Pembrolizumab ‘Promising’ For Advanced Urothelial Cancer

Preliminary trial results support further investigation of pembrolizumab in patients with locally advanced or metastatic urothelial cancer

medwireNews: KEYNOTE-012 findings suggest that the programmed cell death 1 (PD-1) inhibitor pembrolizumab may be feasible for the treatment of locally advanced or metastatic urothelial cancer.

“Pembrolizumab was well tolerated in this patient population and showed an acceptable safety profile that was generally consistent with safety reports of pembrolizumab in other tumour types”, the investigators report in The Lancet Oncology.

“Additionally, promising anti-tumour activity was recorded in response to pembrolizumab.”

The phase Ib open-label study of pembrolizumab 10 mg/kg on a 2-weekly basis included 33 patients with cancers of the renal pelvis, ureter, bladder or urethra who tested positive for at least 1% programmed death-ligand 1 (PD-L1) expression on tumour cells or tumour stroma by immunohistochemistry.

Fatigue and peripheral oedema were the most common treatment-related side effects, affecting 18% and 12% of patients, respectively. In addition, there were 11 reports of grade 3 treatment-related adverse events affecting 15% of the group and five serious adverse events affecting 9%. None of the grade 3 or serious events occurred in more than one patient.

There were four deaths in the study but none were considered to be related to treatment.

Elizabeth Plimack, from Fox Chase Cancer Center in Philadelphia, Pennsylvania, USA, and co-investigators also report activity data for 27 patients with a full assessment including at least one post-baseline scan.

After a median of 13 months, 26% of these patients had achieved an overall response, including a complete response in 11% and a partial response in 15%.

The response lasted more than 6 months in four of the patients and more than 12 months in three of the group; at time of data cutoff, one patient with a complete response was continuing with treatment and another had maintained their complete response after 2 years of treatment before discontinuing due to grade 3 hypercalcaemia.

Stable disease was the best response in 15% of patients, while 52% experienced progressive disease.

Median progression-free survival was 2 months, with 15% achieving progression-free survival at 12 months. Median overall survival was 13 months, with 50% of patients alive after 12 months, the researchers add.

“Studies with larger patient populations (KEYNOTE-052 [NCT02335424], KEYNOTE-045 [NCT02256436], and KEYNOTE-361 [NCT02853305]), including those with PDL1-negative patients, are underway to further assess the activity and safety of pembrolizumab in urothelial cancer, and to explore the association between PD-L1 expression and other potential biomarkers and clinical response in greater detail”, Elizabeth Plimack and co-investigators conclude.

The authors of a linked comment say the KEYNOTE-012 findings “add to the increasing number of studies of immune checkpoint inhibitors in urothelial cancer” and offer “a promising result when compared with the median overall survival of 6 to 9 months reported with standard salvage chemotherapy”.

But when also taking into consideration KEYNOTE-045 results comparing pembrolizumab and chemotherapy in advanced bladder cancer, they caution: “Although the survival benefit for pembrolizumab is extremely promising, it still seems that only a few patients treated with checkpoint inhibitors achieve a durable benefit with monotherapy.”

Furthermore, the study “highlights the inconsistency in the assessment of PD-L1 status as an integral biomarker for clinical trial eligibility”, write Tracy Rose and Matthew Milowsky, from the University of North Carolina in Chapel Hill, USA.

They note that 16% of the patients who were accepted for the study based on PD-L1 positivity were later reclassified as negative by a different assay. “The findings also suggest that the inclusion of immune cell PD-L1 status might have better predictive value for response to immune checkpoint inhibitors than tumor cell staining alone”, the commentators say.


Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol; Advance online publication 9 January 2017. doi:

Rose TL, Milowsky MI. Checkpoint inhibition: a new beginning for urothelial cancer. Lancet Oncol; Advance online publication 9 January 2017.

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