Could PD-1 inhibitors become the new standard of care for metastatic urothelial cancer?
- Nivolumab demonstrated a durable objective response rate (ORR) of 19.6% (95% confidence interval (CI) 15.0-24.9) in the treatment of metastatic urothelial cancer (mUC)
- The safety profile of nivolumab was associated with a low rate of treatment-related grade 3-4 adverse events
- Patients who responded to treatment included those with low-to-no tumour PD-L1 expression
Results from the largest study of a programmed death (PD)-1 inhibitor in bladder cancer to date, CheckMate 275, were presented at this year’s European Society for Medical Oncology, Copenhagen. The efficacy of nivolumab, a monoclonal antibody that inhibits the PD-1 signalling pathway, was studied in a total of 270 patients with advanced/ unresectable mUC.
“Immune checkpoint inhibitors have dramatically impacted the landscape of treatment for mUC” explained Professor Matthew Galsky, Professor of Medicine at the Mount Sinai School of Medicine, New York.
“…the responses were durable, as has been shown with other immune checkpoint inhibitors across disease indications.”
Professor Matthew Galsky, Professor of Medicine, Mount Sinai School of Medicine, New York, US
Previously the mainstay treatments for mUC included cytotoxic chemotherapy and radiation for palliation, but there were “really no other systemic treatments that worked well until the development of immune checkpoint blockade,” Professor Galsky continued.
The phase II trial set out to investigate whether immune checkpoint inhibition could improve outcomes in the mUC setting. Patients, who had received platinum-based chemotherapy first line, were given 3 mg/kg nivolumab intravenously every 2 weeks until progression or unacceptable toxicity.
The primary objective investigated was estimated ORR, based on Blinded Independent Central Review (BIRC; RECIST version 1.1). “The primary analysis demonstrated that, compared to historical control chemotherapy with an ORR of about 10%, nivolumab resulted in an ORR of 19.6%,” Professor Galsky explained. “Perhaps, more importantly, the responses were durable, as has been shown with other immune checkpoint inhibitors across disease indications.”
Secondary and exploratory endpoints included progression-free survival (PFS), overall survival (OS), safety, quality of life and biomarkers associated with efficacy.
The median PFS recorded was 2 months (95% CI 1.87-2.63) and the median OS was 8.74 months (95% CI 6.05 – not estimable).
The safety profile of nivolumab was associated with a low rate of treatment-related grade 3-4 adverse events, which occurred in 18% of patients treated; the most common events reported were fatigue (2%) and diarrhoea (2%).
Time to response was 1.9 months (1.6-5.9), with an ongoing response among responders of 77% (n=40). The median duration of response has not been reached yet.
Biomarker analyses allowed Professor Galsky and his team to evaluate whether PD-L1 expression affected the efficacy of nivolumab. They found that, although PD-L1 expression was associated with a higher ORR and OS, patients with low-to-no PD-L1 expression had an ORR that exceeded 10%.
Based on the findings presented, the European Medicines Agency has initiated an official review. The Food and Drugs Administration granted nivolumab a breakthrough therapy designation in June this year, for its use second line for mUC.
Professor Galsky summarised by reflecting on how this could affect future care, “I believe that these study results demonstrate that nivolumab has the potential to become a treatment standard for this disease.”
Based on Choueiri T, Halabi S et al. CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial (LBA30_PR).
Presented on Monday 10 October 2016.
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