The results from an interim analysis of KEYNOTE-057, a phase 2 trial evaluating Pembrolizumab ( Keytruda ), an anti-PD-1 therapy, for previously treated patients with high-risk non-muscle invasive bladder cancer ( NMIBC ) with carcinoma in situ ( CIS ) or CIS plus papillary disease ( Cohort A ) were presented.
An interim analysis of the study’s primary endpoint showed a complete response ( CR ) rate of 38.8% ( 95% CI, 29.4-48.9 ) ( n=103 ) at 3 months with Pembrolizumab in patients whose disease was unresponsive to Bacillus Calmette-Guérin ( BCG ) therapy, the current standard of care for this disease, and who were ineligible for or who refused to undergo radical cystectomy.
Treatment options for high-risk non-muscle invasive bladder cancer have historically been limited, with many patients relying on surgery as their only option following disease recurrence.
Additionally, about 40% of patients with high-risk non-muscle invasive bladder cancer progress to muscle invasive disease.
These data from KEYNOTE-057 are encouraging for patients with this hard-to-treat form of bladder cancer who are ineligible for surgery.
KEYNOTE-057 is a phase 2, single-arm, multi-cohort study evaluating Pembrolizumab as monotherapy in patients with high-risk NMIBC that has not responded to treatment with BCG therapy and who are ineligible for or who have refused to undergo radical cystectomy.
The study’s primary endpoints are CR rate ( Cohort A only ) and disease-free survival rate ( Cohort B only ). The secondary endpoints include safety and duration of response.
Data presented at ESMO are from an interim analysis of patients with CIS or CIS plus papillary disease ( Cohort A ) ( n=103 ).
Findings showed a CR rate of 38.8% ( 95% CI, 29.4-48.9 ) ( n=40/103) at three months. The non-CR rate was 55.3% ( 95% CI, 45.2-65.1 ) ( n=57/103 ) at three months, and patients had either persistent disease ( CIS +/- papillary tumor ), NMIBC stage progression ( CIS +/- high-grade Ta at baseline to T1 disease ) or extravesical disease.
At the time of analysis, 72.5% of responding patients had an ongoing response ( n=29/40 ) and 25% experienced recurrent disease after CR ( n=10/40 ).
One patient who did not develop recurrent disease discontinued study treatment and started alternative therapy.
No patients in Cohort A developed muscle invasive or metastatic urothelial carcinoma. Of the patients who achieved a CR at three months, 80% had a CR lasting for six months or longer, based on the Kaplan-Meier method.
The median duration of response was not yet reached ( range, 0+ to 14.1+ ).
The median follow-up was 14.0 months ( range, 4.0-26.3 months ).
The safety of Pembrolizumab in KEYNOTE-057 was consistent with what has been seen in previous trials among patients treated with Pembrolizumab monotherapy.
Treatment-related adverse events ( TRAEs ) occurred in 63.1% of patients.
The most common TRAEs with an incidence of 5% or more were pruritus ( 10.7% ), fatigue ( 9.7% ), diarrhea ( 8.7% ), hypothyroidism ( 5.8% ) and maculopapular rash ( 5.8% ).
Grade 3-5 TRAEs occurred in 13 patients ( 12.6% ), and there was one treatment-related death, per investigator assessment.
The target enrollment for KEYNOTE-057 is 260 patients across two cohorts: patients with CIS or CIS plus papillary disease ( Cohort A ) ( n=130 ) and patients with papillary disease without CIS ( Cohort B ) ( n=130 ).
Patients in both cohorts receive Pembrolizumab ( 200 mg fixed dose intravenously every three weeks ) until recurrence, disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
In this study, BCG-unresponsive high-risk NMIBC is defined as persistent or recurrent disease despite adequate BCG therapy or stage progression despite adequate BCG induction therapy.
Patients were considered high risk if their tumors were classified as T1, high-grade Ta and/or CIS based on the American Joint Committee on Cancer ( AJCC ) TNM system.
Pembrolizumab is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells.
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. As more cancer cells develop, they can form a tumor and spread to other areas of the body. Bladder cancers are described based on how far they have invaded into the wall of the bladder.
Non-muscle invasive bladder cancer occurs when the cancer has not grown into the main muscle layer of the bladder.
80% of bladder cancer patients are diagnosed with NMIBC.
Worldwide, bladder cancer is the tenth most common cancer and the thirteenth most common cause of cancer death. It is estimated that almost 550,000 new cases of bladder cancer will be diagnosed in 2018. ( Xagena )
Source: European Society for Medical Oncology - ESMO Congress, 2018