Page 7 - 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

between 15 – 31% with complete responses ranging between 2% and 11%. Median progression
free survival has ranged between 1.6 months and 2.8 months, reflecting the relatively overall low
proportion who benefit. Nonetheless, those who do respond seem to obtain durable benefit.
Grade 3 – 5 toxicity has been observed in 8 – 22% of patients.

The role of PD-L1 testing in selecting patients for immunotherapy
– In the second line setting PD-L1 testing by IHC should not be used to select patients
for immunotherapy
In the second line setting, findings from both the Keynote 045 and IMvigor 211
randomized phase III studies suggest that benefit of checkpoint inhibitors is not limited to those
with PD-L1-positive tumours by IHC. In Keynote 045, the ORR to pembrolizumab was similar
in the CPS > 10% population (22%) compared to the overall population (21%). Superior OS of
pembrolizumab compared with chemotherapy was demonstrated in both the CPS >10%
population and the overall population. In the IMvigor 211 trial, ORR was higher in the IC2/3
population (23%) compared to the ITT population (13%). Paradoxically, superior OS of
Atezolizumab compared with chemotherapy was seen in the exploratory analysis of the ITT
population , but not in the primary analysis of the IC2/3 subgroup.
Di Nunno et al combined the results of both randomized control trial s (RCT)s in a meta-analysis
and found that immunotherapy improved OS in the ITT population but not in the high PD-L1
population. Heterogeneity between trials was greater in the PD-L1 high population compared
with the ITT population demonstrating the need to further elucidate the role of PD-L1 as a
48
predictive biomarker
As illustrated in Tables 1 and 2, numerous phase I and II studies of checkpoint inhibitors
have evaluated ORR according to PD-L1 status in both first and second line settings. In some,
but not all studies, PD-L1 positivity has been associated with a higher ORR. These findings are
exploratory in nature. To date no single biomarker has been able to predict response to I-O
49
therapies in urothelial carcinoma.
In the first line setting, the role of PD-L1 as a predictive biomarker will become clearer
once results from ongoing RCTs become available. Recent safety reports have been issued from
the Data Monitoring Committees of two current phase III trials comparing PD-1 / PD-L1
inhibitors (pembrolizumab in Keynote – 361, and atezolizumab in IMvigor 130) to either
cisplatin or carboplatin combined with gemcitabine in first line urothelial carcinoma. Reduced
efficacy of checkpoint blockade compared to chemotherapy was observed in patients with low
50
PD-L1 expression.
Current approvals and the status of the evidence of immunotherapy in advanced urothelial
carcinoma
In the first line setting, neither pembrolizumab nor atezolizumab has been approved by Health
51
Canada (Health Canada, 2018). Both agents received accelerated approval by both the FDA