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W. Harb



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    MA09 - Immunotherapy Combinations (ID 390)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA09.06 - Viagenpumatucel-L Bolsters Response to Nivolumab Therapy in Advanced Lung Adenocarcinoma: Preliminary Data from the DURGA Trial (ID 4650)

      14:20 - 15:50  |  Author(s): W. Harb

      • Abstract
      • Presentation
      • Slides

      Background:
      Viagenpumatucel-L (HS-110) is an allogeneic whole-cell vaccine, selected for high expression of adenocarcinoma tumor antigens, transfected to secrete gp96-Ig. Prior studies with HS-110 (and related gp96-Ig vaccines) have shown a correlation between increases in CD8+ tumor infiltrating lymphocytes (TIL) and tumor response. The DURGA trial was designed evaluate the combination of HS-110 and nivolumab, in an attempt to increase tumor inflammation and improve the response rates observed with nivolumab alone. Clinical Trial identifier: NCT02439450

      Methods:
      Patients with advanced lung adenocarcinoma who received at least one prior line of therapy were assigned to two cohorts based on baseline levels of TIL in patient biopsies: low TIL (≤10% CD8+ T cells) or high TIL (>10% CD8+ T cells). All patients received standard of care nivolumab 3 mg/kg every 2 weeks and weekly HS-110 for 18 weeks until intolerable adverse events, disease progression, or death. Each 9-patient Phase 1b cohort could be expanded to 30 patients in Phase 2 based on exhibited efficacy. The primary endpoint was safety and tolerability. Biopsies at baseline and Week 10 were used to track changes in TIL and PD-L1 staining. Peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry for detection of circulating leukocyte subsets. ELISPOT was used to track antigen-specific immune response.

      Results:
      HS-110 vaccine and nivolumab combination was well tolerated with a safety profile consistent with single-agent nivolumab. Among the 8 initial patients, only 4 had optimal biopsies which showed 2 patients with high and 2 with low TILs. PD-L1 was >1% in 3 patients. IFNγ ELISPOT assay defined 4 patients as immune responders (doubling of IFNγ-secreting cells after re-stimulation with total vaccine antigen and individual cancer antigens, IR) and 4 patients as non-immune responders (NIR). The overall response rate (ORR) was 50% in the IR patients and 0% in the NIR patients. At the time of the data cutoff, 6 patients remain alive, including the 4 IR patients, with ongoing responses for 150 to 326 days. Patients with objective response also exhibited injection site reactions and maculopapular rash consistent with HS-110 mechanism of action, decreased Myeloid Derived Suppressor Cells (MDSC) in the blood, and increased markers of activated CD8+ T cell subsets by flow cytometry (CD8+CTLA-4+, CD8+Tim3+). Although the pathology specimens were sub-optimal in the two responding patients, the limited tissue available showed lower baseline TILs in both patients.

      Conclusion:
      Allogeneic gp96-based vaccination may have synergistic activity in combination with immune checkpoint inhibitors.

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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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      P2.06-011 - Phase 2 Study of MM-121 plus Chemotherapy vs. Chemotherapy Alone in Heregulin-Positive, Locally Advanced or Metastatic NSCLC (ID 4158)

      14:30 - 15:45  |  Author(s): W. Harb

      • Abstract

      Background:
      The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. The correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS) were retrospectively analyzed in three completed randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone (NSCLC, breast cancer and ovarian cancer). In each of these studies, high levels of HRG mRNA predicted shortened PFS for patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS for patients with HRG-positive (HRG+) tumors. This is consistent with the hypothesis that HRG expression defines a drug tolerant cancer cell phenotype shielded from the effects of cytotoxic or targeted therapies and that blockade of HRG-induced HER3 signaling by seribantumab counters the effects of HRG on cancer cells, with the potential to improve outcomes for HRG+ patients. It is estimated that up to approximately 50% of cases of all solid tumor indications are HRG+. This HRG expression may contribute to rapid clinical progression in a subset of patients with poor prognosis.

      Methods:
      In the ongoing randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors are being prospectively selected using a HRG RNA in situ hybridization assay performed on a recent tumor tissue sample collected via fine needle aspiration, core needle biopsy or excision. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies, one of which must be an anti-PD-1 or anti-PD-L1 therapy, for locally advanced and/or metastatic disease. Overall survival (OS) is the primary endpoint of the study and secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. An interim analysis is planned when 50% of final OS events have been reported. Enrollment has been initiated with approximately 80 sites expected to participate worldwide. Clinical Trials Registry number: NCT02387216

      Results:
      Section not applicable

      Conclusion:
      Section not applicable