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G. Giaccone



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    ED15 - Thymic Malignancies: Update on Treatment (ID 285)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      ED15.01 - Biology of Thymic Epithelial Tumors (ID 6506)

      14:30 - 14:50  |  Author(s): G. Giaccone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-041 - Integrated Proteo-Genomics Analyses Reveal Extensive Tumor Heterogeneity and Novel Somatic Variants in Lung Adenocarcinoma (ID 6082)

      14:30 - 14:30  |  Author(s): G. Giaccone

      • Abstract

      Background:
      Tumor heterogeneity is a major impediment to targeted treatment response in a variety of cancers, including lung cancer, the commonest cause of cancer death. However, the extent of heterogeneity at the genomic and proteomic level along with its effects on treatment response may be patient-specific.

      Methods:
      We undertook comprehensive whole genome, exome or targeted sequencing, together with mass spectrometry-based proteomics analyses on twelve sequentially procured lung and lymph node metastatic sites and normal blood from an African American never-smoker lung adenocarcinoma patient who had survived with metastatic disease for over seven years while being treated with single or combination ERBB2-directed therapies.

      Results:
      Surprisingly, only 1% of somatic variants were common between the two sites, as revealed by WGS. Interestingly, one novel somatic translocation, PLAG1-ACTA2 was identified in both sites resulting in overexpression of ACTA2 that may have been the driver of early metastasis in this patient. The likely predominant driver of proliferation, ERBB2, was focally amplified along with CDK12, greater in the lung compared to the lymph nodes. However, an ERBB2 L869R mutation was specific to the lymph node. We also discovered a novel CDK12 G879V mutation that was specific to the lung. Isogenic MCF10A cells expressing ERBB2 L869R were more proliferative than those expressing wild type ERBB2. Cells expressing ERBB2 L869R that developed lapatinib resistance showed a mesenchymal phenotype, increased migration, and produced significantly more lung metastases than lapatinib-sensitive ERBB2 wild-type cells in a tail-vein injection assay, implicating this mutation in repeated progression of lymph node metastases. The CDK12 mutation is expected to have resulted in a non-functional kinase, lower expression of DNA damage response genes, greater instability of the lung tumor genome, and increased sensitivity to chemotherapy. Accordingly, there was no metastatic sites evident at autopsy in the lung, suggesting the lung metastatic sites were essentially cured. We further sought to correlate the genomic heterogeneity with alterations in the proteome and phosphoproteome using high-resolution mass spectrometry. For this purpose, we first assembled patient-specific database including all somatic variants, as revealed by WGS, from the lung and lymph node to interrogate the mass spectrometry data. Several aspects of the genomic heterogeneity were evident at the protein-level. These include the identification of the mutant CDK12 G879V peptide and higher expression of ERBB2 in the lung.

      Conclusion:
      The integrated proteo-genomics analyses reveal unprecedented tumor heterogeneity in a patient with lung adenocarcinoma. However, similarities in key tumor driver pathways remain.

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    P2.03a - Poster Session with Presenters Present (ID 464)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03a-014 - A Dose-Finding and Phase 2 Study of Ruxolitinib plus Pemetrexed/Cisplatin for Nonsquamous Non–Small Cell Lung Cancer (NSCLC) (ID 3874)

      14:30 - 14:30  |  Author(s): G. Giaccone

      • Abstract

      Background:
      Dysregulation of the JAK/STAT pathway contributes to abnormal inflammatory responses, oncogenesis, treatment resistance, and poor prognosis in NSCLC. This phase 2 clinical trial evaluated the JAK1/JAK2 inhibitor ruxolitinib+pemetrexed/cisplatin as first-line treatment for patients with stage IIIB/IV or recurrent nonsquamous NSCLC and systemic inflammation (per modified Glasgow Prognostic Score [mGPS]).

      Methods:
      Key inclusion criteria were mGPS of 1/2 and ECOG performance status ≤1. Part 1, an open-label, 21-day safety run-in, assessed ruxolitinib (15 mg BID [chosen dose for Part 2]) plus pemetrexed (500 mg/m[2] IV on Day 1) and cisplatin (75 mg/m[2] IV on Day 1). Ruxolitinib dose selection for Part 2 required <3 dose-limiting toxicities (DLTs) for 9 evaluable patients. Part 2 randomized patients to ruxolitinib+pemetrexed/cisplatin or placebo+pemetrexed/cisplatin. The trial was terminated early for lack of efficacy in other solid tumor programs in patients with high systemic inflammation.

      Results:
      All 15 patients enrolled in Part 1 received ruxolitinib 15 mg BID plus pemetrexed/cisplatin. Median age was 64 years; male, 80%; mGPS 1, 80%. Median treatment duration was 140 days. The Table reports Part 1 safety data. Four patients were inevaluable for DLTs (<80% compliance, n=2; disease progression, n=2). No DLTs occurred in 11 evaluable patients. The Part 1 overall response rate (ORR) was 53% (8/15; all partial responses). At study termination, 39 and 37 patients were randomized in Part 2 to ruxolitinib and placebo, respectively. Median treatment duration was 43 days. ORR was 31% (12/39) with ruxolitinib+pemetrexed/cisplatin versus 35% (13/37) with placebo+pemetrexed/cisplatin (all partial responses). The short follow-up duration may limit interpretation of Part 2 efficacy. The Part 2 safety profile was consistent with Part 1 (data to be presented).

      Table. The Most Common Treatment-Emergent Adverse Events in Part 1
      Ruxolitinib+Pemetrexed/Cisplatin (N=15)
      Event, n (%) All-Grade Grade 3/4
      Nonhematologic*
      Nausea 11(73) 1(7)
      Fatigue 8(53) 3(20)
      Vomiting 8(53) 1(7)
      Constipation 7(47) 0
      Diarrhea 7(47) 0
      Dizziness 7(47) 0
      Peripheral edema 7(47) 0
      Decreased appetite 6(40) 0
      Pyrexia 6(40) 0
      Dyspnea 5(33) 1(7)
      Pneumonia 4(27) 3(20)
      Pulmonary embolism 2(13) 2(13)
      Sepsis 2(13) 2(13)
      New/worsening hematologic laboratory abnormalities
      Anemia 13(87) 5(33)
      Lymphopenia 11(73) 2(13)
      Leukopenia 9(60) 1(7)
      Neutropenia 9(60) 5(33)
      Thrombocytopenia 9(60) 1(7)
      *Common all-grade (≥30%) or grade 3/4 (≥10%) events.

      Conclusion:
      Ruxolitinib 15 mg BID had an acceptable safety profile in combination with pemetrexed/cisplatin as first-line treatment of patients with stage IIIB/IV or recurrent nonsquamous NSCLC.

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    P2.04 - Poster Session with Presenters Present (ID 466)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P2.04-019 - A Peripheral Immune Signature Associated with Clinical Activity of Sunitinib in Thymic Carcinoma (ID 6184)

      14:30 - 14:30  |  Author(s): G. Giaccone

      • Abstract

      Background:
      We have previously reported an objective response rate of 26% and disease stabilization in 65% of patients with advanced thymic carcinoma (TC) treated with the multikinase inhibitor sunitinib after failure of platinum-based chemotherapy. The current study investigates the impact of sunitinib on systemic immunity in patients with thymic epithelial tumors with an aim to discover blood-based, predictive immune biomarkers.

      Methods:
      Patients with thymoma and TC received sunitinib at a dose of 50 mg once daily in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment. Results from 15 patients with TC are reported here. Blood samples were collected before initiation of sunitinib therapy (Cycle 1 day 1; C1D1), and prior to treatment on day 1 of cycles 2 and 3 (C2D1; C3D1). Multiparameter flow cytometry was used to study T-cell subsets with immune checkpoint expression, four phenotypes of myeloid-derived suppressor cells (MDSCs) with CD40, and CD14+ monocytes with HLA-DR expression. Expression of 730 immune-related genes in peripheral blood was analyzed by NanoString technology. Differences in paired markers or changes in markers between two time points was evaluated by the Wilcoxon signed rank test. The Kaplan-Meier method was used to obtain estimates of progression-free survival (PFS) and overall survival (OS).

      Results:
      Immunosuppressive Tim-3-positive Tregs declined after 2 cycles of sunitinib (p=0.024). A decrease in granulocytic MDSCs (p=0.012), lineage negative (CD3-CD19-CD56-) MDSCs (p=0.013), and immature MDSCs (p=0.01) but not monocytic MDSCs was observed after 1 cycle of sunitinib. TC patients with no objective response to sunitinib had a higher baseline immature MDSC level than responders (p=0.0044). Greater than median declines in granulocytic MDSC CD40 (C2D1 p=0.027, C3D1 p=0.0046) and lineage-MDSC CD40 (C3D1, p=0.0046) after sunitinib therapy was associated with improved PFS. Similarly, a greater than median decline in CD14[+]HLA-DR[lo/neg ]monocyte levels on C2D1 was associated with longer PFS (p=0.020). Among the immune genes examined, higher baseline FEZ1 expression was associated with improved PFS and OS.

      Conclusion:
      Our findings suggest significant interplay between sunitinib and systemic immunity impacts therapeutic outcome in TC. Monitoring CD40 expression on specific MDSC phenotypes and FEZ1 gene expression may predict a survival benefit after treatment with sunitinib. These results, if validated in larger studies, can serve as potential blood-based predictive biomarkers in TC patients treated with sunitinib.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-024 - Tedopi vs Standard Treatment as 2nd or 3rd Line in HLA-A2 Positive Advanced NSCLC Patients in a Phase 3, Randomized Trial: ATALANTE-1 (ID 5329)

      14:30 - 14:30  |  Author(s): G. Giaccone

      • Abstract

      Background:
      HLA-A2 is expressed in 40 to 50% of NSCLC patients. TEDOPI is a combination of neoepitopes that generates cytotoxic T lymphocytes responses. It consists of nine HLA-A2 supertype binding epitopes covering five tumor-associated antigens overexpressed in advanced NSCLC and the universal helper pan-DR epitope. In a phase II trial (NCT00104780, Barve et al. JCO 2008), TEDOPI showed a promising median overall survival of 17.3 months with a manageable safety profile in pre-treated HLA-A2 positive patients with advanced NSCLC. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy.

      Methods:
      Section not applicable

      Results:
      Trial design: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements, with progressive disease to first-line platinum-based chemotherapy or second-line immune checkpoint inhibitors (IC) are eligible if they have HLA-A2 positivity and ECOG PS 0-1. Treated and asymptomatic brain metastases are allowed. Patients are randomized 1:1 to receive 1 ml TEDOPI subcutaneously Q3W for 6 cycles, then every two months for the reminder of the year and finally every three months or standard treatment with: 75 mg/m[2] docetaxel Q3W or 500 mg/m[2] pemetrexed Q3W (in non-squamous histology and pemetrexed-naïve patients). In both arms, treatment continues until progression, intolerable toxicity, consent withdrawal, or investigator decision. In TEDOPI arm, treatment may continue beyond initial radiographic disease progression in case of clinical benefit. Randomisation is stratified by histology (squamous vs. non-squamous), initial response to first-line chemotherapy (partial or complete response vs. stabilization or progression), and previous treatment with IC (yes vs. no). Tumor assessment is performed every 6 weeks and adverse events are collected throughout the study and for 60 days and 90 days thereafter and graded per NCI CTCAE v4.0. Archival biopsies samples are required for assessing PD-L1 status (IHC22C3 pharmDx from Dako). Primary endpoint is overall survival; and secondary are progression free survival based on RECIST 1.1 criteria, objective response rate, disease control rate, duration of response, and quality of life measured by QLQ-C30 and QLQ-LC13 global scores. This is a superiority study with a hazard ratio of 0.7391, two-sided alpha 5% and power 80%, after 356 events are observed over 500 patients. The first patient was enrolled on 25th January 2016. Enrolment is ongoing in Europe and the US. Clinical trial identification: NCT02654587 Legal entity responsible for the study & Funding: OSE Immunotherapeutics, France

      Conclusion:
      Section not applicable