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Jose Carlos Ruffinelli



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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.02 - Early Change of dNLR Is Correlated with Outcomes in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 2676)

      13:30 - 15:00  |  Author(s): Jose Carlos Ruffinelli

      • Abstract
      • Presentation
      • Slides

      Background

      The [neutrophils/[leucocytes-neutrophils] ratio (dNLR) correlates with immune checkpoint inhibitors (ICI) outcomes in advanced non-small cell lung cancer (aNSCLC) patients. Significance of early dNLR change after the first course of ICI is unknown.

      Method

      Patients with NSCLC treated with ICI (PD(L)1+/-CTLA4) between Nov. 2012 and Jun. 2018 at 16 EU/US centers were included. A control group treated with chemotherapy (CT) only was also evaluated (NCT02105168). dNLR was collected at baseline (B) and at cycle 2 (C2). Patients were categorized as low vs high dNLR at each timepoint (defined as < vs > 3, as previously done), and the change between B and C2 (good = low at both timepoints, poor = high at both timepoints, mixed = different at each timepoint).

      Result

      1485 patients treated with ICI were analyzed. PDL1 was negative in 162 (11%), 1-49% in 178 (12%), ≥50% in 201 (14%), and missing in 944 (64%). dNLR at B and C2 did not associate with PD-L1 status.

      At baseline, dNLR was high in 509 (34%) patients and associated with worse PFS compared to those patients with low dNLR at baseline (HR 1.56, P<0.0001) and OS (HR 2.02, P<0.0001). At C2, dNLR was high in 484 (34%) and similarly associated with worse outcomes compared to patients with low dNLR at C2 (PFS HR 1.64, P<0.0001; OS HR 2.13, P<0.0001).

      Between B and C2, dNLR remained low in 804 (56%, « good ») or high in 327 (23%, « poor ») or changed in 310 pts (22%, « intermediate »). Those with a good dNLR demonstrated mPFS 5.3, mOS 18.6 mo), followed by those intermediate with mixed dNLR (mPFS 3, mOS 9.2 mo), and finally poor dNLR (mPFS 2, mOS 5mo). Outcomes were independant of PD-L1 expression (adjusted HR for PFS 1.94 for intermediate and 3.16 for poor groups, compared to good dNLR group, P<.001; adjusted HR for OS was 2.08 for intermediate and 3.67 for poor groups, P<0.001).A bootstrap tested the stability of OS/PFS prediction (P<0.001).

      In the chemo-cohort (n=173), high C1-dNLR (n=81, 47%) was not associated with OS (P=0.84).

      Conclusion

      dNLR at baseline, at cycle 2, and the change between these two timepoints associated with outcomes in patients treated with immunotherapy independent of PD-L1, but not in patients treated with chemotherapy alone. dNLR is specifically prognostic in the context of immunotherapy.

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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA12.07 - Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma Reveals a Clinically-Relevant Immune-Based Classification (Now Available) (ID 1680)

      14:00 - 15:30  |  Author(s): Jose Carlos Ruffinelli

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lining of the lungs. Immune checkpoint inhibitors in MPM have not been extremely successful, likely due to a poor identification of suitable candidate patients for the therapy. The aims of this study were: to identify immune fractions associated with clinical outcome and classify MPM samples based on their immune contexture; to characterize the immune-based groups at the genomic and transcriptomic levels; and to identify potential therapeutic strategies for each group.

      Method

      Seven gene-expression datasets of MPM were used to assess the immune microenvironment of 516 samples. The abundance of 20 immune fractions in each sample was inferred using Gene Set Variation Analysis. Identification of clinically-relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology.

      Result

      T-Helper 2 (TH2, HR=2.14, p=1.5x10-4) and cytotoxic T cells (CTC; HR=0.57, p=9.1x10-3) were found to be consistently associated with overall survival in multiple datasets. Three immune clusters (IG) were subsequently defined based on TH2 and CTC immune infiltration levels: IG1 (54.5% of samples) was characterized by high TH2 and low CTC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high CTC levels. This classification was associated with overall survival independently of tumor histology, with an improving survival from IG1 to IG3 (HRIG2=0.52 (0.39–0.69); HRIG3=0.32 (0.19–0.53); p=8.4x10-8).

      kaplanmeier_immunegroups.png

      IG3 was significantly enriched in epithelioid tumors (90% IG3 vs. 62% IG1, p=0.001) and patients were younger compared to the other groups (60 years IG3 vs. 66 years IG1, p=0.021). These groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation and DNA repair-related gene-sets, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, integration of gene expression with functional signatures of in vitro drug response showed that IG3 patients are more likely to respond to immune checkpoint inhibitors, while IG1 patients could be more sensitive to PARP inhibitors.

      Conclusion

      Analysis of publicly available MPM transcriptome data reveals three major immune-based groups, based on TH2 and CTC composition. These clusters are associated with distinct genomic profiles and clinical outcome. Further validation of this classification is warranted in an independent cohort of MPM.

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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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      P1.01-54 - Somatic Genome Alterations in Lung Cancer Patients Diagnosed with Li Fraumeni Syndrome (Now Available) (ID 1014)

      09:45 - 18:00  |  Author(s): Jose Carlos Ruffinelli

      • Abstract
      • Slides

      Background

      Li-Fraumeni syndrome (LFS) is a rare hereditary condition that consists of TP53 mutations inherited in autosomal dominant manner that confer high risk of developing cancer, including lung adenocarcinoma (LUAD). EGFR-mutated LUAD were reported in the context of LFS but there is no systematic description of somatic mutations and characteristics of lung cancer (LC) patients with LFS.

      Method

      We present a retrospective analysis of clinical and molecular characteristics of patients with LFS diagnosed with LC at the Catalan Institute of Oncology from 1999 to 2019. We collected demographical and clinicopathological features, germline and somatic mutational alterations, treatment and progression-free survival (PFS) and overall survival (OS).

      Result

      A total of 7 patients with LC and LFS were identified in the Genetic Counseling Unit database. They were carriers of germline mutations in TP53. Five of them were classified as pathogenic: c.638G>A; p.(Arg213Gln), c.725G>A; p.(Cys242Tyr), c.742C>T; p.(Arg248Trp), c.844C>T; p.(Arg282Trp) and c.1010G>A; p.(Arg337His) and two of them as likely pathogenic: c.374C>T; p.(Thr125Met) and c.473G>A; p.(Arg158His). Six out of 7 patients were female and 5 out of 7 never smoker. Median age at diagnosis was 38 year-old (range: 29-74). Five patients had stage IV at diagnosis and the most common histologic subtype was LUAD (5). Six patients had first grade family history of cancer with a median of 2 family members (range: 1-4) and 2 patients had prior history of cancer. Tumor somatic profile in LC was obtained in 6 patients, consisting on a ROS-1 rearrangement in one patient and EGFR mutations in 5 patients (exon 19 deletion in 3 patients and missense mutations in 2 patients, p.(Gly719Ala) at exon 18 and p.(Leu858Arg) at exon 21) and in 1 patient was unknown. All patients with mutant EGFR received EGFR tyrosine kinase inhibitors (TKI) with a median PFS of 29 months (95% CI 0-67). Four had partial response and one a complete response to TKI treatment. At disease progression, one patient had small cell transformation and another acquired EGFR T790M mutation. Median lines of treatment were 4 (range 1-6). Two patients are alive at data cut off. Median OS is 47 months (95% CI 32-62).

      Conclusion

      Patients diagnosed with LC and LFS are enriched with actionable genomic alterations and have an earlier onset of the disease. Clinical outcome of patients with EGFR mutations and LFS did not differ from EGFR mutated LC patients who do not carry TP53 germline mutations.

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