Anti-PD-L1 antibody shows promising activity in advanced bladder cancer after decades of silence

Lugano/Madrid, 29 September 2014 -- The engineered anti-PD-L1 antibody MPDL3280A shows promising activity in advanced bladder cancer after decades of silence, according to Dr Maria De Santis, medical oncologist at the Centre for Oncology and Hematology, Kaiser Franz Josef Hospital, Vienna, Austria. De Santis said that emerging data on the antibody “give hope for a new and effective treatment strategy for advanced bladder cancer” as the latest research in the field was presented at the ESMO 2014 Congress in Madrid, Spain.

De Santis said: “Bladder cancer is the ninth most commonly diagnosed cancer worldwide, with more than 380,000 new cases each year and more than 150,000 deaths per year. It is a highly aggressive and deadly disease and no major progress has been made for more than a decade.”

She continued: “Cisplatin based combination chemotherapy is still the standard of care in advanced or metastatic bladder cancer. However, about 50% of patients are not eligible for standard cisplatin based chemotherapy because of a variety of reasons including poor performance status, impaired renal function and comorbidities.”

“Given the modest response durations with traditional cytotoxic chemotherapy, in particular in cisplatin-ineligible patients and those relapsing or progressing after platinum based combination chemotherapy, there has been an interest in exploring novel treatment strategies in this patient population,” added De Santis.

Commenting on the difficulty of treating urothelial bladder cancer, which is the most common type of bladder cancer, De Santis said: “Looking at the tumour itself, urothelial bladder cancer has a high mutational complexity. This fact makes it more difficult to treat with conventional chemotherapy and specific targeted therapies. This same fact offers the potential for many neo-antigens to be seen as foreign by the host immune system and might be an advantage for immunotherapy to work in bladder cancer.”

It has been known for many years that urothelial bladder cancer is an immune-responsive disease, said De Santis. “This goes back to the treatment of non-muscle invasive bladder cancer with instillation of bacillus Calmette-Guérin (BCG) into the bladder. BCG proved to be able to significantly reduce the progression to muscle invasive bladder cancer or to metastases and treatment with BCG resulted in superior 10 year disease specific survival.”

“The immune system is also active in muscle invasive urothelial bladder cancer,” continued De Santis. “CD8 tumour-infiltrating lymphocytes in the primary tumour have been shown to be predictive of survival.2 In addition the presence of some immune co-regulatory proteins (including PD-1) in advanced or metastatic urothelial cancer is frequent, and some of them correlated with survival.

Inhibition of PD-L1 interactions can restore antitumour T-cell activity and enhance the cellular immune attack on antigens. The anti-PD-L1 antibody MPDL3280A is a novel immunotherapeutic approach that has proven noteworthy activity in heavily pre-treated patients with metastatic urothelial bladder cancer in early phase trials. A promising 43% response rate in a subset of patients was recently reported, including some complete responses and a considerable number of durable responses. “Such results have been lacking with conventional chemotherapy,” said De Santis.

PD-L1 inhibition is also being explored further as first-line treatment in cisplatin-ineligible patients. De Santis said: “Higher grade toxicities with MPDL3280A were very rare and there has been no evidence of renal toxicity so far. This fact is of major importance because many bladder cancer patients are elderly, have a decreased performance status and suffer from renal function impairment and other comorbidities.”

She concluded: “For the first time in many years exciting news has emerged for patients with bladder cancer. Immunotherapy and, more specifically, treatment with the engineered anti-PD-L1 antibody MPDL3280A may offer a new, effective, safe and well tolerated treatment option for advanced and metastatic bladder cancer patients while preserving quality of life. Further studies are needed to confirm the preliminary data. Most importantly, these early data are important enough for a breakthrough therapy designation that has been granted by the FDA.”


Notes to Editors

808O: Inhibition of PD-L1 by MPDL3280A leads to clinical activity in pts with metastatic urothelial bladder cancer (UBC)

Session info

808O                      Monday, September 29, 2014 – 11:00 AM – 12:30 PM  - Hall Sevilla

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Abstract: 808O

Inhibition of PD-L1 by MPDL3280A leads to clinical activity in pts with metastatic urothelial bladder cancer (UBC)

J. Bellmunt1, D.P. Petrylak2, T. Powles3, F. Braiteh4, N. Vogelzang5, C. Cruz6, H. Burris7, J.P. Eder8, G. Fine9, M.S.L. Teng10, X. Shen11, J. Bruey11, Z. Boyd11, P. Hegde11, D. Chen9, Y. Loriot12
1Medical Oncology, Dana Farber Cancer Institute, Boston/UNITED STATES OF AMERICA, 2Medical Oncology, Columbia University Medical Center, New York/UNITED STATES OF AMERICA, 3Barts Cancer Institute, St Bartholomew's Hospital QMUL, London/UNITED KINGDOM, 4Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas/UNITED STATES OF AMERICA, 5Develop Therapeutics & Co-chair Gu Comm, US Oncology Research c/o Comprehensive Cancer Crts of NV, Las Vegas/UNITED STATES OF AMERICA, 6Medical Oncology Department, Vall d'Hebrom Institute of Oncology and Vall d'Hebron University Hospital, Barcelona/SPAIN, 7Dept. Drug Development, Sarah Cannon Research Institute, Nashville/UNITED STATES OF AMERICA, 8Medical Oncology, Yale Cancer Center, New Haven/UNITED STATES OF AMERICA, 9Medical Director, Genentech, South San Francisco/UNITED STATES OF AMERICA, 10Oncology Dept, Genentech, South San Francisco/UNITED STATES OF AMERICA, 11Clinical Research, Genentech, Inc., South San Francisco/UNITED STATES OF AMERICA, 12Medical Oncology, Institut de Cancérologie Gustave Roussy, Villejuif/FRANCE

Aim: New treatments are needed for metastatic UBC. PD-L1 expression is prevalent in UBC and may help protect cancer cells from immune-mediated destruction. MPDL3280A is a human anti-PD-L1 mAb with an engineered Fc-domain which disrupts PD-L1 binding to its receptors PD-1 and B7.1.

Methods: In a Ph I study, UBC pts received MPDL3280A 15 mg/kg IV q3w for up to 1 y. Objective response (OR; unconfirmed and confirmed) was assessed by RECIST v1.1. PD-L1 IHC was centrally evaluated on tumor biopsies. Circulating biomarkers were evaluated.

Results: As of Jan 1, 2014, 68 UBC pts were treated with MPDL3280A. 67 were evaluable for efficacy (dosed by Nov 20, 2013; with ≥ 6 wk follow-up) and included 30 PD-L1 IHC 2/3, 35 PD-L1 IHC 0/1 and 2 PD-L1 unknown pts. The 67 efficacy evaluable pts were 72% male, had a median age of 65 y (36-86) and 59% were ECOG PS 1. 75% had visceral metastases and 33% had liver metastases. 72% received ≥ 2 prior therapies, 93% received prior platinum-based chemo, 79% received prior cisplatin and 42% received MPDL3280A ≤ 3 mo from last prior chemo. For IHC 2/3 pts, ORR was 43% (95% CI 26-63; 2 CRs, 11 PRs); the median duration of response (DOR) was not reached (range 0.1+ - 30.3+ wk). For IHC 0/1 pts, ORR was 11% (95% CI 4-26; 4 PRs); the median DOR was not reached (range 0.1+ - 6.0+ wk). 16/17 responders were still responding as of clinical cutoff date and included pts with poor prognostic factors. For the 17 responders, the median time to first response was 42 d (38-85 d). The 68 safety-evaluable pts received MPDL3280A for a median duration of 65 d (1-259 d). All grade study drug-related AEs occurred in 57% of pts, most often decreased appetite, fatigue and nausea. Treatment-related G3/4 AEs were seen in 4% of pts (no G4 AEs or treatment-related deaths were observed); there was 1 event each of asthenia, thrombocytopenia and decreased blood phosphorus. Treatment resulted in transient increases in pharmacodynamics biomarkers, including Ki-67+CD8+ T cells and plasma proteins (eg, IL-18). Updated data will be presented, including PFS.

Conclusions: MPDL3280A was well tolerated in this heavily pretreated UBC population. The majority of responses were rapid and on-going, and PD-L1 status correlated with response to MPDL3280A.

Disclosure: J. Bellmunt: J Bellmunt: Genentech consultant, stock. F. Braiteh: Fadi Braiteh has served as a consultant on the speakers bureau for Amgen/Onyxx, Bayer, BMS, Caris Life Sciences, Celgene, Genomic Health, Incyte, INSYS, Novartis, Pfizer, Sanofi and as consultant to Agendia, Foundation Medicine, and Saladax.
N. Vogelzang: Nicholas N. Vogelzang has served as a consultant for Celgene and Roche/Genentech and has received research funding from Novartis and honoraria from Pfizer. G. Fine: Gregg Fine is an employee of Genentech, Inc.
M.S.L. Teng: Melinda S.L. Teng is an employee of Genentech, Inc. X. Shen: Xiaodong Shen is an employee of Genentech, Inc. J. Bruey: Jean-Marie Bruey is an employee of Genentech, Inc. Z. Boyd: Zach Boyd is an employee of Genentech, Inc. P. Hegde: Priti Hegde is an employee of Genentech, Inc. D. Chen: Daniel S. Chen is an employee of Genentech, Inc. Y. Loriot: Yohann Loriot has served as a consultant for Astellas, Sanofi, Celgene and Pierre Fabre, and received research grants from Astellas and Sanofi.
All other authors have declared no conflicts of interest.