Pembrolizumab Demonstrates Antitumor Activity in Phase II Bladder Cancer Study


Early results from a pre-planned interim analysis in the KEYNOTE-052 phase II trial of first-line pembrolizumab in cisplatin-ineligible patients with metastatic urothelial cancer demonstrated antitumor activity.

Arjun Balar, MD

Arjun Balar, MD

Early results from a pre-planned interim analysis in the KEYNOTE-052 phase II trial of first-line pembrolizumab in cisplatin-ineligible patients with metastatic urothelial cancer demonstrated antitumor activity and a favorable response rate that paralleled the expression levels of PD-L1 on the tumor and surrounding immune cells.

According to results presented at the ESMO 2016 Cancer Conference, the objective response rate (ORR) at a median follow-up of 8 months was 24.0% in the overall cohort (95% CI, 16.0-33.6). Pembrolizumab treatment yielded a rapid response with a median time to response of 2 months (Range: 0.1—13.4 months).

When patients were stratified according to a combined positive score (CPS) depicting the level of PD-L1 expression on the tumor and surrounding immune cells, 33 patients with CPS <1% had an ORR of 18%; 33 patients with a CPS &ge;1% but <10% achieved an ORR of 15%, and 33 patients with CPS &ge;10% expression levels achieved an ORR of 37%.

Complete response (CR) was reported for 6 patients and partial response for 17 patients in the overall cohort. Stable disease was reported in 15 patients, and 48 patients experienced progressive disease. Four patients were nonevaluable and 10 patients were not assessed.

The best change in tumor size was -30% from baseline, by RECIST 1.1, Central Review. A decrease in the target lesion was reported for 52% of patients.

&ldquo;Cisplatin-based chemotherapy is the standard first-line treatment in advanced urothelial cancer but patients with impaired renal function, poor performance status, and comorbidities, such as hearing loss, neuropathy or heart failure are not eligible for this treatment,&rdquo; explained lead author Arjun Balar, MD, director of the Genitourinary Medical Oncology Program at NYU Langone Medical Center.

&ldquo;For these patients, a gemcitabine and carboplatin combination is generally used, which is associated with a 36% response rate; however, there is substantial toxicity, and 21% of patients discontinue treatment due to toxicity,&rdquo; he said.

Balar presented findings on behalf of colleagues from the first 100 patients participating in the KEYNOTE-052 phase II trial of pembrolizumab. To date, this KEYNOTE study has enrolled 375 adult, cisplatin-ineligible patients with pathologically confirmed and measurable urothelial cancer.

Patients were a median age of 75 years (range: 44 to 94). A total of 87 patients had visceral metastases at baseline, and 46% of patients were ECOG performance status (PS) 2/3; 13% of patients had perioperative chemotherapy. Cisplatin ineligibility was due to renal insufficiency in 45% of patients, and ECOG PS 2 plus renal insufficiency in 11% of patients. All patients received pembrolizumab at 200 mg every 3 weeks until progressive disease, unacceptable toxicity, or 24 months of treatment.

The primary endpoint was RECIST v1.1 confirmed ORR by independent review in all patients and in PD-L1—positive patients by CPS. The secondary objective was the determination of the CPS-high biomarker cut point.

Primary tumor location and metastases affected pembrolizumab activity. Patients with a primary tumor in the upper tract had an ORR of 10%, whereas patients with lower-tract disease had an ORR of 28%. ORR was 40% in 10 patients having lymph node involvement only, compared with an ORR of 21% in 87 patients with visceral disease.

The median duration of response (DOR) has not been reached in the 100 patients (range: 1.4+ to 9.8+ months). The DOR rate &ge;6 months was 83% by Kaplan-Meier estimate.

&ldquo;Pembrolizumab demonstrated antitumor activity in first-line cisplatin-ineligible advanced urothelial cancer and a favorable safety profile in this interim analysis of 100 patients,&rdquo; Balar said.

The PD-L1 inhibitor was well tolerated, with 67% of patients experiencing a drug-related adverse event (DRAE). The most commonly reported DRAE by 14% of patients was fatigue. A grade 3/4 DRAE occurred in 16% of patients, and 5 patients discontinued therapy due to a DRAE.

&ldquo;The PD-L1 high cut point was CPS &ge;10%; this biomarker cut point will be validated in the remaining study population, but it seems to identify patients most likely to respond well to pembrolizumab.&rdquo;

Balar added that KEYNOTE-052 is ongoing and pembrolizumab will be further investigated as first-line treatment for advanced urothelial cancer in the phase III KEYNOTE-361 study.


Balar A, Bellmunt J, O&rsquo;Donnell PH, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase II KEYNOTE-052 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA32.

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