KEYNOTE-045 Supports Pembrolizumab For Platinum-Refractory Urothelial Cancer

Patients with urothelial carcinoma resistant to or progressing on platinum chemotherapy may have longer overall survival with pembrolizumab than conventional chemotherapy agents

medwireNews: KEYNOTE-045 findings suggest that pembrolizumab significantly extends overall survival (OS) for patients with advanced urothelial carcinoma refractory to platinum-based chemotherapy compared with standard treatments.

“The survival benefit that was observed with pembrolizumab in this previously treated population of patients with a poor prognosis supports its study in earlier stages of the disease”, the study investigators believe.

Median OS was 3 months longer in the 270 patients treated with pembrolizumab 200 mg every 3 weeks compared with that among 272 participants who were given an investigator’s choice of paclitaxel, docetaxel or vinflunine, at 10.3 versus 7.4 months (hazard ratio for death [HR]=0.73).

The estimated 12-month survival rates were 43.9% versus 30.7%, report Joaquim Bellmunt, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-investigators.

Subgroup analysis indicated that pembrolizumab provided an OS benefit over chemotherapy for all patient subgroups including among those patients who had a tumour PD-L1 positive score of 10% or higher on tumour and infiltrating immune cells, with OS of 8.0 versus 5.2 months (HR=0.57).

The objective response rate was also significantly higher with pembrolizumab than chemotherapy (21.1 vs 11.4%); the median duration of response was unreached in the pembrolizumab group versus 4.3 months for chemotherapy, with continuing responses reported at time of data cutoff in 72% of 57 patients versus 35% of 31 patients, respectively.

As reported in The New England Journal of Medicine,however, the open-label, phase III trial did not show any significant difference in progression-free survival between the treatment groups in either the full patient population or patients with a PD-L1 score of 10% or above.

Nevertheless, pembrolizumab-treated patients did show a lower rate of both all-grade (60.9 vs 90.2%) and grade 3–5 treatment-related adverse events (15.0 vs 49.4%) compared with the chemotherapy group.

“The better safety profile of pembrolizumab than of standard chemotherapy is important, considering that patients with recurrent or refractory urothelial carcinoma are generally older and have poor performance status and multiple coexisting conditions”, the researchers say.

Guru Sonpavde, from the University of Alabama at Birmingham in the USA, agrees in a linked editorial that “[t]he KEYNOTE-045 trial will have a practice-changing effect” with the caveat that this represents only an “incremental advance overall” as patients requiring salvage therapy are as yet incurable.

Highlighting the “extraordinary molecular heterogeneity of urothelial carcinoma”,he recommends further research into the use of targeted agents, noting that randomized phase III studies are now assessing first-line PD-1 and PD-L1 inhibitors in combination with platinum-based chemotherapy or CTLA-4 inhibitors, as well as adjuvant treatment for high-risk patients.


Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med; Advance online publication 17 February 2017. DOI: 10.1056/NEJMoa1613683

Sonpavde G. PD-1 and PD-L1 inhibitors as salvage therapy for urothelial carcinoma. N Engl J Med; Advance online publication 17 February 2017. DOI: 10.1056/NEJMe1701182

medwireNews ( ) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2017