Atezolizumab (also known as MPDL3280A; Roche/Genentech), a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1), is poised to become a major bladder cancer therapy in the race for U.S. Food & Drug Administration (FDA) approval, following its promising performance in recent Phase II trials. This is the conclusion of research analysts working for the London-based (UK) research and consulting firm GlobalData.

In a potential bladder cancer breakthrough, the researchers involved in the clinical trial announced that atezolizumab met its primary endpoint of objective response rate in the Phase II IMvigor 210 study. During the trial, patients with higher PD-L1 expression levels showed better responses to the drug.

Last year, the FDA granted Breakthrough Therapy Designation for atezolizumab in people whose metastatic bladder cancer expresses PD-L1. This designation is designed to expedite the development and review of medicines intended to treat serious diseases.

Following positive Phase II trial results, atezolizumab is poised to become a major bladder cancer therapy in the race for FDA approval. However, analysts expect that the drug will face strong competition in the bladder cancer treatment arena, especially fromnivolumabandpembrolizumab.

Clinical trial
The IMvigor 210 is an open-label, multicenter, single-arm Phase II study that evaluated the safety and efficacy of atezolizumab in people with locally advanced or metastatic UBC, regardless of PD-L1 expression. People in the study were enrolled into one of two cohorts. Cohort 1 consisted of people who had received no prior therapies for locally advanced or metastaticurothelial bladder cancer (UBC), but who were ineligible for first-line cisplatin-based therapy; results for this cohort are not yet mature. Cohort 2, for which results were announced today, included people whose disease progressed during or following previous treatment with a platinum-based chemotherapy regimen (second-line or later). People received a 1200-milligram intravenous dose of atezolizumab on day one of 21-day cycles until progressive disease (Cohort 1) or loss of clinical benefit (Cohort 2). The primary endpoint of the study was ORR. Secondary endpoints included duration of response (DoR), overall survival (OS), progression-free survival (PFS) and safety. PD-L1 expression was assessed using an investigational immunohistochemistry (IHC) test being developed by Roche Diagnostics. The testuses the antibody SP142 to measure PD-L1 expression on both tumor cells and infiltrating immune cells.

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Companion biomarker tests
According to Cai Xuan, Ph.D., GlobalData’s Analyst covering Oncology and Hematology, the observation that atezolizumabmaybecome a major bladder cancer therapy, along with similar results for other Programmed Cell Death Protein 1 (PD-1) inhibitors in development for various cancers, opens up a market for companion biomarker tests that can be used to identify patients who would likely benefit from PD-1/PD-L1-targeted therapies.

Xuan says: ?Atezolizumab?s Phase II results were preceded by an encouraging Phase Ia trial, during which the drug caused tumors to shrink in 50% of patients previously treated for PD-L1-positive, metastatic urothelial bladder cancer.

?In this trial, 20% of patients made a full recovery, while 57% with the highest PD-L1 expression levels were still alive one year after treatment. The most frequently observed adverse events were fatigue, asthenia, and nausea, affecting 16%, 13% and 11% of patients, respectively.?

Strong competition
Xuan expects atezolizumab to face strong competition in the bladder cancer treatment arena, especially from Bristol-Myers Squibb?s nivolumab (Opdivo?) and Merck & Co.?s pembrolizumab (Keytruda?). These three drugs have initially been targeted towards patients with locally-advanced and/or metastatic bladder cancer, with the possibility of expanding to multiple indications within the bladder cancer setting in the future.

Ongoing Phase III study
Xuan continues: ?With regards to future indications, Roche/Genentech currently have a broader development program for atezolizumab in bladder cancer, with the IMvigor 211 Phase III trial evaluating the drug in comparison with standard-of-care chemotherapy in patients with relapsed urothelial bladder cancer.

?Additionally, the IMvigor 010 Phase III trial will evaluate atezolizumab as an adjuvant therapy in early-stage, PD-L1-positive, muscle-invasive bladder cancer patients, who are at risk of recurrence. The potential to expand into multiple indications will make this drug an important player in a wave of long-awaited bladder cancer treatment innovation.?

These studies all include the evaluation of a companion test to determine PD-L1 status.

For more information
[1] Highlights of prescribing Informationnivolumab (Opdivo?); Bristol-Meyers Squibb/BMS)
[2] Highlights of prescribing Informationpembrolizumab (Keytruda?; Merck & Co

Last editorial review: July 28, 2015

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