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Pembrolizumab, Atezolizumab New Standards for Bladder Cancer

Silas Inman @silasinman
Published: Friday, Nov 17, 2017

Andrea Necchi, MD
Andrea Necchi, MD
A wealth of new clinical trial data for immune checkpoint inhibitors has recently been reported for the treatment of patients with metastatic muscle-invasive urothelial carcinoma, with the PD-1 inhibitor pembrolizumab (Keytruda) and the PD-L1 inhibitor atezolizumab (Tecentriq) leading the pack of promising agents.

In May 2016, the immune checkpoint inhibitors gained initial approvals for patients with urothelial carcinoma in the second-line setting following treatment with a platinum-based chemotherapy, setting the stage for a wave of new therapies. For select patients, these agents have now become the standard of care, with ongoing studies exploring combination approaches, and phase III results now available showing improvements in overall survival (OS).  

In the first-line setting, the utility of these agents is currently less clear, as phase II findings led to EMA and FDA approvals for both pembrolizumab and atezolizumab for cisplatin-ineligible patients with metastatic urothelial carcinoma. In this setting, in the absence of phase III results, cisplatin-eligible patients should continue to receive chemotherapy and a clinical trial should be considered before administering immunotherapy, said Andrea Necchi, MD, during a presentation at the 2017 European Multidisciplinary Meeting on Urological Cancers (EMUC).

"Atezolizumab and pembrolizumab are well-tolerated with durable responses seen in the urothelial carcinoma patients who are not eligible for chemotherapy," Necchi, a medical oncologist at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, said during his presentation at the EMUC meeting. "The results are supporting the use of immunotherapy, the patients respond very long term, allowing them to avoid chemotherapy for the long-term. This is one of the most important results of the last decade."

Frontline Patient Populations Differ

Frontline approvals for pembrolizumab and atezolizumab were based on findings from the phase II KEYNOTE-052 and IMvigor210 studies. The KEYNOTE-052 study treated 370 patients at a median age of 74 years with pembrolizumab, and in the frontline cohort of the IMvigor210 trial, 119 patients at a median age of 73 years received atezolizumab.

"There were differences between the populations in the studies, which may have impacted the overall results," Necchi said. "These factors included the proportion of patients with upper tract tumors, visceral metastases, and those with an ECOG performance status of 2."

Overall, there were more patients with high-risk characteristics in the pembrolizumab trial. In the KEYNOTE-052 and IMvigor210 trials, respectively, the rates of those with ECOG performance status 2 were 42% versus 20% and 85% compared with 66% had visceral disease. The primary tumor location was in the renal pelvis or upper urinary tract for 19% and 28% of patients, respectively.

In the KEYNOTE-052 trial,1 the objective response rate (ORR) was 24%, which included a complete response (CR) rate of 5%. When including stable disease, the disease control rate was 47%. The median duration of response was not yet reached and the 6-month OS rate was 67%. Median OS has not yet been reached.

In the IMvigor210 trial,2 the ORR was 23%, with a CR rate of 9%. The disease control rate was 47%. The median OS was 15.9 months. "The immunotherapy option can be included in the recommendation for cisplatin ineligible fit patients in the first line, based on the results of these studies," Necchi said.

There are several phase III studies currently exploring immunotherapy in the first-line setting for those with metastatic bladder cancer. The KEYNOTE-361 (NCT02853305) and the IMvigor130 (NCT02807636) studies are exploring pembrolizumab and atezolizumab with or without chemotherapy compared with chemotherapy alone. Additionally, the DANUBE trial is exploring the PD-L1 inhibitor durvalumab (Imfinzi) with the CTLA-4 inhibitor tremelimumab (NCT02516241) and the CheckMate 901 trial is looking at the anti–PD-1 agent nivolumab (Opdivo) with the CLTA-4 inhibitor ipilimumab (Yervoy) (NCT03036098).

Clinical trials are also starting to explore these agents in patients with non-muscle invasive bladder cancers (NMIBC), Necchi noted. The single-arm phase II KEYNOTE-057 study is enrolling participants with high-risk NMIBC who are unresponsive to bacillus Calmette-Guérin (BCG) therapy (NCT02625961). Additionally, studies are ongoing to assess neoadjuvant treatment with pembrolizumab prior to cystectomy for patients with muscle-invasive bladder cancer (NCT02736266).

Second-Line Data Mixed

In the second-line setting, the first agent to gain approval was atezolizumab, based on cohort 2 of the phase II IMvigor210 trial.3 In this study, 310 platinum-pretreated patients received atezolizumab, with an ORR of 15%, which included a CR rate of 5%. The median OS was 7.9 months.

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