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J. Powderly



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    ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL02.07 - Atezolizumab (MPDL3280A) Combined with Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer (NSCLC): A Phase Ib Safety and Efficacy Update (ID 2208)

      10:45 - 12:15  |  Author(s): J. Powderly

      • Abstract
      • Presentation
      • Slides

      Background:
      Despite advances in treatment for NSCLC, the standard first-line treatment for metastatic disease remains platinum-based doublet chemotherapy with historical overall response rates (ORRs) of ≈30%. Preclinical data suggest that chemotherapy treatment can result in antigen release in the tumor microenvironment, potentially enhancing effects of cancer immunotherapy. Atezolizumab (MPDL3280A) is a human monoclonal antibody that targets the PD-L1/PD-1 immune checkpoint, while leaving the PD-L2/B7.1 interaction intact (which may reduce the risk of autoimmune lung toxicity). As atezolizumab has shown promising activity in advanced NSCLC, we investigated atezolizumab in combination with chemotherapy.

      Methods:
      A Phase Ib study was conducted to evaluate atezolizumab with chemotherapy in locally advanced or metastatic NSCLC patients who had not received chemotherapy for advanced disease. Pts received atezolizumab 15 mg/kg IV q3w with standard chemotherapy (carboplatin plus either paclitaxel [Arm C], pemetrexed [Arm D; nonsquamous] or weekly nab-paclitaxel [Arm E]) for 4-6 cycles followed by atezolizumab maintenance until progression. RECIST v1.1 was used to assess ORRs (unconfirmed) in pts dosed by Jun 29, 2014 (data cutoff: Sep 29, 2014). PD-L1 expression was centrally evaluated using the SP142 IHC antibody assay.

      Results:
      37 NSCLC pts were safety evaluable (8 in Arm C; 14 in Arm D; 15 in Arm E). Across these arms, 54% of pts were male, with a median age of 65 y (range, 40-82 y). 81% had non-squamous NSCLC, and 19% had squamous NSCLC. Median safety follow-up was 22.0 wks (range, 0.1-49.4 wks). Across arms, all-Grade AEs regardless of attribution included those commonly associated with chemotherapy, such as nausea (Arms C & D, 50%; Arm E, 73%), fatigue (Arm C, 38%; Arm D, 36%; Arm E, 73%) and constipation (Arm C, 25%; Arm D, 71%; Arm E, 27%). The most common Grade 3-4 atezolizumab-related AEs included anemia (Arms D & E, 7%), neutropenia (Arm C, 13%; Arm D, 7%) and thrombocytopenia (Arms D & E, 7%), with no pneumonitis or autoimmune renal toxicity observed. One potentially atezolizumab-related Grade 5 AE was observed in Arm D (candidemia after prolonged neutropenia). 30 pts were efficacy evaluable, and responses were observed in all arms regardless of PD-L1 expression (Table). Updated clinical data will be presented.

      Table. RECIST v1.1 Responses in Patients with NSCLC
      Arm C: carboplatin + paclitaxel (n = 5) Arm D: carboplatin + pemetrexed (n = 12) Arm E: carboplatin + nab-paclitaxel (n = 13) All Indicated Arms (n = 30)
      ORR, % 60% 75% 62% 67%
      95% CI, % 19%-92% 45%-93% 33%-83% 48%-82%
      CR, n 0 0 2 2
      PR, n 3 9 6 18


      Conclusion:
      Atezolizumab plus standard first-line chemotherapy was well tolerated in advanced NSCLC pts, with no unexpected toxicities. Clinical activity was promising and supportive of a potential synergy of atezolizumab with chemotherapy. Based on these results, several Phase III studies have been initiated.

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    P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P3.08-011 - Avelumab (MSB0010718C), an Anti-PD-L1 Antibody, Evaluated in a Phase Ib Trial in Patients with Advanced Mesothelioma (ID 790)

      09:30 - 17:00  |  Author(s): J. Powderly

      • Abstract
      • Slides

      Background:
      The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel group expansion trial in patients with metastatic or locally advanced solid tumors that includes a cohort of patients with advanced, unresectable mesothelioma.

      Methods:
      This trial cohort is enrolling patients with histologically or cytologically confirmed unresectable mesothelioma (pleural or peritoneal) that has progressed after treatment with either a platinum-pemetrexed–containing regimen or a platinum-based regimen followed by pemetrexed (or vice versa). Eligible patients must have available tumor archival material or fresh biopsy, and an ECOG performance status of 0 or 1 at trial entry, and disease with at least 1 measurable lesion that has not been irradiated. Exclusion criteria include prior therapy with immune checkpoint drugs, a known history of autoimmune disease, or recent anticancer treatment (within the 28 days prior to study start). Up to 50 eligible patients will receive avelumab at 10 mg/kg as an infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Treatment may be continued despite progression according to RECIST 1.1 if the patient’s clinical status is stable and, according to investigator opinion, there is no need to start salvage therapy. The primary objective of the trial is to assess the safety and tolerability of avelumab. Select secondary objectives include: assessment of best overall response (BOR) and progression-free survival (PFS) according to RECIST 1.1; assessment of immune-related BOR and immune-related PFS (using the modified Immune-Related Response Criteria); and assessment of overall survival. Association between tumor PD-L1 expression and efficacy will be evaluated. Changes in soluble factors and immune cell profiling will be characterized and immunomonitoring will occur at each visit. Tumor assessments will be performed every 6 weeks until progression. Tumor tissue from the most recent biopsy or surgical specimen will be collected prior to the initiation of trial treatment, and fresh biopsies may be optionally collected on day 43 and at the end-of-treatment visit. At each visit during the treatment phase, adverse events will be assessed and graded according to NCI-CTCAE v4.0. Enrollment in this study began in September 2014. *Proposed INN.

      Results:
      not applicable

      Conclusion:
      not applicable

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