De Wit R, et al. ESMO 2017:LBA37
Petrylak DP, et al. ESMO 2017:851PD

Mature results and subgroup analyses from the KEYNOTE-045 trial of pembrolizumab versus chemotherapy for recurrent, advanced urothelial cancer


In Canada, pembrolizumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or within 12 months of completing neoadjuvant or adjuvant platinum-containing chemotherapy.1 The KEYNOTE-045 trial was stopped prematurely after pembrolizumab was shown to significantly improve overall survival (OS) when compared with chemotherapy in this patient population.2 Mature results from the trial and subgroup analyses of pembrolizumab compared to each investigator’s choice of chemotherapy were presented at the ESMO 2017 Annual Congress.3,4

Study design

  • KEYNOTE-045 was an international, open-label, phase III trial of pembrolizumab versus investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) in patients with advanced UC that had failed platinum-based chemotherapy.
  • Key inclusion criteria were:
    • Histologically or cytologically confirmed UC of the renal pelvis, ureter, bladder, or urethra;
    • Disease progression after platinum-based chemotherapy or recurrence <12 months after perioperative platinum-based therapy;
    • No more than two prior lines of systemic chemotherapy;
    • Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2; and
    • Provision of tumour sample for biomarker assessment.
  • Patients were randomized 1:1 to receive pembrolizumab (200 mg intravenously every 3 weeks [q3w]) or investigator’s choice of paclitaxel (175 mg/m2 q3w), docetaxel (75 mg/m2 q3w), or vinflunine (320 mg/m2 q3w).
  • Patients were stratified based on ECOG PS, presence/absence of liver metastases, hemoglobin level, and time from last chemotherapy dose.
  • Response was assessed at Week 9, then every six weeks for the first year, and every 12 weeks thereafter.
  • The primary endpoints were overall survival (OS) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (blinded, independent central review).
  • Secondary endpoints included objective response rate (ORR) per RECIST version 1.1 (blinded, independent central review), duration of response (DOR), and safety.
  • Efficacy outcomes with pembrolizumab compared to chemotherapy were assessed in the total intention-to-treat population and in the subgroup of patients whose tumours expressed programmed death-ligand 1 (PD-L1).
  • Safety with pembrolizumab compared to chemotherapy was assessed in all patients who received at least one dose of study treatment (as-treated population).
  • The median duration of follow-up was 22.5 months for both pembrolizumab (range: 18.5–30.5) and chemotherapy (range: 18.2–29.3).
  • Detailed inclusion and exclusion criteria can be found at

Key findings

Baseline characteristics and disposition

  • A total of 270 patients were assigned to the pembrolizumab arm and 272 patients to the chemotherapy arm (paclitaxel, n = 84; docetaxel, n = 84; vinflunine, n = 87). (Figure 1)
  • Baseline demographics were generally balanced between the treatment arms.
    • The median age was 67 years in the pembrolizumab arm and 65 years in the chemotherapy arm.
    • The majority of patients had an ECOG PS ≤1 (97.0% in the pembrolizumab arm and 97.1% in the chemotherapy arm).
    • First-line therapy was the most recent prior therapy in the majority of the patients in both arms (68.1% in pembrolizumab arm versus 58.1% in the chemotherapy arm).
    • The majority of patients in both arms had received cisplatin as prior platinum therapy (73.7% vs. 78.7%).
    • A PD-L1 combined positive score (CPS) of ≥10 was found in 27.4% of patients on pembrolizumab versus 33.1% of patients on chemotherapy.
  • At the time of data analysis, all patients in the chemotherapy arm had discontinued treatment, whereas 9% of patients in the pembrolizumab arm continued to receive treatment.

Figure 1. Patient disposition


  • Median OS was significantly longer with pembrolizumab when compared with chemotherapy in all patients (10.3 months vs. 7.4 months) and in patients with CPS ≥10 (8.0 months vs. 5.2 months). (Figure 2)
    • A significant benefit in OS was also demonstrated in the pembrolizumab arm when compared to paclitaxel (7.0 months), docetaxel (7.4 months), and vinflunine (7.4 months) arms.
    • An OS benefit for the pembrolizumab arm was observed across all subgroups analyzed including age, hemoglobin levels, presence of visceral disease, and presence of liver metastases. An OS benefit was observed with pembrolizumab regardless of age, presence of liver metastases, hemoglobin levels, and presence of visceral disease.
  • PFS was not significantly different between the pembrolizumab and chemotherapy groups or between the pembrolizumab group and each type of chemotherapy. (Figure 3)
    • In the pembrolizumab arm, a plateau can be seen in the tail of the Kaplan-Meier curve, representing a subset of patients with long-term benefit.
  • The ORR was higher in patients receiving pembrolizumab when compared with those receiving chemotherapy in all patients (21.1% vs. 11.0%) and in patients with CPS ≥10 (20.3% vs. 6.7%).
    • A similar trend was observed when the pembrolizumab arm was compared to each chemotherapy group (11.9% for paclitaxel, 6.0% for docetaxel, and 17.2% for vinflunine).
  • The median time to response was 2.1 months in both arms for all patients and 2.0 months in the pembrolizumab arm versus 2.1 months in the chemotherapy arm for patients with CPS ≥10.
  • Responses were more durable with pembrolizumab than with chemotherapy in all patients and in patients with CPS ≥10 (median DOR not reached vs. 4.4 months [range: 1.4–24.0] for both).
    • The median duration of response in the paclitaxel, docetaxel, and vinflunine chemotherapy groups were 5.6 months (range: 2.8–20.9), 4.4 months (range: 1.4– 20.8), and 4.3 months (range: 1.5–24.0), respectively.
    • Sixty-seven percent of the responses in the pembrolizumab arm lasted ≥12 months, compared to 38%, 38%, and 30% in the paclitaxel, docetaxel, and vinflunine arms, respectively.
  • Responses were ongoing at data cutoff.
    • In all patients, 57.9% were still responding in the pembrolizumab arm versus 20.0% in the chemotherapy arm.
    • In patients with CPS ≥10, 73.3% were still responding in the pembrolizumab arm versus 33.3% in the chemotherapy arm.

Figure 2. Overall survival

Figure 3. Progression-free survival


  • Fewer treatment-related adverse events (TRAEs) of any grade were observed in the pembrolizumab arm (62.0%) than the chemotherapy arm (90.6%). (Figure 4)
    • This trend was also observed in subgroup analyses of the pembrolizumab arm versus each of the chemotherapy groups.
  • TRAEs of grade ≥3 were observed in 16.5% of patients in the pembrolizumab arm versus 50.2% in the chemotherapy arm (44.0% for paclitaxel, 54.8% for docetaxel, and 51.7% for vinflunine).
  • Some TRAEs demonstrated a primary drug association.
  • Immune-mediated adverse events (AEs) were observed in 19.5% of patients in the pembrolizumab arm versus 7.5% in the chemotherapy arm (6.0% for paclitaxel, 8.3% for docetaxel, and 8.0% for vinflunine). (Figure 4)
  • The discontinuation rate due to TRAEs was 7.1% in the pembrolizumab arm versus 12.5% in the chemotherapy arm (10.7% for paclitaxel, 11.9% for docetaxel, and 14.9% for vinflunine).
  • There were eight deaths due to TRAEs: four patients in the pembrolizumab arm, one patient in the paclitaxel arm, and three patients in the vinflunine arm.

Figure 4. Treatment-related (A; ≥10% of patients) and immune-mediated adverse events (B; ≥2% of patients) in either treatment arm

Key conclusions

  • Pembrolizumab is the first immunotherapy to demonstrate a superior, clinically meaningful OS benefit when compared with paclitaxel, docetaxel, and vinflunine chemotherapies.
  • However, no statistically significant PFS difference was observed.
  • ORR continues to be higher and responses are more durable with pembrolizumab when compared with any of the chemotherapies assessed.
  • The median DOR was not reached in the pembrolizumab group, whereas the response ranged between 4.3 and 5.6 months in the chemotherapy groups.
  • The results in patients with PD-L1 CPS ≥10 were consistent with the primary analysis.
  • No new safety signals were identified in KEYNOTE-045 and pembrolizumab continues to demonstrate a better safety profile than chemotherapy.
  • Overall, pembrolizumab should be considered a standard of care in patients with advanced UC after failure on platinum-based therapy.

References: 1. Merck Canada. PrKEYTRUDA® (pembrolizumab) Product Monograph. September 20, 2017. 2. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376(11):1015–26. 3. De Wit R, Vaughn DJ, Fradet Y, et al. Pembrolizumab versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer: mature results from the phase 3 KEYNOTE-045 trial. ESMO Annual Congress Abstracts 2017:LBA37. 4. Petrylak DP, Vogelzang NJ, Fradet Y, et al. Subgroup analyses from KEYNOTE-045: Pembrolizumab (pembro) versus individual investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (uc). ESMO Annual Congress Abstracts 2017:851PD.