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Pembrolizumab delivers longer overall survival in advanced urothelial carcinoma

by ecancer reporter Janet Fricker

In second-line therapy for platinum-refractory advanced urothelial carcinoma, pembrolizumab (Keytruda®) was associated with significantly longer overall survival and lower rates of adverse events than chemotherapy, reports the phase 3 KEYNOTE-045 trial in ‘The New England Journal of Medicine’.

Patients with advanced urothelial carcinoma progressing after platinum-based chemotherapy have a poor prognosis, with median overall survivals of second-line therapy being only 6 to 7 months.

Pembrolizumab is a highly selective, humanized monoclonal antibody blocking interaction between PD-1 and its ligands, PD-L1 and PDL2; thereby activating T lymphocytes which may affect both tumour and healthy cells.

Pembrolizumab was the first anti-PD-1 antibody to be approved by the US Food and Drug Administration for treatment of patients with unresectable or metastatic melanoma with disease progression following ipilimumab, and if BRAF mutation positive, a BRAF inhibitor.

Pembrolizumab has also received breakthrough status for the treatment of EGFR mutation-negative, ALK rearrangement-negative non-small cell lung cancer (NSCLC) that has progressed on or following platinum-based chemotherapy.

For the current study between November 2014 and November 2015, Joaquim Bellumn and the Keynote investigators randomly assigned 542 patients with advanced urothelial cancer (that recurred or progressed after platinum-based chemotherapy) 1:1 to receive pembrolizumab (at a dose of 200 mg every 3 weeks) (n=270) or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine (n=272).

The assigned treatment was not blinded.

Patients were recruited from 120 sites in 29 countries

Results show the median overall survival for the total population was 10.3 months in the pembrolizumab group, versus 7.4 months  in the chemotherapy group (HR 0.73; 95% CI, 0.59 to 0.91; P=0.002).

Response rate was 21.1% for pembrolizumab versus 11.4% for placebo; and the estimated rate of duration of response of 12 months or longer was 68% with pembrolizumab versus 35% with placebo.

However, no significant difference in median progression-free survival was observed - 2.1 months in the pembrolizumab group versus 3.3 months in the chemotherapy group (HR 0.98; 95% CI, 0.81 to 1.19; P=0.42).

The same progression free survivals for patients who had tumour PD-L1 combined positive score of 10% or more (HR 0.89; 95% CI, 0.61 to 1.28; P=0.24).

Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than chemotherapy group (15.0% versus  49.4%).

“Pembrolizumab resulted in significantly longer overall survival — by approximately 3 months — than the investigator’s choice of paclitaxel, docetaxel, or vinflunine and was associated with a higher rate of objective response and a lower rate of treatment-related adverse events than chemotherapy as second-line therapy in patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, regardless of tumor PD-L1 expression status,” concluded the authors.

Addressing pembrolizumab’s lack of effect on progression free survival, the authors wrote, “Similar findings have been observed with checkpoint inhibitors in other tumor types and suggest that in contrast to its use as a surrogate end point in historical chemotherapy studies, progression-free survival may not be a reliable surrogate end point for the clinical benefit of immunotherapy.”

On the basis of these results pembrolizumab is expected to gain regulatory approval for use in second-line therapy for platinum-refractory advanced urothelial carcinoma Guru Sonpavde, from the University of Alabama at Birmingham Comprehensive Cancer Center, wrote in an accompanying editorial.

“As we celebrate the major advance that is provided by pembrolizumab, it is important to remember that this remains an incremental advance overall, although the responses were remarkably durable.

Patients who require salvage therapy remain incurable,” he wrote.

Key questions, Sonpavde added, remain.

First, is there a preferred agent among pembrolizumab, nivolumab, and atezolizumab?

Second, when should PD-1 or PD-L1 inhibitor therapy be discontinued?

And third, can a biomarker inform the selection of patients?

Bellmunt J, de Wit R, Vaughn D, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.  New England Journal of Medicine. February 17, 2017
Sonpavde G. PD-1 and PD-L1 Inhibitors as Salvage Therapy for Urothelial Carcinoma. New England Journal of Medicine. February 17, 2017



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