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TPS2601Background: T cells naturally undergo activation-induced upregulation of co-inhibitory pathways, which may limit the antitumor immune response. Blocking these inhibitory pathways may enhance...

TPS2596 Background: Enoblituzumab, is an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276), a member of the B7 family. It is Fc-engineered to enhance effector function including antibody dependent cellular cytotoxicity (ADCC). IHC analyses with the parental anti-B7H3 mAb specificity incorporated in enoblituzmab revealed limited B7-H3 expression in normal tissues but high expression in many cancers (Loo et al., 2012). Among pediatric solid tumors, high expression of B7-H3 has been reported in neuroblastoma, rhabdomyosarcoma, osteosarcoma, Wilms tumor, Ewing’s sarcoma and desmoplastic small round cell tumor. B7-H3 overexpression correlates with poor prognosis in a broad range of cancers in adults suggesting a potential role in enabling tumor immune escape. ADCC and potential modulation of T cell function resulting in enhanced antitumor immune response are presumed mechanisms of action of enoblituzumab. Methods: This is an open-label, dose escalation / cohort expansion phase 1 study (NCT02982941) designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of enoblituzumab in children and young adults with B7-H3-expressing relapsed or refractory malignant solid tumors. A 3+3 design is used in escalating dose cohorts of weekly intravenous (IV) enoblituzumab starting at 10 mg/kg. Response is first determined at 8 weeks. irRECIST is used for response assessment for patient management. Enoblituzumab may continue up to 2 years based on response. Cohort expansion phase, to further define the safety and initial antitumor activity of enoblituzumab, will start after maximum tolerated dose is determined. The patients are assigned to 1 of 5 cohorts based on disease type as follows: 1) neuroblastoma - measurable disease, 2) neuroblastoma - non-measurable disease, 3) rhabdomyosarcoma, 4) osteosarcoma, and 5) Ewing’s sarcoma, Wilms’ tumor and desmoplastic small round cell tumors. Enrollment is ongoing. Ref : Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Loo D, Alderson RF, Chen FZ, Huang L et al. Clin Cancer Res. 2012; 18:3834-45. Clinical trial information: NCT02982941.

Aim: Squamous cell carcinoma of the head and neck (SCCHN) is associated with tobacco use, human papillomavirus (HPV) infection, and PD-L1 expression. An ongoing Phase I, multicenter, open-label study (NCT01693562) is evaluating the safety and efficacy of MEDI4736, a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. Methods: MEDI4736 is administered IV every 2 weeks (q2w) at a dose of 10 mg/kg in a recurrent/metastatic SCCHN expansion cohort. Retreatment is permitted upon progression after 12 months of therapy. Smoking history, HPV status and prior treatments are collected at baseline. PD-L1 expression within the tumor is assessed by immunohistochemistry. Response is assessed by RECIST v1.1. Results: As of 14 Apr, 2014, 50 pts with SCCHN; mean age 58 y (range 24–96); 86% male, 63% current/prior smokers, with median 3 prior treatments (1–11), received median 3 doses (1–12) of MEDI4736 10 mg/kg q2w. Treatment-related adverse events (TRAE) were observed in 39% of pts; most frequently nausea (6%), diarrhea, dizziness, and rash (4% each). Dyspnea, syncope, raised gamma-glutamyltransferase (GGT) and sepsis (each 5%) were the most common grade ≥3 AEs; only raised GGT (n = 1) was considered treatment-related. No TRAEs led to study discontinuation and no pts had pneumonitis or colitis. Median time of follow up was 8 wks at data cutoff. In all, 29 SCCHN pts were evaluable for efficacy (first assessment at 6 weeks), with 7 having radiographic shrinkage in target tumor lesions ranging from 7% to 76%. Five of the 7 pts have been followed for at least 12 wks (6–24 wks) and none have evidence of objective progression. Four pts have a partial response (confirmed + unconfirmed). Further assessment of clinical activity and its potential relationship to clinical attributes (HPV status, smoking history, prior therapies), and biomarkers, including PD-L1 expression, are ongoing. Conclusions: Preliminary clinical activity in pts with SCCHN has been observed with manageable safety profile consistent with previous reports for MEDI4736. These data support continued clinical development of MEDI4736 in SCCHN. Disclosure: M. Fury: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.; S.I. Ou: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.; A. Balmanoukian: Our clinic, including myself, is involved with research/clinical trials funded by MedImmune. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I have agreed to be a speaker for BI.; A. Hansen: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.; E. Massarelli: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.; A. Blake-Haskins: Employee of MedImmune and owns stock/stock options in AstraZeneca X. Li: Employee of MedImmune and owns stock/stock options in AstraZeneca; P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; J. Vasselli: Employee of MedImmune and owns stock/stock options in AstraZeneca; N.H. Segal: Ad Board participation with MedImmune, Alkermes Scientific, Imugene Research funding from BMS and Pfizer. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

Aim: This ongoing Phase I, multicenter, open-label study (NCT01693562) evaluates the safety and efficacy of MEDI4736 in patients (pts) with multiple solid tumor types including non-small cell lung cancer (NSCLC). MEDI4736 is a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. PD-L1 is expressed in many NSCLC tumors and may be associated with poor prognosis. Methods: MEDI4736 was administered IV every 2 weeks (q2w) or every 3 weeks (q3w) using a standard 3 + 3 dose escalation (6 dose levels: 0.1–10 mg/kg q2w; 15 mg/kg q3w). In dose expansion, NSCLC pts were assigned to cohorts by histology and line of therapy and administered MEDI4736 10 mg/kg q2w. Retreatment was permitted for progression after 12 months of therapy. Response is assessed by immune-related response criteria in escalation and RECIST v1.1 in expansion. Results: As of 14 April 2014, 114 NSCLC pts have been treated with MEDI4736 in dose escalation and expansion cohorts. Of the 101 pts treated at the 10 mg/kg q2w dose (median 3 doses received; range 1–14), mean age 63 y (37–83), all were PS 0–1, with a median of 2.5 prior treatments (range1–8). In this group, treatment-related adverse events (AEs) were reported in 20% of pts; most frequently dyspnea (16%), fatigue (15%) and nausea (15%). Grade ≥ 3 treatment-related AEs were reported in 4 pts. AEs led to study discontinuation in 6 pts, none of which were treatment-related. Pneumonitis (grade 2) occurred in 1 pt. With a median follow up of 10 wks, 46 pts were followed ≥ 12 wks. Objective response + stable disease was observed in 18 pts to date. While some responses or stabilization were reported at first assessment (6 wks), others appeared following initial progression. Benefit was durable; 72/114 pts remain on study (including 4 pts >52 wks) at data cutoff. Assessment of clinical activity by PD-L1 expression, underlying mutation, smoking history, and line of therapy continues. Conclusions: Durable clinical activity has been observed with manageable AEs, no grade ≥3 pneumonitis, and no colitis of any grade. Further development of MEDI4736 alone and in combination is ongoing in NSCLC. Disclosure: S. Antonia: Received honoraria from BMS and MedImmune/AstraZeneca for work related to designing, implementing, and analyzing various clinical trials. MedImmune considers research funding received for conduct of a MedImmune-sponsored study as conflict of interest; Ou: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Khleif: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I also function as a clinical advisor; J.R. Brahmer: My institution receives funding for the conduct of a MedImmune-sponsored study. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins: Employee of Medimmune and own stock/stock options in AstraZeneca; P.B. Robbins: Employee of Medimmune and own stock/stock options in AstraZeneca; X. Li: Employee of Medimmune and own stock/stock options in AstraZeneca; J. Vasselli: Employee of Medimmune and own stock/stock options in AstraZeneca; N. Rizvi: I receive consulting income from MedImmune, Roche, Merck and BMS MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

Aim: MEDI4736 is a human IgG1 mAb, engineered to prevent antibody-dependent cell-mediated cytotoxicity (ADCC) activity, that blocks PD-L1 binding to PD-1 and CD-80. This expansion study (NCT01693562) assessed MEDI4736 in pts with NSCLC, melanoma (cutaneous and uveal), hepatocellular carcinoma (ca), squamous cell ca of the head and neck (SCCHN), gastroesophageal ca, pancreatic ca, and triple negative breast ca. Methods: 10–20 pts (performance status [PS] 0–1) were initially enrolled per tumor type/study arm, with expansion allowed upon observation of clinical activity. MEDI4736 was administered as 10 mg/kg IV every 2 wks (q2w) for up to 12 months, with retreatment permitted for progression during follow-up. Response was assessed by RECIST v1.1. Results: This multi-arm dose expansion study was initiated in Sep 2013. As of 14 April 2014, 288 pts median age 61y (20–96), 57% male, PS 0/1/unknown (31%/65%/4%), median 3 (1–11) prior treatments, had received a median of 3 (1–20) doses of MEDI4736 10 mg/kg q2w and were evaluable for safety. Safety profile appeared to be consistent across tumor types and with previous reports. Treatment-related adverse events (AE) in 34% of pts (any Grade [Gr]); Gr ≥3 in 5.6%; no Gr 4–5); AEs led to discontinuation of study drug in 5.8% (drug-related in 1 pt). Most frequent treatment-related AEs were fatigue (14%), nausea (8.7%), and rash (5%). Gr 2 pneumonitis (resolved with drug interruption/steroids) was seen in 1 pt (0.4%). No colitis reported. No immunogenicity detected at the 10 mg/kg dose; 1/89 with antidrug antibodies impacting PK. Tumor shrinkage has been seen across all histologies, with responses as early as 6 wks and after initial progression in some pts. Clinical activity to date appears durable (maintained ≥ 48 wks in 5 pts). Analysis of correlation between activity and clinical attributes or biomarkers including PD-L1 expression is ongoing. Conclusions: Results indicate that MEDI4736 has a manageable safety profile even in heavily pretreated pts. Evidence of clinical activity has been seen across all 9 tumor types; other tumor types will be evaluated. Current experience supports development of MEDI4736 as monotherapy and in combination with other anti-cancer therapies for multiple tumor types. Disclosure: N.H. Segal: Ad Board participation with MedImmune, Alkermes Scientific and Imugene. Research funding from BMS and Pfizer. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; O. Hamid: My only conflict here is the research funding that I received from Medimmune. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; W. Hwu: No financial interest in MedI4736,process involved in the research.I dont own stock,serve on ad board,board of director or other substantive relationship with research sponsor who consider research fund rec'd for conduct of Medi-sponsored study a COI; C. Massard: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Butler: Received financial support from MedImmune Inc. to cover the costs of conducting MedImmune-sponsored clinical studies of Medi4736. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Antonia: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins: Employee of MedImmune and owns stock/stock options in AstraZeneca; P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; X. Li: Employee of MedImmune and owns stock/stock options in AstraZeneca; J. Vasselli: Employee of MedImmune and owns stock/stock options in AstraZeneca; S. Khleif: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I also function as a clinical advisor.

3002^ Background: Checkpoint blockade of the PD-1/PD-L1 and CTLA-4 pathways has shown to be active in multiple tumor types. MEDI4736 is a human IgG1 monoclonal antibody which binds specifically to ...

3001^ Background: Immune-suppressing molecules such as PD-L1 can be co-opted by cancer cells to suppress the natural immune response to cancer. Upregulation of PD-L1 and inhibition of antitumor T-c...

8021^ Background: Lung cancer is the leading cause of cancer death in both men and women. PD-L1 is upregulated in NSCLC and may be associated with a poor prognosis. MEDI4736 is a human IgG1 antibod...

2602 Background: MEDI4736 is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against human programmed death ligand 1 (PD-L1). MEDI4736 blocks inhibitory interaction of PD-L1 wi...