1. Goodwin, Peter M.

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AMSTERDAM, Netherlands-"We have a new standard of care in the second-line setting of advanced or metastatic bladder cancer-pembrolizumab-that can be administered to patients who have failed one prior platinum-based chemotherapy regimen for metastatic disease."

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So said Andrea Necchi, MD, from the Faculty Department of Medical Oncology at the Fondazione IRCCS, Istituto Nazionale Dei Tumori, Milan, Italy, at the 2017 European Cancer Conference.



In Necchi's group findings from the KEYNOTE-045 randomized phase III study, there was a benefit in overall survival over chemotherapy.


"Most strikingly, the median overall survival in the total population with pembrolizumab was 10.3 months compared to 7.4 months with chemotherapy, a hazard ratio of 0.7 and a significant difference in terms of 'p' value," he said.


The study randomized 542 patients to receive pembrolizumab (200 mg every 3 weeks) or investigator choice of paclitaxel (175 mg/m2 every 3 weeks), docetaxel (75 mg/m2 every 3 weeks), or vinflunine (320 mg/m2 every 3 weeks).


"The objective of [this] phase III study in the second-line setting of bladder cancer was to compare overall and progression-free survival (PFS) of patients who have failed a chemotherapy regimen," Necchi said. Objective response rate (ORR) and tolerability were secondary endpoints.


He said there had clearly been an unmet medical need for this patient population because there had been no standard of care that led to a median overall survival beyond 7 months or so.


"There were no unexpected toxicities seen in this study," Necchi said, noting that-as expected-the toxicity profile of pembrolizumab favored it over chemotherapy. It was associated with fewer adverse events (AE) of any grade (60.9% compared with 90.2%), and grade 3-5 treatment-related AEs were much less common (15% of patients compared with 49.4% for chemotherapy).


"This is very important because we know this patient population is frail [and] usually has a lot of comorbidities. This will be important to allow more patients to access new effective treatments compared to chemotherapy. So we'll expand the basis of patients who will access treatment with respect to chemotherapy."


KEYNOTE-045 concluded that longer survival accompanied by a much lower rate of any-grade and high-grade treatment-related AEs supports the choice of pembrolizumab as a new standard of care for advanced urothelial cancer that has progressed on-or after-platinum-based chemotherapy.


ORR was nearly doubled with pembrolizumab (21.1% compared with 11.4%). "And the complete response rate was greater-7 percent with pembrolizumab compared to 3 percent with chemotherapy," he said.


There was no difference in PFS, but Necchi said this was not surprising. "We already know PFS is not a good surrogate for efficacy of this family of drugs. But it should be noted the 1-year projection of PFS is greater with pembrolizumab compared to chemotherapy-meaning that, [in the] long term, patients [could] even benefit from better PFS rates," he said.


Patient Selection

Since pembrolizumab is a humanized monoclonal antibody that blocks interaction between PD-1 and its ligands PD-L1 and PD-L2, and activates T lymphocytes, patients with PD-L1 positivity would intuitively be expected to do better than those without the marker.


"The results we have already collected with other drugs seem to suggest greater activity of the immune checkpoint inhibition in PDL-1 positive patients," Necchi said.


But it had been unclear from phase I and II study findings whether any advantage of pembrolizumab over chemotherapy would be confined to patients testing positive for PD-L1. And KEYNOTE-045-which included patients both negative and positive for the marker-found the opposite.


Survival in patients positive for PD-L1 was 8 months compared to 11.4 months in the total population, said Necchi. And he suggested this may be because PD-L1 was an indicator of poor prognosis in urothelial cancers, and this is an issue to be resolved in future trials


Practice Change

Necchi insisted the effectiveness of pembrolizumab regardless of PD-L1 positivity was the most important message. And he is optimistic other checkpoint inhibitors could also prove to be of value in second-line therapy for bladder cancer.


"We are waiting for the results of a phase III study with atezolizumab-very similar to KEYNOTE-045. And we already have important phase II single-arm studies with atezolizumab and nivolumab in this disease. So finally-after decades of stagnant results in bladder cancer treatment-we have fantastic practice-changing outcomes coming from clinical research."


Martine Piccart, MD, PhD, Head of the Medicine Department at Jules Bordet Institut in Brussels, Belgium, who chaired a news briefing on the KEYNOTE-045 findings, agreed the results were practice-changing and that-subject to affordability-there were important reasons for using pembrolizumab and other PD-1-targeted checkpoint inhibitors.


"This is an important study. This is becoming the most attractive treatment. We are not talking about just a progression-free survival benefit-in fact there was none-but we are really talking about a prolongation of survival and reduced side effects which-on the magnitude of clinical benefits-will put these drugs pretty high on the scale," she said. Piccart expressed hopes these immunotherapies would be prioritized by governments for "rapid access by patients."


Peter M. Goodwin is a contributing writer.