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Pembrolizumab for high-risk non-muscle invasive bladder cancer unresponsive to Bacillus Calmette-Guérin: KEYNOTE-057 trial


Activation of the PD-1 pathway has been implicated in resistance to BCG ( Bacillus Calmette–Guérin ) therapy.
Pembrolizumab ( Keytruda ), a checkpoint inhibitor with significant activity in patients with metastatic urothelial carcinoma, was evaluated in this population.

KEYNOTE-057 is a single-arm phase 2 study of the efficacy and safety of Pembrolizumab in patients with high-risk non–muscle invasive bladder cancer ( HR NMIBC ), BCG-unresponsive NMIBC.

Preliminary results for cohort A ( carcinoma in situ [ CIS ] or CIS plus papillary tumor ) are presented.

Eligible patients had histologically confirmed high-grade BCG-unresponsive NMIBC, including carcinoma in situ alone or combination of carcinoma in situ and papillary disease ( cohort A ), had been treated with adequate BCG therapy ( at least 5/6 induction instillations and 2/3 maintenance instillations ), and were unable or unwilling to undergo radical cystectomy.
Patients received Pembrolizumab 200 mg Q3W ( every three week ) for 24 months or until recurrence, progression, or unacceptable toxicity.

The primary end point for cohort A was complete response ( CR ); key secondary end points were safety and duration of response.

Patients found to have HR NMIBC or progressive disease during treatment were required to discontinue.

At the time of data cutoff, 101 patients were enrolled in cohort A. Median follow-up was 9.4 months ( range 0.2-21.2 ).

At month 3, complete response rate by central assessment was 36.5% ( 95% CI 26.3-47.6 ) in 85 evaluable patients.
Among the 31 patients with complete response at month 3, median duration of complete response was 8.1 months ( range 0+ to 13.7+ ).
Estimated proportion of patients with response duration greater than or equal to 6 months was 85.6%.

Treatment-related adverse events occurred in 54 patients ( 55.7% ); most common effects ( greater than or equal to 5% ) were diarrhea ( 9.3% ), pruritus ( 9.3% ), fatigue ( 7.2% ), hypothyroidism ( 5.2% ), maculopapular rash ( 5.2% ), and arthralgia ( 5.2% ).

Treatment-related grade 3-5 adverse effects occurred in 11 patients ( 11.3% ); 1 death was considered treatment related.
Immune-mediated adverse effects occurred in 15 patients ( 15.5% ) and were grade 3-4 in 2 patients ( 2.1% ).

In conclusion, Pembrolizumab exhibits encouraging antitumor activity in patients with high risk and BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ.
The safety profile of Pembrolizumab in this population is consistent with that of previous studies. ( Xagena )

Source: European Society of Medical Oncology - ESMO Congress, 2018

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