ASCO GU 2019: Updated Results of Keynote 057: Pembrolizumab for Patients with High-risk Nonmuscle Invasive Bladder Cancer Unresponsive to BCG

San Francisco, CA ( Dr. Arjun Balar presented updated results of the Keynote-057 trial of Pembrolizumab for high risk non-muscle invasive bladder cancer (NMIBC) patients who were unresponsive to Bacillus Calmette-Guerin (BCG) therapy. This was a single arm open-label phase 2 study.

First, an introduction and review of BCG unresponsive high-risk NMIBC. Adequate BCG therapy is defined as at least 5-6 instillations of induction BCG + at least 2 of 3 doses of maintenance therapy or 2 of 6 doses of a second induction course. BCG refractory disease is defined as stage progression at three months after adequate BCG induction, or persistent high-risk disease at six months despite adequate BCG. Finally, BCG relapsing disease is defined as recurrence of high-risk NMIBC after the patient achieves a disease-free state within 12 months after adequate BCG therapy. In the absence of treatment, BCG-unresponsive carcinoma in situ (CIS) will persist and progress. Radical cystectomy is the standard option for patients with BCG-unresponsive NMIBCdue to the high risk of progression. However, radical cystectomy entails significant morbidity and mortality, has a negative impact on the quality of life, and many patients refuse or are
ineligible for this surgical treatment. Therefore, there is an urgent need for novel therapies to reduce the risk for recurrence and preserve the bladder. With the lack of a suitable comparator, single arm-designs have been found suitable in the BCG unresponsive population.

Activation of the PD-1 pathway has been implicated in resistance to BCG therapy. The PD-1 inhibitor pembrolizumab has demonstrated significant antitumor activity in patients with metastatic urothelial carcinoma. Little is known about anti-PD-1 monotherapy for NMIBC.

The study design is shown below:

ASCO GU 2019 keynote 057 study design

High-risk NMIBC patients, who were unresponsive to BCG, and refuse, or are ineligible for radical cystectomy, were enrolled in this study. There were two cohorts in this study-cohort A –patients with CIS with or without papillary disease (high-grade Ta or T1), and cohort B –Papillary disease (high-grade Ta or any T1) with no CIS. Patients were given pembrolizumab 200 mg every three weeks and evaluated with cystoscopy, cytology, and a biopsy every 12 weeks for two years, and then every 24 weeks for two years and once yearly after that. Patients also underwent CT urogram every 24 weeks for two years. The primary endpoints were complete response rates(CRR)in cohort A and disease-free survival in cohort B.

As of this reporting and first data cutoff of Sept 2018, 102 patients have enrolled in Cohort A. Their median age is 73 years, 63.8% had CIS alone, and the median number of prior BCG instillations was 12. Full demographic info is below:

ASCO GU 2019 keynote 057 baseline characteristics

  • -1 patient has completed therapy. 78 have discontinued therapy. 23 (22.5%) have treatment ongoing

  • -Median follow-up is 15.8 months

  • -38% had high PDL-1 status (CPS >= 10%)
In terms of outcomes, 3-mo CRR rate was 40.2% (95% CI 30.6%-50.4%) by central assessment. Among 41pts who achieved CR at 3 months, 58.5% maintained CR at last follow-up (median 16.7mo; range 4.0-26.3) and median CR duration was 12.7 months (range 0+ to 20+ months). 75% of pts had a CR duration of ≥6 mo (Kaplan-Meier method). Of the patients that recurred, 15patients experienced recurrent NMIBC after CR.

Importantly, at the time of analysis, none progressed to muscle-invasive or metastatic disease. Of the patients who did not achieve CR, 40.2% had persistent disease.

The swimmer’s plot below highlights the outcomes of the 41 patients who achieved 3 month CR:

ASCO GU 2019 keynote 057 response and development

The duration of CR response can be seen in the KM plot below:

ASCO GU 2019 keynote 057 month 3 response

On subgroup analysis, certain subgroups appeared to have better CR rates –include non-white patients, non-US patients, CIS only patients, and PDL-1 negative (CPS < 10%) patients. Overall, pembrolizumab was moderately tolerated. Treatment-related adverse events (AEs) occurred in 66(64.7%) patients, and the most frequent were pruritus (10.8%), fatigue (9.8%), diarrhea (10.8%), hypothyroidism (6.9%), and maculopapular rash (5.9%). More serious Grade 3/4 treatment-related AEs occurred in only 13 (12.6%) patients -1 death was considered treatment-related (colitis in patient inadequately treated with steroids). Immune-mediated AEs occurred in 19 (18.6%) pts.

Based on this, pembrolizumab appears to have had encouraging activity in patients with high-risk, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience.

This abstract will also be presented as an oral abstract and will be covered by Zachary Klaassen.

Finally, Phase 3 randomized clinical trials to study the efficacy and safety of pembrolizumab, in combination with BCG in patients with high-risk NMIBC, that is persistent or recurrent following BCG induction will be initiated (Keynote-676).

Presented by: Arjun Balar, MD, Perlmutter Cancer Center at NYU Langone Health, NewYork, New York

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA