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R.S. Herbst



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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO18.01 - An analysis of the relationship of clinical activity to baseline EGFR status, PD-L1 expression and prior treatment history in patients with non-small cell lung cancer (NSCLC) following PD-L1 blockade with MPDL3280A (anti-PDL1) (ID 2347)

      16:15 - 17:45  |  Author(s): R.S. Herbst

      • Abstract
      • Presentation
      • Slides

      Background
      NSCLC may utilize PD-L1 overexpression to escape immune surveillance. This mechanism has been suggested by recent clinical studies showing that NSCLC can respond to PD-L1/PD-1 blockade. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 from binding to its receptors, PD-1 and B7.1.

      Methods
      Patients received MPDL3280A IV q3w for up to 1 year in a Phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tissue was analyzed centrally for PD-L1 expression by IHC.

      Results
      As of Feb 1, 2013, 52 NSCLC patients were evaluable for safety and treated at doses of 0.03-20 mg/kg. The median age of patients was 61 years (range, 24-83). 17 (33%) of patients were ECOG PS 0 and 35 (67%) of patients were ECOG PS 1. Prior treatments included surgery (89%), radiotherapy (54%) and systemic therapy (98%). 15% of patients received 1 prior regimen, 21% received 2 and 62% received ≥3. Additionally, 14%, 62% and 25% of patients were EGFR-mutation positive, EGFR WT and EGFR status unknown/undetermined, respectively, and 12%, 40% and 48% of patients were KRAS-mutation positive, KRAS WT and KRAS status unknown/undetermined, respectively. Patients received treatment with MPDL3280A for a median duration of 106 days (range 1-450). Treatment-related Gr3/4 AEs occurred in 12% of patients, including fatigue (4%) and hypoxia (4%). 1 patient experienced a Gr3/4 immune-related AE (Gr3 hyperglycemia). No Gr3-5 pneumonitis or diarrhea was reported. 41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy. An ORR of 22% (9/41) was observed in patients (squamous [n=9]/nonsquamous [n=31]) with a duration of response range of 1+ to 214+ days. Additional patients had nonconventional responses after apparent radiographic progression but were considered to have progressive disease in this analysis. All responses were ongoing or improving at data cutoff. The 24-week PFS was 46%. ORR by patient characteristics was also examined. The ORR for patients with ≤2 prior therapies was 23% (4/17) and 23% (5/22) for patients with >2 prior therapies. Additionally, the response for former/current smokers was 23% (8/35) versus 17% (1/6) for never smokers. Between EGFR-mutation positive and EGFR WT patients, the ORRs also did not differ (25% [1/4] and 19% [5/26], respectively). In contrast, PD-L1 status was associated with ORR response as patients with PD-L1–positive tumors had an ORR of 80% (4/5) and patients with PD-L1–negative tumors had an ORR of 14% (4/28). Updated data, including responses by KRAS status, will be presented.

      Conclusion
      Treatment with MPDL3280A was generally well tolerated, with no cases of Gr3-5 pneumonitis. Rapid and durable responses were observed, including in an EGFR-mutation positive patient. Responses to MPDL3280A did not appear influenced by the number of prior treatment regimens but did appear to be associated with PD-L1 tumor status. Additional studies have been initiated in NSCLC.

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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.09 - Molecular correlates of PD-L1 status and predictive biomarkers in patients with non-small cell lung cancer (NSCLC) treated with the anti-PDL1 antibody MPDL3280A (ID 1653)

      10:30 - 12:00  |  Author(s): R.S. Herbst

      • Abstract
      • Presentation
      • Slides

      Background
      In NSCLC, antitumor immune response may be inhibited by PD-L1 expression. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 binding to its receptors, PD-1 and B7.1.

      Methods
      Patients with squamous or nonsquamous NSCLC received MPDL3280A IV q3w up to 1 year as part of a phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tumor tissues were evaluated centrally by IHC for PD-L1 and CD8. A qPCR-based gene expression panel measuring ≈90 immune-related genes was used to characterize the tumor immune microenvironment at baseline and during MPDL3280A treatment.

      Results
      41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy with an ORR of 22%. Baseline tumor samples were available for IHC (n=33) and for gene expression analysis (n=29). Of patients with available tissue, 5 were PD-L1 tumor status positive and 28 were PD-L1 tumor status negative. Relationship between PD-L1 status and EGFR/KRAS status is described below (table). Elevated baseline PD-L1 expression was associated with response to MPDL3280A (80% ORR vs 14% ORR for PD-L1negative patients), and PD-L1 expression coordinated with CD8+ T cells. A Th1-type T-cell gene signature (including CD8, Granzyme-B and EOMES) was associated with treatment response. Non-responders exhibited at least a 2-fold higher ratio over CD8 of genes associated with immunosuppression, including RORC, FOXP3, TGFb1 and IL10 compared with responders. On treatment, responding tumors across indications showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 up-regulation.

      Conclusion
      PD-L1 expression and a Th1 driven T-cell gene signature correlated with response to MPDL3280A in NSCLC, and MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. Additionally, expression of immune suppressive factors in NSCLC tumors is associated with a lack of benefit from MPDL3280A. These data provide mechanistic insights into immunotherapy and patient selection for MPDL3280A monotherapy. Preliminary observations suggest clinical activity and molecular characteristics may be associated with PD-L1 tumor expression. Updated data will be presented. Table: Relationship between PD-L1 status and EGFR/KRAS mutational status

      PD-L1-Positive (n = 5) PD-L1-Negative (n = 28) PD-L1 Unknown (n = 7) Overall (n = 40)*
      EGFRm, n 1 2 1 4
      EGFR WT, n 2 20 4 26
      EGFR Unknown, n 2 6 2 10
      KRASm, n 1 4 1 6
      KRAS WT, n 2 8 3 13
      KRAS Unknown, n 2 16 3 21
      * 1 patient had missing data.

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-005 - VEGF signaling inhibition by cediranib enhances the antitumor and anti-metastatic effects of radiation therapy more substantially than chemotherapy in orthotopic lung cancer models (ID 1443)

      09:30 - 16:30  |  Author(s): R.S. Herbst

      • Abstract

      Background
      The outcome for lung cancer patients remains poor and new therapeutic approaches are urgently needed. Cediranib is an orally available inhibitor of all 3 VEGFR tyrosine kinases. We evaluated the therapeutic efficacy and radiosensitizing effects of cediranib and paclitaxel, alone or in combination, in orthotopic models of human lung adenocarcinoma that mimic clinical patterns of malignant progression.

      Methods
      PC14PE6 or NCI-H441 human lung adenocarcinoma cells (1 x 10[6]) were injected into the left lungs of nude mice. Mice were randomized (8/group) to treatment with vehicle control, cediranib (3 mg/kg/day po), paclitaxel (200 µg/week ip), radiation to the left lung and mediastinum (20 Gy in 5 fractions over 2 weeks), or radiation with cediranib and/or paclitaxel. When controls became moribund, all mice were sacrificed and assessed for lung tumor burden and mediastinal nodal metastasis. Lung tumors and adjacent tissues were analyzed immunohistochemically.

      Results
      All treatments were well tolerated without significant differences in body weight between groups. In both models, cediranib or radiation therapy alone inhibited tumor growth and lymph node metastasis with efficacy superior to paclitaxel. Cediranib markedly enhanced the antitumor and antimetastatic effects of radiation with 99.3% and 92.1% reductions in primary lung tumor volume in the PC14PE6 and NCI-H441 models, respectively, while paclitaxel only modestly improved the effects of radiation therapy. Trimodality therapy resulted in a near-complete suppression of tumor growth and metastasis, with 99.8% and 98.3% reductions in tumor volume compared to control in the PC14PE6 and NCI-H441 models, respectively, without evidence of lymph node metastasis. Immunohistochemical analyses of lung tumors revealed that cediranib inhibited angiogenesis and tumor cell proliferation and increased tumor and endothelial cell apoptosis. The antiangiogenic and apoptotic effects of cediranib were substantially enhanced when combined with radiation and paclitaxel. Cediranib alone or in combination with radiation and/or paclitaxel increased VEGFR2 expression, but VEGF expression was not significantly impacted by treatment. VEGFR2/3 activation was blocked by cediranib alone or in combination therapy.

      PC14PE6 NCI-H441
      Treatment Left Lung Weight (mg) Left Lung Tumor Volume (mm[3]) Mediastinal Lymph Node Metastasis Left Lung Weight (mg) Left Lung Tumor Volume (mm[3]) Mediastinal Lymph Node Metastasis
      Vehicle 710 (490-1210) 753 (254-1089) 7/8 935 (800-1230) 1146 (860-1601) 8/8
      Paclitaxel 200ug/week 545 (150-860) 506 (37-817) 6/8 785 (485-820) 820 (576-1208) 7/8
      Radiation 20Gy/5fractions 220** (50-360) 154* (34-270) 4/8 485** (330-820) 501* (333-879) 6/8
      Cediranib 3mg/kg/day 215* (70-540) 137* (13-316) 4/8 395** (230-570) 414** (261-698) 5/8
      Radiation +Paclitaxel 185** (60-260) 87** (21-268) 2/8 360** (260-650) 327** (236-651) 5/8
      Cediranib + Paclitaxel 125** (60-260) 41** (0-150) 1/8[†] 225** (160-630) 241** (79-651) 4/8[†]
      Radiation + Cediranib 50* (40-60) 0** (0-28) 0/8[†] 120** (70-190) 88** (1-182) 2/8[†]
      Radiation + Cediranib + Paclitaxel 40** (40-60) 0** (0-1) 0/8[†] 100** (60-120) 9** (1-64) 0/8[†]
      Data are presented as medians and ranges or as incidence. [†]p<0.05 versus vehicle (lymph nodes), *p<0.01, **p<0.001 versus vehicle (others)

      Conclusion
      Trimodality therapy with cediranib, paclitaxel, and radiation resulted in the near complete suppression of lung tumor growth and metastasis with markedly enhanced antiangiogenic and apoptotic effects. The radiosensitizing effects of cediranib upon lung tumors and their vasculature was superior to those of paclitaxel with markedly enhanced apoptosis. The combination of cediranib with radiotherapy or chemoradiotherapy is a potentially promising therapy for cancer and our data provides a strong basis for the design of clinical trials in lung adenocarcinoma patients.