John A. Blake-Haskins

Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer

PURPOSE To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). METHODS A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1. RESULTS A total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks). CONCLUSION Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.

Abstract A047: Safety and clinical activity of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC)

Background: Durvalumab (D) is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to programmed cell death-1 (PD-1) and CD80 with high affinity and selectivity. PD-L1 is expressed in NSCLC tumors and may be associated with response to anti-PD-L1 treatment. This ongoing Phase 1/2, multicenter, open-label study (NCT01693562) evaluates the safety and clinical activity of D in patients (pts) with multiple solid tumor types including NSCLC. Methods: D is administered at 10 mg/kg IV every 2 weeks (wks) (q2w) until unacceptable toxicity, disease progression, or for up to 12 months. Safety evaluations occur prior to each dose (toxicities graded by CTCAE v4.0). Response is based on investigator assessment (RECIST v1.1; includes confirmed/unconfirmed responses) at 6, 12, and 16 wks, then every 8 wks. Retreatment is permitted upon disease progression after 12 months of therapy. PD-L1 expression within the pre-treatment tumor is assessed using Ventana PD-L1 immunohistochemistry (IHC) (SP263). Results: As of February 27, 2015, 228 pts (126 non-squamous and 102 squamous histology; mean age 64 [range 26 – 87]; Eastern Cooperative Oncology Group Performance Status 0 [25%] or 1 [74%]; 83% current/prior smokers; 0 [12%], 1 [29%], or ≥2 [56%] prior lines of therapy) have been treated with D 10 mg/kg q2w (median 6 doses; range 1 – 27). Drug-related adverse events (AEs) were reported in 50% of pts; most frequently fatigue (15%), decreased appetite (9%), and nausea (8%). Grade ≥3 drug-related AEs were reported in 8% of pts. Drug-related AEs led to study discontinuation in 5% of pts with no treatment-related deaths. Pneumonitis occurred in 3 (1%) pts; none were Grade ≥3. In all, 200 pts were evaluable for response with ≥12 wks of follow-up; objective response rate (ORR) was 16% (27% in PD-L1+), and disease control rate at 12 wks was 42%. ORR was higher in squamous (21%) than non-squamous pts (13%). Responses were durable with 66% ongoing (duration of response range 0.1+ – 54.4+ wks). Data from translational studies will be presented. Conclusions: With longer follow-up, the safety profile of D in NSCLC is manageable and consistent with our previous reports. Responses are durable; ORR appears to be higher in squamous NSCLC and PD-L1+ pts. A broad development program of D alone and in combination with other treatments in NSCLC is underway. Citation Format: Scott Antonia, Naiyer Rizvi, Julie Brahmer, Sai-Hong Ou, Samir N. Khleif, Wen-Jen Hwu, Martin Gutierrez, Patrick Schoffski, Omid Hamid, Jared Weiss, Jose Lutzky, Michele Maio, John Nemunaitis, Dirk Jaeger, Ani Balmanoukian, Marlon C. Rebelatto, Keith E. Steele, Xiaoping Jin, Paul B. Robbins, John A. Blake-Haskins, Neil H. Segal. Safety and clinical activity of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A047.

Abstract B005: An immunohistochemical PD-L1 companion diagnostic assay for treatment with durvalumab (MEDI4736) in NSCLC patients

Background: A high quality PD-L1 companion diagnostic may help predict which patients are more likely to respond to PD-1/PD-L1 antibody-based therapy. Here we describe a PD-L1 immunohistochemical (IHC) diagnostic test developed by Ventana Medical Systems for use with durvalumab. Methods: An anti-human PD-L1 rabbit monoclonal antibody (SP263) was optimized for use with Ventana OptiView DAB IHC Detection Kit on the automated BenchMark ULTRA platform. The PD-L1 IHC assay was validated for use in formalin-fixed, paraffin-embedded samples of NSCLC in a series of studies addressing sensitivity, specificity, robustness, and precision. Durvalumab is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity. A subset of clinical trial samples from a Phase 1/2 study of durvalumab (NCT01693562) was analyzed to determine optimal cut-off for enriching response to durvalumab. Inter-reader precision was established by 3 pathologists who evaluated 81 NSCLC samples across the range of expression levels. Results: The Ventana PD-L1 IHC (SP263) assay met all pre-defined acceptance criteria. The scoring algorithm was defined using statistical analysis of clinical response data and PD-L1 staining parameters observed in a set of NCT01693562 clinical trial samples. Samples of both cancer types are considered test positive when the membrane of ≥ 25% of tumor cells stain for PD-L1 at any intensity. Inter-reader precision in determining PD-L1 status resulted in an overall percentage agreement of 97% for NSCLC. PD-L1+ patients identified by the scoring algorithm had a higher response rate than PD-L1- patients. Interlaboratory testing was performed at 3 external laboratories and demonstrated an overall agreement rate of 86.4%. Conclusions: These results highlight the robustness and reproducibility of the PD-L1 IHC (SP263) assay in a clinical setting. In NSCLC patients treated with durvalumab, PD-L1+ patients identified by the scoring algorithm had a higher response rate than PD-L1- patients. The clinical utility of the PD-L1 diagnostic assay will be further validated in a prospective manner using additional patients in this study and in other durvalumab studies. Citation Format: Marlon C. Rebelatto, Amita Mistry, Constantine Sabalos, Nicole Schechter, Jill Walker, Anita Midha, Keith E. Steele, Paul B. Robbins, Xia Li, Li Shi, John A. Blake-Haskins, Ramy A. Ibrahim, Laura Richman. An immunohistochemical PD-L1 companion diagnostic assay for treatment with durvalumab (MEDI4736) in NSCLC patients. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B005.