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Adding an immune checkpoint inhibitor to first-line platinum-based chemotherapy was not associated with clear survival benefits in advanced urothelial carcinoma, according to findings from the KEYNOTE-361 trial.

The found no significant improvement in progression-free survival (PFS) or overall survival (OS) with pembrolizumab (Keytruda) plus chemotherapy versus chemotherapy alone, reported Thomas Powles, MD, of the Barts Cancer Institute in London, and colleagues.

Median PFS was 8.3 months in the combination therapy group versus 7.1 months in the chemotherapy group (HR 0.78, 95% CI 0.65-0.93), but failed to meet prespecified statistical criteria. OS missed on significance as well, at a median 17.0 months in the combination arm versus 14.3 months in the chemotherapy group (HR 0.86, 95% CI 0.72-1.02, P=0.0407), Powles' group stated in the .

"Platinum-based chemotherapy remains the current first-line standard of care for patients able to receive it, with avelumab [Bavencio] maintenance therapy for those who have a clinical benefit," wrote Powles and co-authors.

An exploratory analysis of patients for whom pembrolizumab monotherapy is currently approved as a first-line therapy -- cisplatin-ineligible patients with a combined positive score (CPS) of at least 10 -- showed durable antitumor activity.

"Although overall survival with pembrolizumab was not markedly different to that with chemotherapy in this patient subgroup, pembrolizumab monotherapy could be an attractive treatment option for some patients," the authors wrote.

Neither PD-L1 nor choice of platinum chemotherapy appeared to be associated with improved benefit from the addition of pembrolizumab to chemotherapy.

In an , Sumanta Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, California, and colleagues, said the well-designed KEYNOTE-360 study joins IMvigor130 in an "array of influential frontline trials in advanced urothelial carcinoma."

They noted that the negative results from these two studies contrast with those of JAVELIN Bladder 100, which showed significantly prolonged PFS and OS with the PD-L1 checkpoint inhibitor avelumab (Bavencio) as a maintenance therapy for patients with stable disease following first-line platinum-based chemotherapy, findings that led to FDA approval in this setting.

"Based on KEYNOTE-361 and the totality of the available data, the use of concurrent chemoimmunotherapy is only experimental, whereas induction platinum-based chemotherapy followed by switch maintenance avelumab remains the standard frontline therapy in advanced urothelial carcinoma," Pal's group stated.

KEYNOTE-361 enrolled 1,010 patients from 2016 to 2018 at 201 centers across 21 countries, and randomized them to either pembrolizumab plus chemotherapy (n=351), chemotherapy alone (n=352), or pembrolizumab monotherapy (n=307). Median age across the three arms was about 69 years and approximately 75% were men. Median follow-up was 31.7 months.

Eligible patients had locally advanced, unresectable, or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra, and no previous systemic treatment for advanced disease. Urothelial carcinoma was required to be the predominant histology (≥50%).

Treatment protocols were:

• Combination therapy: IV pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus IV chemotherapy (gemcitabine plus investigator's choice of cisplatin or carboplatin) for a maximum of six cycles
• Chemotherapy alone, stratified by choice of platinum therapy and PD-L1 CPS
• Pembrolizumab alone

In terms of safety, no new or unexpected signals emerged with pembrolizumab plus platinum-based chemotherapy, and the treatment had a similar safety profile to that of chemotherapy alone.

The most common grade 3/4 treatment-related adverse events (AEs) were anemia with combination therapy (30%) or chemotherapy alone (33%), as well as diarrhea, fatigue, and hyponatremia (1% each) with pembrolizumab alone. Six patients died owing to a treatment-related AE (two in each arm).

Limitations of the study included a prespecified sequential statistical analysis strategy, wherein formal statistical testing could not be done for the pembrolizumab monotherapy versus chemotherapy treatment groups. Also, data on mixed responses were not collected.

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