1. Goodwin, Peter M.

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First-line immunotherapy with the anti-programmed cell death protein (PD-1) antibody pembrolizumab did not improve outcomes among patients with advanced urothelial carcinoma in the KEYNOTE-361 Phase III, randomized, open-label study published in The Lancet Oncology (2021;

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"This trial adds to the growing body of evidence showing that immune checkpoint inhibitors given with chemotherapy are not associated with clear survival benefits for urothelial carcinoma," wrote first author Thomas Powles, MD, from Barts Cancer Institute, Queen Mary University of London, and co-authors from Hungary, Turkey, Japan, Canada, France, Belgium, Spain, and the U.S.


"Platinum-based chemotherapy remains the current first-line standard of care for patients able to receive it, with avelumab maintenance therapy for those who have a clinical benefit," they wrote in their comment on the study's primary findings.


KEYNOTE-361 enrolled patients at 201 medical centers in 21 countries who were at least 18 years old with locally advanced, unresectable, or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra, and had no previous systemic treatment for advanced disease.


Since inhibitors of PD-1 and PD-L1 had already shown activity in second-line therapy for metastatic urothelial carcinoma, the study was designed to determine whether positive randomized data could be found to support their use for initial treatment.


Outcomes were reported among patients treated with first-line pembrolizumab used alone or in combination with chemotherapy, and then compared these with outcomes among a control group of patients who received standard platinum-based chemotherapy. There were no statistically significant differences between the three groups in terms of progression-free survival (PFS) or overall survival (OS). The finding was that this checkpoint inhibitor immunotherapy failed to improve outcomes in comparison with chemotherapy alone.


A total of 1,010 patients were randomized: 351 had treatment with pembrolizumab plus platinum-based chemotherapy, 307 received pembrolizumab monotherapy, and 352 had platinum-based chemotherapy.


Patients had been followed up for a median of 31.7 months. PFS in patients treated with pembrolizumab plus chemotherapy was a median of 8.3 months, compared with 7.1 months in the chemotherapy group. Median OS was 17.0 months in the pembrolizumab plus chemotherapy group and 14.3 months among patients who had chemotherapy without the checkpoint inhibitor. OS was reported as 15.6 months in the exploratory analysis for pembrolizumab monotherapy, compared with 14.3 months with chemotherapy-statistically similar results.


Neither did any patient subgroup emerge with an indication of benefit from using the checkpoint inhibitor. Although the genetic features PD-1 and programmed death cell ligand (PD-L1) had been known theoretically to be involved with pembrolizumab targeting, the presence of these markers made no differences to outcomes. Specifically, the trial checked for the relevance of PD-L1 overexpression on pembrolizumab effectiveness. Outcomes for patients with PD-L1 combined positive scores (CPS) of at least 10 were compared with those of all patients treated with pembrolizumab irrespective of CPS. Immunotherapy failed to improve outcomes in any patient subgroup. Patients treated with pembrolizumab therapy who had CPS of at least 10 survived for a median of 16.1 months compared with 15.2 months OS among those treated with chemotherapy.


Toxicity wasn't an issue. There were no "new or unexpected safety signals" with pembrolizumab plus platinum-based chemotherapy. The study found a similar safety profile irrespective of pembrolizumab use.


There was no statistically significant difference in median progression-free survival between the pembrolizumab plus chemotherapy group (8.3 months) and the group receiving chemotherapy alone (7.1 months).


Looking at the details: 73 percent of all patients had "progression-free survival events." The proportion was only slightly different between the three study groups: 74 percent of the pembrolizumab plus chemotherapy group had progression events, while 78 percent of patients treated with pembrolizumab alone had such relapses. There were slightly fewer patients with events (66%) in the group treated with chemotherapy alone.


The most common Grade 3/4 adverse event attributed to study treatment was anemia-reported in 30 percent of patients treated with pembrolizumab plus chemotherapy and 33 percent of patients receiving chemotherapy alone. Six patients died due to an adverse event attributed to study treatment; two patients in each treatment group.


The investigators reported that at the time of the final analysis 717 (71%) of the patients had died. These included 70 percent of those treated with pembrolizumab plus chemotherapy, 68 percent of patients in the pembrolizumab monotherapy group, and 75 percent of the chemotherapy group. Median overall survival was 17.0 months in the pembrolizumab plus chemotherapy group compared with 14.3 months in the chemotherapy group-a non-significant difference.


The study findings suggested that combining first-line pembrolizumab plus chemotherapy had not improved survival of unselected patients with advanced urothelial carcinoma, and no subgroups had performed any better than others. The authors concluded: "The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma."


Peter M. Goodwin is a contributing writer.