First-Line Pembrolizumab in Cisplatin-Ineligible Advanced Urothelial Cancer

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As reported in The Lancet Oncology by Arjun V. Balar, MD, of Perlmutter Cancer Center of New York York Langone Medical Center, and colleagues, first-line pembrolizumab (Keytruda) produced durable responses in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer in the phase II KEYNOTE-052 trial.1 The trial supported the accelerated approval of pembrolizumab in this setting in May 2017. More than half of patients with advanced urothelial cancer cannot receive standard first-line cisplatin-based chemotherapy due to renal dysfunction, poor performance status, or other comorbidities.

Study Details

In the study, 370 patients with no prior systemic therapy were enrolled at 91 sites in 20 countries between February 2015 and August 2016 and treated with pembrolizumab at 200 mg every 3 weeks. The primary endpoint was objective response in all patients and by programmed cell death ligand 1 (PD-L1) expression status according to the Response Evaluation Criteria in Solid Tumors v1.1, as assessed by independent central review. PD-L1 expression was measured in tumor and inflammatory cells from tumor biopsies provided at study entry. Study follow-up is ongoing.

The median age of patients was 74 years (82% ≥ 65 years); 77% were male; 42% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2; 14% had metastases to lymph nodes only and 85% had visceral metastases (liver metastases in 21%); 10% had received neoadjuvant or adjuvant cisplatin-based therapy; and reasons for cisplatin ineligibility were renal dysfunction in 49%, performance status of 2 in 32%, performance status of 2 and renal dysfunction in 9%, and other in 9%.

Response Rates and Durations

The median follow-up was 5.0 months. Overall, objective response was observed in 89 patients (24%, 95% confidence interval [CI] = 20%–29%), with a complete response in 17 patients (5%); as of data cutoff in September 2016, the median duration of response had not been reached, with responses ongoing in 74 of 89 responders (83%) and 78% of responses lasting > 6 months. Stable disease was observed in 84 patients (23%), for a disease control rate of 47%.

Pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy.
— Arjun V. Balar, MD and colleagues

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A total of 83 patients had been enrolled < 4 months before data cutoff and had insufficient time for response assessment. Among the 307 patients enrolled for ≥ 4 months, the objective response rate was 27%, with a complete response in 17 patients (6%), and stable disease was observed in 19%. Among 110 patients with a combined PD-L1 expression score ≥ 10%, objective response was observed in 42 (38%, 95% CI = 29%–48%).

Objective response rates were 30% vs 26% by age < 65 vs ≥ 65 years, 27% vs 27% for performance status 0 or 1 vs 2, 47% vs 23% for lymph node only vs visceral metastases, and 17% vs 30% for liver metastases vs no liver metastases. Response rates were 26%, 27%, 29%, and 31% among patients with renal dysfunction, performance status of 2, both, or other reasons for cisplatin ineligibility, respectively.

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 15% of patients, with the most common being fatigue (2%), increased alkaline phosphatase (1%), colitis (1%), and muscle weakness (1%). Serious treatment-related adverse events occurred in 36 patients (10%), including pyrexia (1%) and adrenal insufficiency, arthritis, colitis, diabetic ketoacidosis, hepatitis, pneumonitis, and type 1 diabetes (all in < 1%). Immune-related adverse events occurred in 63 patients (17%), with the most common being hypothyroidism (6%), hyperthyroidism (2%), colitis (2%), and pneumonitis (2%). One patient died of treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis).

Pembrolizumb in Advanced Urothelial Cancer

  • Pembrolizumab produced a response in 24% of all patients, with 78% of responses longer than 6 months at data cutoff.
  • The response rate was 38% in patients with a combined PD-L1 expression score ≥ 10%.

The investigators concluded: “First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy. Pembrolizumab in the first-line setting is being further assessed in the phase 3 KEYNOTE-361 trial.” ■

DISCLOSURE: The study was funded by Merck & Co. For full disclosures of the study authors, visit


1. Balar AV, Castellano D, O’Donnell PH, et al: First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol. September 26, 2017 (early release online).

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