
      • Slides

      Background

      Despite osimertinib is moving to the first-line for advanced NSCLC harboring EGFR activating mutations, some patients still receive a frontline first- or second-generation EGFR-TKI. In this setting, factors predicting the emergence of T790M resistance mutation at progression (PD) are lacking. The aim of this retrospective study was to investigate the correlations between clinic-pathological features and T790M positivity (T790M+) in a single-center cohort of EGFR mutated stage IV or recurrent NSCLC patients, who underwent liquid (LB) or tissue biopsy (TB) at PD when treated with first- or second-generation EGFR-TKIs.

      Method

      Data from 122 patients (80 female, 42 male) treated between 2012 and 2019 were considered for the analysis. EGFR mutations were detected with real time-polymerase chain reaction (RT-PCR) on LB and pyrosequencing or next generation sequencing on TB. PD was determined by RECIST 1.1 criteria. Univariate analysis by Fisher exact test was performed to assess any association.

      Result

      At diagnosis, 117 patients carried common EGFR mutations (84 exon 19 deletions; 33 exon 21 mutations), 5 had rare mutations (3 exon 18 mutations; 2 exon 20 mutations other than T790M) . At PD, 29 patients (24%) underwent only LB, 29 only TB (24%), 64 both (52%). The overall T790M+ rate was 67% (82/122). T790M+ was significantly higher among patients with exon 19 deletion than in those with exon 21 mutation (77% vs 51%, p=0.008). T790M+ was significantly more frequent in patients with exclusively intrathoracic PD as compared to extrathoracic PD (81% vs 56%, p=0.007). Patients with pleural involvement (PI), considered as pleural effusion or/and pleural disease, as site of PD (n=45) had a significantly higher frequency of T790M+ than those with stable or absent PI (n=77) (82% vs 58%, p=0.009), irrespectively of the pattern of PD. No correlation with other sites of PD was found.

      Conclusion

      Exon 19 deletion, intrathoracic PD and PI as site of PD are significantly associated with higher frequency of T790M+ in patients progressing to first-or second-generationEGFR-TKIs. These results, if confirmed by an independent validation cohort, may allow the development of a T790M+ predictive score accounting for type of mutation and sites of progression.

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