Page 5 - Canadian Urological Association/Genitourinary Medical Oncologists of Canada consensus statement: Management of unresectable locally advanced and metastatic urothelial carcinoma

CUAJ – Consensus Statement Warren et al
Unresectable locally advanced and metastatic urothelial carcinoma

Immunotherapy in cisplatin-ineligible patients
Checkpoint inhibitors active on the PD-1 / PD-L1 interaction between tumour cells and cytotoxic
T cells, have demonstrated efficacy in a first line setting in cisplatin-ineligible patients with
advanced UC. Pembrolizumab, a monoclonal antibody against the PD-1 receptor on T cells and
other immune cells, was evaluated in 370 cisplatin-ineligible patients with advanced urothelial
carcinoma in a single arm phase II study. An ORR of 29% was in the range of that seen with
chemotherapy, with a potential advantage over chemotherapy existing in both the durability of
responses and overall tolerability of this regimen. Sixty eight percent of responses were ongoing
at 12 months and grade 3-4 toxicity mostly from immune-related adverse events (irAEs) was
seen in 16% (Table 2). Median OS was 11.5 months. Responses were more likely in patients
with PD-L1 positivity on immunohistochemistry (IHC) as measured by a combined positive
score (CPS) > 10%. 26,27 Similar outcomes were obtained with atezolizumab which is a
monoclonal antibody against the PD-L1 receptor on tumour and immune cells. In a single arm,
phase II study in 119 patients, the ORR was 23% with 70% of responses ongoing after a median
follow up of 17.2 months and a median OS of 15.9 months. Grade 3 / 4 toxicity was seen in 16%
of patients. The differential effect of PD-L1 expression by IHC on ORR% was not as obvious
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(Table 2). GUMOC currently does not endorse these agents for first line therapy. This is
discussed below in ‘Current approvals and status of the evidence of immunotherapy in advanced
UC’.

Second-line systemic therapy:
– In patients who have progressive disease during or after platinum-based
chemotherapy, pembrolizumab is the preferred regimen (if available)
– Where pembrolizumab is unavailable or a patient is ineligible, single agent
paclitaxel or docetaxel is preferred for the majority of patients.
– Re-treatment with a platinum based regimen is a reasonable option in a patient who
has disease progression following a prolonged (> 6 – 12 month) initial response to
platinum-based chemotherapy.

1. Chemotherapy
Prior to the advent of checkpoint inhibitors in unresectable locally advanced and metastatic UC,
there was no standout salvage chemotherapy regimen for patients progressing during or after
platinum-based regimens. Re-treatment with a platinum regimen can be a successful strategy in
patients with an initial response lasting greater than 6 – 12 months. 29–31 Patients progressing
within this timeframe are likely to be refractory to further platinum therapy. The only
randomized phase III study in this group of patients compared vinflunine to best supportive care.
Although OS was not improved in the ITT population, analysis of those patients fulfilling
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eligibility criteria revealed a median OS benefit of 2 months. Vinflunine is not available in
North America. Although doublet chemotherapy regimens are associated with higher response