KEYNOTE-361: PFS and OS benefits of pembrolizumab and chemotherapy versus chemotherapy alone are not statistically significant for advanced urothelial carcinoma

Platinum-based chemotherapy, remains the standard of care in first-line (1L) treatment of advanced urothelial carcinoma (UC). In second-line (2L) therapy for patients with UC, multiple anti-PD-L1 therapies, including pembrolizumab, are approved for use. Pembrolizumab is also recommended as 1L monotherapy for patients with tumors ineligible for cisplatin-based treatment and any platinum agent.

The KEYNOTE-361 study (NCT02853305) is a global, randomized, open-label, Phase III clinical trial of pembrolizumab alone or combined with platinum-based chemotherapy versus chemotherapy as 1L treatment for patients with advanced UC, comparing the efficacy and safety.1

The eligibility criteria were outlined as:

  • UC of renal pelvis, ureter, bladder or urethra
  • Locally advanced unresectable or metastatic disease
  • No prior systemic therapy for advanced disease
  • ECOG performance status 0, 1 or 2
  • Tissue sample for PD-L1 assessment

Patients were randomized as 1:1:1 to platinum-based chemotherapies in combination with pembrolizumab, pembrolizumab alone or platinum-based therapies alone. Dual primary endpoints were progression-free survival (PFS) per response evaluation criteria in solid tumors (RECIST) 1.1 assessed by blinded independent central review (BICR) and overall survival (OS). A number of secondary endpoints were used, including safety.

Results demonstrated a median PFS for pembrolizumab and chemotherapy, pembrolizumab alone and chemotherapy alone for total patients (n = 1010) was 8.3 months, 3.9 months and 7.1 months respectively, and median OS was 17.0 months, 15.6 months and 14.3 months, respectively. Further results with respect to hazard ratio (HR), objective response rate (ORR), duration of response (DOR), subsequent therapy and discontinuation rate are highlighted in the abstract.

To summarize, PFS and OS benefits of pembrolizumab and chemotherapy versus chemotherapy alone did not reach statistical significance in patients with previously untreated advanced UC, however, pembrolizumab was associated with a more durable response.

DANUBE: the longest follow-up to date for a randomized trial of immunotherapy in previously untreated, unresectable metastatic UC

Platinum-based chemotherapy, such as cisplatin-based, remains the standard of care for the first-line (1L) treatment of metastatic urothelial carcinoma (UC). While responses are initially high, patients’ relapse, and long-term durable remissions are rare and survival outcomes are poor. Previously, there have been two single-arm Phase II trials, with relatively modest numbers, which approved the use of atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1L) for the 1L treatment of cisplatin-ineligible patients with metastatic UC and high tumor PD-L1 expression. However, this setting lacks mature, randomized, overall survival data.


Durvalumab (anti-PD-L1) is FDA approved for the treatment of platinum-refractory, metastatic UC. Tremelimumab (anti-CTLA-4) has been used alone and in combination with durvalumab in platinum-refractory, metastatic UC, demonstrating activity regardless of the PD-L1 expression. DANUBE (NCT02516241) is a randomized, Phase III clinical trial evaluating durvalumab, with or without tremelimumab, versus platinum-based chemotherapy (gemcitabine + cisplatin [GemCis] or carboplatin [Carbo]) as a 1L treatment for metastatic UC.2

The inclusion criteria were outlined as:

  • 18 years of age, or above
  • ECOG performance status of 0 or 1
  • Unresectable, stage IV UC (including renal pelvis, ureter, bladder and urethra)

Patients were randomized 1:1:1 to durvalumab, durvalumab + tremelimumab, and chemotherapy, for a set number of cycles, until disease progression or unacceptable toxicity. The median follow-up for survival was 41.2 months. Dual primary endpoints compared overall survival (OS) for (1) durvalumab versus chemotherapy in patients with high PD-L1 expression and (2) durvalumab + tremelimumab versus chemotherapy in the ITT population.

There was no significant difference between median OS in groups (1) and (2), meaning the trial did not meet either of the dual primary endpoints. However, secondary analyses suggested that the combination of durvalumab and tremelimumab has activity, which is enhanced in patients with tumors that have high PD-L1 expression. This suggests that even though neither primary endpoints were met, it provides potential data for a combination in the biomarker positive population for future trials.


  1. Alva A, et al. Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. Annals of Oncology. 2020;31(suppl4): S1142-S1215.
  2. Powles T, et al. A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). Annals of Oncology. 2020;31 (suppl 4):S550-S550.

Written by Frankie Lewns

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