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Giovanni Randon



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    MA03 - Clinomics and Genomics (ID 119)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA03.10 - Prospective Evaluation of a Prognostic Clinico-Molecular Score (DEMo) to Predict Outcome of Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 1378)

      10:30 - 12:00  |  Author(s): Giovanni Randon

      • Abstract
      • Presentation
      • Slides

      Background

      We have already reported three different molecular (MSC: plasma miRNA-signature classifier, Boeri, Clin Cancer Res 2019) and clinico-biochemical scores (DiMaio: Di Maio, EJC 2010; EPSILoN: Ann.Onco 2018 supp) able to differently predict prognosis in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy (IO). Exploiting the ability of each test we developed a combined clinico-biological composite score called DEMo (DiMaio EPSILoN MSC). Objective of the study is to prospectively evaluate the prognostic value of DEMo in aNSCLC patients treated with IO.

      Method

      We enrolled 127 consecutive aNSCLC patients treated with IO in first (n=37) and further-lines (n=90) at Istituto Nazionale dei Tumori, Milan. All patients had complete clinico-laboratoristic data necessary for both scores: DiMaio (ECOG-PS, sex, histology, stage, uses of platinum-based therapy at first-line and response to first-line) and EPSILoN (ECOG-PS, Smoke, Liver, LDH, NLRatio). MSC was prospectively evaluated in plasma samples collected prior starting IO and the risk level were assessed. Progression-free survival (PFS) and overall survival (OS) in strata of MSC/DiMaio/EPSILoN alone or DEMo and overall response rate (ORR), were considered as endpoints. Kaplan Meier were used to generate survival curves and Cox hazard model were employed to perform multivariate analyses.

      Result

      In multivariate analyses, adjusted for age, sex, pack/year and ECOG-PS, patients with high MSC and high DiMaio and EPSILoN scores reported a lower PFS (MSC: HR 1.72 CI95% 1.06 – 2.77, p=0.027; DiMaio: HR 2.63 CI95% 1.40 – 5.00, p=0.002; EPSILoN: HR 2.17 CI95% 1.16 – 4.16, p=0.014) and OS (MSC: HR 2.17 CI95% 1.29 – 3.70, p=0.003; DiMaio: HR 3.57 CI95% 1.66 – 7.69, p=0.001; EPSILoN: HR 2.50 CI95% 1.15 – 5.26, p=0.020). DEMo stratified patients into four risk groups according to the presence of 3–2–1–0 bad markers (High MSC/DiMaio/EPSILoN or none). Groups had 0%–0%–32.2%–53.3% 1-year PFS (p<0.0001) and 4.4%– 19.4% – 66.9% – 75.4% 1-year OS (p<0.0001). We further compared 0/1 to 2/3 combined groups. At the multivariate Cox model group 2/3 had a mPFS 1.9 vs 9.4 mo compared to group 0/1 (HR 3.70 CI95% 2.08 – 6.67, p<0.0001) and mOS 4.1 vs 22.4 mo (HR 4.76 CI95% 2.56 – 9.10, p<0.0001). Regarding ORR, DEMo group 0/1 had a 3.86 (CI95% 1.76-8.47) fold higher probability to respond compare to 2/3 group (p=0.0007).

      Conclusion

      DEMo composite biomarker is able to predict better prognosis compared to each single score and can be a useful tool for guiding IO treatment choices. In particular, DEMo allowed a good selection for those patients who are less likely to benefit from IO.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-135 - Salvage Chemotherapy After Immunotherapy Failure in Non-Small-Cell Lung Cancer Patients (Now Available) (ID 2490)

      09:45 - 18:00  |  Author(s): Giovanni Randon

      • Abstract
      • Slides

      Background

      Objective response rate (ORR) to salvage chemotherapy (sCT) in non-small-cell lung cancer (NSCLC) patients failing upfront platinum-based doublets is limited (≈5-15%). Recently, unexpected favorable outcomes have been reported for sCT upon progression to immune checkpoint inhibitors (ICIs) as compared to historical data, with ORR observed in up to 53% and 27% in Asian and Caucasian patients respectively. Few data are available regarding prior response to ICIs and sCT performance, especially in Caucasian patients.

      Method

      All consecutive patients with advanced NSCLC who started ICIs at our institution from Apr 2013 to Dec 2018 were retrospectively reviewed. Patients who underwent sCT after progression to ICIs and had at least one radiological response assessment were included. ORR was calculated as the percentage of complete or partial responses according to RECIST 1.1 as best response. Survivals were estimated with Kaplan-Meier method. Correlation was assessed using Spearman’s test.

      Result

      Out of 283 patients included, 43 received sCT after ICIs. Among them, 29 (67%) had adenocarcinoma and 14 (37%) squamous cell carcinoma. 11 (26%) patients received sCT as second line therapy and 32 (74%) as third or more advanced treatment. sCT regimens included platinum based doublets (14; 32.5%), docetaxel or paclitaxel (20; 46.5%), and other monotherapies such as gemcitabine or vinorelbine (9; 21%). ORR to sCT was 30%. Median progression free survival and overall survival were 3.6 and 8.4 months, respectively. All patients receiving taxanes as sCT had already been treated with platinum based therapy and their ORR to sCT was 40%. ORR to upfront chemotherapy was 50%, while ORR to the last chemotherapeutic regimen prior to ICIs was 35%. ORR to sCT in pretreated patients was non-inferior to that observed in chemo-naïve ones (31% and 27%, respectively). High ORR (25%) was observed even in patients receiving sCT beyond third line. Neither response to ICIs (P=0.36) nor to prior chemotherapeutic regimens (P>0.05) were associated to the likelihood of achieving tumor response to sCT.

      Conclusion

      We provide further evidence that NSCLC patients progressing to ICIs might still benefit from sCT even if heavily pretreated, regardless of sensitivity to ICIs or previous chemotherapy regimens. Further investigations are needed for uncovering bases of increased sensitivity to genotoxic agents in patients with innate or acquired resistance to ICIs and exploiting optimal treatment sequence.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-38 - Efficacy and Safety of Immunotherapy in Elderly Patients with Non-Small Cell Lung Cancer (Now Available) (ID 1383)

      09:45 - 18:00  |  Author(s): Giovanni Randon

      • Abstract
      • Slides

      Background

      Most trials with Immune Checkpoint Inhibitors (ICIs) for Non-Small Cell Lung Cancer (NSCLC) included only small subgroups of patients (pts) aged ≥65. As NSCLC is often diagnosed in pts aged ≥70, real-world data about efficacy and safety of IO in elderly pts are essential.

      Method

      We retrospectively collected data about all pts with advanced NSCLC treated with IO at our Institution between April 2013 and March 2019. All ICIs administered for ≥1 cycle were admitted. Pts were stratified for age as follows: <70 year-old (yo), 70-79 yo, ≥80 yo. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox model.

      Result

      We reviewed 290 cases, with a median age of 67 (range: 29-89). Pts aged<70, 70-79 and ≥80 yo were 180, 94 and 16, respectively. Two hundred five pts received an anti-PD1, 77 an anti-PDL1, 8 an anti-CTLA4 or a combo-IO. Clinical/pathological variables were uniformly distributed across age classes, except for a higher rate of males (p 0.0228) and squamous histology (p 0.0071) in the intermediate class. Response Rate (RR) was similar across age groups (21.5% vs 22.3% vs 18.8% for pts aged<70 vs 70-79 vs ≥80 yo, respectively; p 0.9470). Median PFS did not differ according to age (2.8 vs 3.5 vs 2.6 mos for pts aged<70 vs 70-79 vs ≥80 yo, respectively; p 0.2020). Similarly, median OS was similar across age classes (9.1 vs 11.3 vs 9.6 mos for pts aged<70 vs 70-79 vs ≥80 yo, respectively; p 0.9144). These results did not change after stratification for sex (p 0.516 for PFS, p 0.5154 for OS) and histology (p 0.9057 for PFS, p 0.1002 for OS). The incidence of toxicity was comparable across subgroups (grade ≥2 adverse events in 35.8% vs 32.7% vs 37.5% for pts aged<70 vs 70-79 vs ≥80 yo, p 0.6493). The only variables influencing outcome at both univariate and multivariate analyses were performance status (p<0.0001 for PFS, p 0.0192 for OS), number of metastatic sites (p 0.0842 for PFS, p 0.0235 for OS) and IO line (p<0.0001 for both PFS and OS), regardless age group.

      Conclusion

      Advanced age is apparently not associated to a reduced efficacy of IO in our case series. Furthermore, no toxicity concern emerges even among the eldest pts. Therefore, to our opinion ICIs should be considered irrespective of age, provided an optimal PS at baseline. Of note, IO is often the only therapeutic option applicable to these cases considering the toxicity of chemotherapy.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-05 - Clinical and Biological Characterization of Lung Enteric Adenocarcinoma (Now Available) (ID 1650)

      10:15 - 18:15  |  Author(s): Giovanni Randon

      • Abstract
      • Slides

      Background

      Lung Enteric Adenocarcinoma (LEA) is a rare and poorly characterized variant of Lung Adenocarcinoma (LA), defined by an intestinal differentiation in ≥50% of tumor and ≥1 colorectal biomarker at Immunohistochemistry.

      Method

      We retrospectively identified the cases of LEA diagnosed at Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy between 01/2013 and 12/2018. Next Generation Sequencing was performed with IonTorrent (ThermoFisher Scientific, Life Technologies) by using the commercial Hot Spot Cancer Panel (HCP) on DNA derived from formalin-fixed paraffin-embedded tissues. ALK and ROS-1 status was assessed with fluorescent in situ hybridization. PD-L1 expression was determined with DAKO22C3 assay. Biological data obtained from our cases were compared with those reported in Tumor Cancer Genome Atlas (TCGA) for LA, restricting the comparison only to the genes targeted by HCP.

      Result

      We identified 38 LEA cases. Main clinical and biological characteristics of the two populations are detailed in the table.

      Variable/

      gene mutation

      INT LEA (N=38)

      TCGA LA (N=660)

      %

      %

      Gender

      Female

      34.1

      51.9

      Male

      65.9

      47.9

      Unknown

      0

      0.2

      Smoking status

      Former/current

      76.3

      78.9

      Never

      15.8

      14.1

      Unknown

      7.9

      7.0

      Disease stage

      I

      2.6

      51.6

      II

      2.6

      23.0

      III

      28.9

      16.4

      IV

      65.9

      4.7

      Unknown

      0

      4.3

      TP53

      52.6

      54.1

      KRAS

      34.2

      32.4

      STK11

      23.7

      15.8

      CDKN2A

      15.8

      3.9

      APC

      7.9

      4.8

      CTNNB1

      7.9

      3.8

      EGFR

      7.9

      15.8

      KIT

      5.3

      2.1

      PI3KCA

      5.3

      5.9

      SMAD4

      5.3

      4.1

      ATM

      2.6

      8.9

      BRAF

      2.6

      8.2

      FGFR

      2.6

      0.8

      GNAS

      2.6

      3.8

      NRAS

      2.6

      0.6

      PDGFRA

      2.6

      7.4

      RB1

      2.6

      5.8

      SMO

      2.6

      2.7

      Neither ALK nor ROS-1 rearrangements were detected in our case series. PD-L1 was negative in 23 cases, 1-49% in 9 cases, not evaluable in 6 cases. Microsatellite were stable except for 3 cases with low instability and 3 not evaluable cases.

      Conclusion

      Our series of LEA was small and differed from TCGA LA for a higher proportions of males and metastatic disease. Given these limitations, our LEA genetic profile showed some difference from that of TCGA LA. In particular, LEA showed a higher incidence of STK11, CTNNB1, FGFR, NRAS, KIT and CDKN2A mutations, and a lower incidence of ATM, BRAF, PDGFRA, RB-1 and EGFR mutations. PD-L1 expression, ALK and ROS-1 rearrangements were lower than literature data in LA. Most cases were microsatellite stable. In conclusion, further research is needed to understand the biology of LEA, which seems partially different from common LA.

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