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Pembrolizumab Update Solidifies Survival Benefit in Bladder Cancer

Angelica Welch
Published: Thursday, Feb 15, 2018

Joaquim Bellmunt MD, PhD
Joaquim Bellmunt MD, PhD
In patients with locally advanced or recurrent urothelial cancer, pembrolizumab (Keytruda) sustained its improvement in overall survival (OS) compared with chemotherapy in a 2-year update of the phase III KEYNOTE-045 trial presented at the 2018 Genitourinary Cancers Symposium.

The KEYNOTE-045 update showed a median OS of 10.3 months after a median follow-up of 27.7 months for patients treated with pembrolizumab.1 This was in comparison with 7.3 months for those treated with chemotherapy (HR, 0.70; P =.00017). Previously reported results for the study showed that median OS was 10.3 months with pembrolizumab versus 7.4 months for chemotherapy (HR, 0.73, P = .0022).2

In an interview with OncLive, lead KEYNOTE-045 investigator Joaquim Bellmunt, MD, PhD, director of the Bladder Cancer Center, Dana-Farber Cancer Institute, discussed the updated pembrolizumab findings, as well as the future of immunotherapy in bladder cancer.

OncLive: Can you give some background on KEYNOTE-045?

Bellmunt: Presently, we have 5 drugs that are approved for treating second-line patients with bladder cancer. Pembrolizumab was shown to be effective in a phase I trial, and then we decided to jump to a phase III study because of the positive results observed in the phase I trial. We started to accrue patients in 2014 and, after 1 year, the trial was completed. A total of 550 patients who failed on first-line platinum-based chemotherapy in the setting of metastatic disease were randomized to receive pembrolizumab or chemotherapy.

Chemotherapy was the standard of care being used at that time; it could have been docetaxel, paclitaxel, or vinflunine in Europe. The main endpoint of this trial was OS and PFS in the overall patient population, as well as in patients who had PD-L1 staining of more than 10% based on composite positive score that was defined by Merck for pembrolizumab. After 1 year of accrual, the first readout of this trial was in September 2016 and was presented at the 2016 SITC Annual Meeting. It was published in the New England Journal of Medicine in March 2017. 

What were the updated results?

At the time that the trial was published, the median follow-up was 14 months. What we presented at the 2018 Genitourinary Cancers Symposium are the updated results after a median follow-up of 27 months. We believe that the trial is now mature, and we can see if the benefits observed at the time of publishing are maintained, and whether there are any concerns in terms of toxicity.

Importantly in this update, we see that 27% of patients who received pembrolizumab are alive, compared with only 14% in patients assigned to receive chemotherapy. Compared with the previously published study, the hazard ratio decreased from 0.73 to 0.70, meaning there is a 30% reduction in the risk of death in patients receiving pembrolizumab. In terms of response rate, this trial has shown that pembrolizumab had a superior response rate to chemotherapy, with 21% compared with 11%.

We have some additional complete responses with subsequent follow-up, and one important thing is that the responses that have been observed are durable. At 2 years, the median duration of response in the pembrolizumab arm has not been reached—but it’s close to 50%—meaning responses are durable. Meanwhile, the median duration of response for the chemotherapy arm is 4.5 months. The main benefit is that the responses achieved are durable. 

Additional data that we have observed are that the duration of response may be even better in patients who are PD-L1 positive based on the composite positive score. Also, an important thing is that the toxicity favors the use of pembrolizumab compared with chemotherapy, and with this long-term follow-up, we have not seen any unexpected toxicities appearing in the long term. What we can conclude is that the results seen with pembrolizumab in the second-line treatment of patients with metastatic bladder cancer who have failed platinum-based chemotherapy are more or less similar to what has been seen in tumors like melanoma, where we see a survival curve that is stable after 2 years. This percentage of patients who responded might have a long-term benefit with pembrolizumab.


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