ASCO 2017: Planned survival analysis from KEYNOTE-045: Phase 3, open-label study of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer

Chicago, IL ( It is known that second-line chemotherapies (chemo) for advanced urothelial carcinoma (UC) have limited clinical benefit (OS, 7-9 mo). Data from the open-label, phase 3 KEYNOTE-045 study (NCT02256436) showed significantly longer OS with pembro compared to 2nd line chemo (median, 10.3 v 7.4 mo; hazard ratio [HR], 0.73; P = 0.002) in recurrent advanced UC.

This study enrolled bladder, renal pelvis, ureter and urethra UC patients with an ECOG 0s 0-2, after 1-2 lines of platinum based chemotherapy or recurrence <12 months, after perioperative platinum based therapy. The patients were randomized to receive either 2nd line chemotherapy (paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W) or Pembrolizumab 200 mg IV every 3 weeks. Dr. Bajorin presented data from a planned survival analysis of this trial. 

In this survival analysis primary efficacy end points were overall survival (OS) and progression free survival (PFS) (RECIST v1.1, blinded central review). Objective response rate (ORR) (RECIST v1.1, blinded central review) was a secondary end point. Patients were stratified by ECOG status, hemoglobin level, presence of liver metastasis and time from last chemotherapy dose. Imaging was done after week 9 and then every 6 weeks for year 1, and every 12 weeks thereafter. Lastly PD-L1 was assessed centrally using the PD-L1 immunohistochemistry 22c3 PHARMdX with the expression score formatted as combined positive score (CPS). The CPS is defined as the number of PD-L1 staining cells divided by the number of all viable tumor cells.

Overall, 542 pts were enrolled (pembro, 270; chemo, 272). Baseline characteristics were generally similar between arms. Median follow-up was 18.5 mo (range, 14.2-26.5). In the pembro arm, 232 discontinued the treatment, 1 completed 2 years, and 33 are still ongoing. In the 2nd line chemotherapy arm 255 discontinued the treatment, 0 completed 2 years and 0 are ongoing. Median OS was significantly longer with pembro compared to chemo (10.3 v 7.4 mo; HR, 0.70; CI 95% 0.57-0.86, p= 0.0004). Significance was maintained regardless of PD-L1 expression as measured by CPS with CPS ≥10%, having a HR of 0.57; CI 95% 0.38-0.86, p=0.0034. Importantly, OS benefit with pembro compared to chemo was seen regardless of age, ECOG PS, prior therapy, liver metastases, histology, and choice of chemo. The 18-mo OS rate (95% CI) was 36.1% (30.1%-42.0%) with pembro compared to 20.5% (15.2%-25.8%) with chemo. PFS was not different between the arms with a median of 2.1 months in the pembro group and 3.3 months in the 2nd line chmoetherapy group, p=0.32. ORR was higher with pembro vs. chemo (21.1% v 11.0%), and median (range) duration of response was longer (not reached in Pembro [1.6+-20.7+ mo] vs. 4.4 mo [1.4+-20.3] for chemo). 69% (Pembro) vs. 36% (chemo) of responses lasted ≥12 mo. 

Finally, when looking at the adverse effects (AE), Pembro was better in this regard as well, with fewer patients experiencing a treatment-related AE when compared to 2nd line chemo (any grade, 61.3% v 90.2%; and grade ≥3, 16.5% v 49.8%). 

Dr. Bajorin concluded his presentation by stating that the OS benefit and superior safety profile of pembro over 2nd line chemo are maintained with longer follow-up. Taken together, these results support the usage of pembro as a new standard of care for patients with UC who previously failed platinum based therapy. Based on these results the FDA provided full approval of pembro for the treatment of advanced urothelial carcinoma after failure of platinum based therapy without the need for PD-L1 staining. 

Presented By: Dean F. Bajorin, Memorial Sloan Kettering Cancer Center, New York, NY

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA
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