Interim Analysis of KEYNOTE-057 Shows Encouraging Antitumor Activity in NMIBC

Arjun V. Balar, MD

The immune checkpoint inhibitor pembrolizumab (Keytruda) continued to demonstrate encouraging antitumor activity in an interim analysis of KEYNOTE-057, which involved a subset of 102 patients with nonmuscle-invasive bladder cancer (NMIBC).

Specifically, at month 3, 40.2% of patients demonstrated a complete response (CR; 95% CI, 30.6%-50.4%), with a median duration of CR of 12.7 months (0.0+ to 20.5+ months), with 53% of patients exhibiting a CR lasting ≥9.

Patients with high-risk disease who had previously received bacille Calmette-Guérin (BCG), an intravesical immunotherapy, and became unresponsive to the treatment or were ineligible for cystectomy received pembrolizumab 200 mg every 3 weeks for 24 months or until recurrence, progression, or unacceptable toxicity.

Although up to 70% of patients with high-grade disease will respond to BCG, “the challenge is that many of these patients do not maintain a response. Durability of response is a major clinical issue,” said Arjun V. Balar, MD, assistant professor of medicine, and director of the Genitourinary Medical Oncology Program, at NYU Langone’s Perlmutter Cancer Center in New York, New York. Balar presented the findings during the 2019 Genitourinary Cancers Symposium in San Francisco, California.¹

Traditionally, these patients undergo radical cystectomy once they become unresponsive to BCG—the disease naturally progresses toward muscle-invasive and, eventually, metastatic disease. Balar noted, however, that surgery carries a great deal of morbidity and also a mortality risk. Many patients either decline to undergo or are ineligible for cystectomy. This represents a significant unmet medical need. The hope is that pembrolizumab could ultimately preserve a patient’s bladder.

Balar highlighted patients in cohort A of the study who were characterized with carcinoma in situ with or without papillary disease (high-grade Ta or T1). Patients were evaluated using cystoscopy, urine cytology, and biopsy if abnormalities were detected, on an every-12-week interval, and also with CT urograms on an every-24-week schedule. For this cohort, the primary endpoint was CR.

At data cutoff, 102 patients had received pembrolizumab with a median follow-up of 15.8 months (range, 4.6-28.2 months) and 23 patients continued on treatment (22.5%). Seventy-eight patients discontinued therapy because of persistent disease (n = 43), recurrent disease or stage progression (n = 22), and 8 patients discontinued treatment because of treatment-related adverse effects (AEs). Other reasons for discontinuation included CR, physician decision, protocol violation, and patient withdrawal.

When the CR rate (CRR) at month 3 was stratified by subgroup factors, Balar noted, ethnicity and geographic location may have had an effect. The investigators reported that Caucasians had a CRR of 31.9% (22 of 69; 95% CI, 21.2%- 44.24%) compared with non-Caucasians, who had a CRR of 55.6% (15 of 27; 95% CI, 35.3%-74.5%). Patients in the United States had a CRR of 27.8% (10 of 36; 95% CI, 14.2%-45.2%), and patients outside the United States had a CRR of 47% (31 of 66; 95% CI, 34.6%-59.7%).

Similarly, the investigators reported the effects of PD-L1 status. Patients who were PD-L1 positive (combined positive score &ge;10) had a 30.8% CRR (95% CI, 17.0%-47.6%), and patients who were PD-L1 negative (combined positive score <10) had a 47% CRR (95% CI, 34.6%-59.7%).

&ldquo;However, we do not want to make too many inferences about these subgroups,&rdquo; Balar said.

Overall, the pembrolizumab AE profile was consistent with that of previous studies, Balar noted. The investigators reported that 98 patients (96.1%) had &ge;1 AE, 66 patients (64.7%) reported treatment-related AEs, 29 patients (28.4%) reported grade &ge;3 AEs, and 13 patients (12.7%) reported grade ---3/4 treatment- related AEs. The most commonly reported treatment-related AEs of any grade were pruritus (n = 11), diarrhea (n = 11), fatigue (n = 10), and hypothyroidism (n = 6). Among grade 3/4 treatment-related AEs, the most commonly reported included hyponatremia (n = 3) and arthralgia (n = 2), with adrenal insufficiency, cholestatic hepatitis, and hypophosphatemia each with 1 case reported.

Balar said that the data reported in this interim analysis need to be tested in a randomized setting, pointing out KEYNOTE-676, a phase III study evaluating the safety and efficacy of pembrolizumab in high-risk NMIBC that is persistent or recurrent after BCG induction, which is currently enrolling patients (NCT03711032).