Pembrolizumab Demonstrates Improved Survival in Pretreated Bladder Cancer

Findings of the phase III KEYNOTE-045 trial showed pembrolizumab (Keytruda) demonstrated improved survival compared with chemotherapy in previously treated patients with advanced urothelial cancer.

Roger M. Perlmutter, MD, PhD

Roger M. Perlmutter, MD, PhD

Findings of the phase III KEYNOTE-045 trial showed pembrolizumab (Keytruda) demonstrated improved survival compared with chemotherapy in previously treated patients with advanced urothelial cancer, according to Merck, the manufacturer of the the PD-1 inhibitor.

After meeting the overall survival (OS) endpoint, the trial was halted based on the recommendation of an independent data monitoring panel. The study data are not yet available; however, Merck reported that the safety profile for pembrolizumab was consistent with previous trials involving patients with advanced urothelial cancer.

The open-label phase III KEYNOTE-045 trial (NCT02256436) included 542 patients with metastatic or locally advanced unresectable urothelial cancer that recurred or progressed after platinum-based chemotherapy. Patients were randomized to pembrolizumab (200 mg) or investigator’s choice of chemotherapy, which included paclitaxel (175 mg/m2), docetaxel (75 mg/m2), or vinflunine (320 mg/m2). All treatments were administered once every 3 weeks.

The coprimary endpoints of the trial were OS and progression-free survival (PFS). Secondary outcome measures included overall response rate (ORR), duration of response, and safety.

Data from the phase Ib KEYNOTE-012 trial for a cohort of patients with advanced urothelial carcinoma were previously reported at the 2015 American Urological Association Annual Meeting.1

As part of the phase Ib KEYNOTE-012 study, investigators screened 95 patients with urothelial cancer, and 61 (64.2%) of the patients had tumors that tested positive for PD-L1. Subsequently, 33 of the 61 patients were enrolled in KEYNOTE-012.

The patients had a median age of 70 and most were men (69.7%). Two-thirds had visceral (liver, 24%) or bone metastases, 73% had an ECOG performance status of 1, and half of the patients had received 2 or more prior therapies for advanced urothelial cancer.

Each patient received pembrolizumab at a dose of 10 mg/kg every 2 weeks and continued until disease progression, intolerable toxicity, discontinuation, withdrawal, or completion of 2 years of treatment.

At a median follow-up of 13 months, 4 of the patients remained on pembrolizumab. The most common reason for discontinuation was progressive disease (n = 17).

Overall, two-thirds (66.7%) of the patients had some degree of tumor shrinkage during treatment with pembrolizumab. In the 28 patients with measurable disease at enrollment, the ORR by RECIST v1.1 criteria was 25% (95% CI, 10.7-44.9). Median time to response was 10 weeks and median response duration had yet to be reached (range, 16 to >50).

Three of 7 objective responses met the criteria for complete response, and the remaining 4 were partial responses. Four patients (14.3%) had stable disease as best response, 13 had progressive disease, and response assessment had not occurred in 4 patients.

The median PFS was 2 months (95% CI, 1.7-4) and the 12-month PFS rate was 19% with pembrolizumab. The 12-month OS rate was 54.7% with a median OS of 12.7 months (95% CI, 5 to not yet reached).

The safety analysis revealed treatment-related adverse events in 21 patients (63.6%), most often fatigue (n = 6; 18.2%), peripheral edema (4; 12.1%), and nausea (3; 9.1%). Five patients (15.2%) had 1 or more grade 3-5 adverse event. One patient discontinued due to grade 3 rhabdomyolysis.

Early results from a preplanned interim analysis from the KEYNOTE-052 phase II trial of first-line pembrolizumab in cisplatin-ineligible patients with metastatic urothelial cancer were recently presented at the 2016 ESMO Congress.2

The ORR at a median follow-up of 8 months was 24% 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).

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 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.

If approved, pembrolizumab would compete with the PD-L1 inhibitor atezolizumab (Tecentriq) in the pretreated advanced bladder cancer space. In May 2016, the FDA granted an accelerated approval to atezolizumab as a treatment for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.


  1. Gupta S, O&rsquo;Donnell P, Plimack ER, et al. A Phase 1b Study of Pembrolizumab (Pembro; MK-3475) for Advanced Urothelial Cancer. Presented at: 2015 AUA Annual Meeting; May 15-19, 2015; New Orleans, LA. Abstract MP68-11.
  2. 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.

&ldquo;The results of KEYNOTE-045 represent a major breakthrough and will be welcome news for patients dealing with previously treated advanced urothelial cancer,&rdquo; Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. &ldquo;We look forward to sharing the findings from this study with the medical community and with regulatory authorities around the world.&rdquo;

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