Hahn NM, et al. ASCO 2017:4525


In urothelial carcinoma (UC), optimal second-line options remain undefined and prognosis has been poor among patients failing platinum-containing chemotherapy.1 However, several inhibitors of programmed death 1 and programmed death-ligand 1 (PD-L1) have demonstrated activity with acceptable safety profiles in patients with advanced UC.2–7 The following study, presented at the 2017 ASCO Meeting, investigated the safety and efficacy of the PD-L1 inhibitor durvalumab in patients with locally advanced or metastatic UC.8

Study design

  • The following results were a planned update of a phase I/II, multicentre, open-label study.9
  • Patients were aged ≥18 years with histologically/cytologically confirmed solid tumours.
    • Patients had locally advanced/metastatic UC and could have progressed on, were ineligible for, or had refused any number of prior therapies.
    • Patients could also be treatment-naïve.
  • Patients had an Eastern Cooperative Oncology Group performance status of 0–1 and had adequate organ and marrow function.
  • Key exclusion criteria included receipt of any immunotherapy or investigational anticancer therapy within the past four weeks (six weeks for monoclonal antibodies) or receipt of any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer.
  • Patients received durvalumab (10 mg/kg) intravenously once every two weeks for up to 12 months or until confirmed progressive disease, initiation of another anticancer therapy, unacceptable toxicity, or consent withdrawal.
  • Primary safety endpoints included adverse events (AEs), serious AEs, laboratory evaluations, vital signs, and physical exams.
    • AEs of special interest (AESIs) and immune-mediated AEs (imAEs) were also assessed.
  • The primary efficacy endpoint was objective response rate (ORR) per blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1.
    • Key secondary endpoints included duration of response (DOR), time to response, change in target lesion size, disease control rate (defined as confirmed response or stable disease ≥6 weeks), progression-free survival (PFS), and overall survival (OS).
  • All patients who received their first dose of durvalumab ≥30 days prior to the data cutoff date for an interim analysis (July 24, 2016) were included in the safety and efficacy analyses (‘as-treated’ population).

Key findings

Baseline characteristics and disposition

  • A total of 191 patients had enrolled and received treatment, all of whom were eligible for safety and efficacy analyses.
  • All patients had stage IV disease and 95.3% of patients (n = 182) had progressed on or after a platinum-based therapy or within 12 months of receiving neoadjuvant therapy (second-line or greater [≥2L] post-platinum subgroup).
  • Of the entire cohort, 177 patients (92.7%) had visceral metastases, 82 (42.9%) had liver metastases, and 14 (7.3%) had lymph node-only disease.
  • PD-L1 expression was high in 98 patients (51.3%), low or negative in 79 patients (41.4%), and unknown in 14 patients (7.3%).
  • In the as-treated population, median duration of exposure was 2.8 months (range: 0.4–12.5) and median follow-up was 5.78 months (range: 0.4–25.9).
  • As of the 90-day update data cutoff of October 24, 2016, 44 patients (23.0%) were still receiving durvalumab.


  • In the as-treated population (n = 191), ORR was 17.8%. (Table 1)
    • Responses were observed across all subgroups, including patients with poor prognosis.
    • ORR was 27.6% in patients with high PD-L1 expression and 5.1% in patients with low/negative PD-L1 expression. (Table 1)
    • ORRs for patients with visceral metastases and liver metastases were 15.3% (95% CI: 10.3–21.4) and 7.3% (95% CI: 2.7–15.2), respectively.
    • ORR for patients with lymph node-only disease was 50% (95% CI: 23.0–77.0).
  • Responses were early (median time to response: 1.41 months), durable (median DOR not reached), and observed regardless of PD-L1 expression. (Figure 1)
    • Complete responses were observed in patients in the high and low/negative PD-L1 subgroups. (Table 1)
    • Seventeen of 34 responders (50.0%) had a response that lasted ≥6 months and 26 responders (76.5%) had a response that was ongoing at the time of data cutoff. (Figure 1Table 1)
  • Among 159 patients with target lesions at baseline and ≥1 post-baseline scan, 51 (32.1%) had a ≥30% target lesion reduction from baseline.
  • Median PFS was 1.5 months. (Figure 2)
  • Median OS was 18.2 months. (Figure 3)
    • Given limited follow-up, OS data were considered immature at the time of data cutoff.


  • Any-grade treatment-related AEs (TRAEs) occurred in 60.7% of patients and grade 3/4 TRAEs occurred in 6.8% of patients. (Table 2)
    • Median time to onset of any-grade TRAE was 6.1 weeks (range: 4.1–10.1).
    • TRAEs leading to death (which were also imAEs) occurred in two patients (1%).
    • TRAEs led to permanent discontinuation in three patients (1.6%) and required infusion interruption or dose delay in 21 patients (11.0%).
  • Any-grade treatment-related AESIs occurred in 34.6% of patients, the majority of which were grade 1/2.
    • Grade 3/4 AESIs occurred in 4.7% of patients.
  • imAEs occurred in 11.5% of patients, the majority of which were grade 1/2. (Table 2)
    • Grade 3/4 imAEs occurred in four patients (2.1%; two with grade 3/4 select hepatic events and one each with grade 3/4 rash and select renal events).
  • The cumulative incidences of TRAEs and AESIs occurred early and appeared to plateau at approximately 32 weeks.

Table 1. Antitumour activity of durvalumab per BICR

Table 2. TRAEs and imAEs

Figure 1. Time to response and DOR

Figure 2. PFS by BICR per RECIST

Figure 3. Overall survival*

Key conclusions

  • Durvalumab demonstrated favourable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC.
  • Responses were early, durable, and observed regardless of PD-L1 expression; however, ORR was numerically higher in patients with high PD-L1 expression compared to those with low/negative PD-L1 expression.
  • Durvalumab was well tolerated with most TRAEs, AESIs, and imAEs being grade 1/2.
    • Grade 3/4 events were generally manageable with established guidelines.
  • The onset of TRAEs and AESIs occurred early in the treatment regimen and plateaued after approximately 32 weeks.
  • Further studies are evaluating durvalumab as monotherapy and in combination with other agents in patients with UC.

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