A Phase I Multi-Arm Dose-Expansion Study of the Anti-Programmed Cell Death-Ligand-1 (Pd-L1) Antibody Medi4736: Preliminary Data

Segal, Neil H.; Hamid, Omid; Hwu, W.; Massard, Christophe; Butler, Marcus O.; Antonia, Scott; Blake-Haskins, Andy; Robbins, Paul B.; Li, X.; Vasselli, Jim; Khleif, Samir N.

doi:10.1093/annonc/mdu342.11

Cited by 50 publications

(38 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…23 Durvalumab was administered for 12 months or until confirmed disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons for study drug discontinuation. 22 Patients with confirmed disease progression could continue to receive durvalumab if they did not have clinical deterioration and were deriving clinical benefit from treatment. Treatment interruptions, but not dose reductions, were permitted.…”

Section: Methodsmentioning

confidence: 99%

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

Massard

Gordon

Sharma

et al. 2016

JCO

760

503

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

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

Massard

Gordon

Sharma

et al. 2016

JCO

760

503

View full text Add to dashboard Cite

show abstract

“…[9][10][11][28][29][30][31][32]. The coupling between the tumor dynamics and the immune response is obtained mathematically by the product of two mechanisms.…”

Section: Biological Hypotheses and Mathematical Interpretationsmentioning

confidence: 99%

Mathematical Modeling of Cancer Immunotherapy and Its Synergy with Radiotherapy

et al. 2016

View full text Add to dashboard Cite

Combining radiotherapy with immune checkpoint blockade may offer considerable therapeutic impact if the immunosuppressive nature of the tumor microenvironment (TME) can be relieved. In this study, we used mathematical models, which can illustrate the potential synergism between immune checkpoint inhibitors and radiotherapy. A discrete-time pharmacodynamic model of the combination of radiotherapy with inhibitors of the PD1-PDL1 axis and/or the CTLA4 pathway is described. This mathematical framework describes how a growing tumor first elicits and then inhibits an antitumor immune response. This antitumor immune response is described by a primary and a secondary (or memory) response. The primary immune response appears first and is inhibited by the PD1-PDL1 axis, whereas the secondary immune response happens next and is inhibited by the CTLA4 pathway. The effects of irradiation are described by a modified version of the linearquadratic model. This modeling offers an explanation for the reported biphasic relationship between the size of a tumor and its immunogenicity, as measured by the abscopal effect (an offtarget immune response). Furthermore, it explains why discontinuing immunotherapy may result in either tumor recurrence or a durably sustained response. Finally, it describes how synchronizing immunotherapy and radiotherapy can produce synergies. The ability of the model to forecast pharmacodynamic endpoints was validated retrospectively by checking that it could describe data from experimental studies, which investigated the combination of radiotherapy with immune checkpoint inhibitors. In summary, a model such as this could be further used as a simulation tool to facilitate decision making about optimal scheduling of immunotherapy with radiotherapy and perhaps other types of anticancer therapies. Cancer Res; 76(17); 4931-40. Ó2016 AACR.

show abstract

“…Most frequent treatment-related adverse events were fatigue, nausea, and rash. Evidence of clinical activity has been seen across all histologies [17]. More recently, a phase II PLAT-FORM study (NCT02678182) is ongoing.…”

Section: Durvalumab (Medi-4736)mentioning

confidence: 99%

Anti-programmed death ligand 1 (PD-L1) inhibitors in metastatic gastric cancer

Cho

Lee

2017

Precis Future Med

View full text Add to dashboard Cite

Metastatic gastric cancer (GC) with limited therapeutic options has a poor prognosis, and therefore, major therapeutic advances are needed. Comprehensive genomic characterization has improved understanding of GC but a great majority of genomic profiling has not been effectively translated to the clinical benefit yet. The introduction of immunotherapy with anti-programmed death ligand 1 (PD-L1) antibody such as pembrolizumab or nivolumab resulted in a rapid paradigm shift in the field of medical oncology and their clinical indication has been expanding in the past few years. Now, the era of immunotherapy in metastatic GC has arrived with recent trial results in survival benefit from anti-PD-L1 antibody. Herein, we review the mechanisms of immunotherapy, clinical trials that have been conducted or are in progress, and the potential for PD-L1 as a predictive biomarker for GC.

show abstract

A Phase I Multi-Arm Dose-Expansion Study of the Anti-Programmed Cell Death-Ligand-1 (Pd-L1) Antibody Medi4736: Preliminary Data

Cited by 50 publications

References 0 publications

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

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

Mathematical Modeling of Cancer Immunotherapy and Its Synergy with Radiotherapy

Anti-programmed death ligand 1 (PD-L1) inhibitors in metastatic gastric cancer

Contact Info

Product

Resources

About