Bladder Cancer Paradigm Expanding to Include Immunotherapy Combos, Targeted Therapies

Gina Columbus @ginacolumbusonc
Published Online: Thursday, Sep 28, 2017

Terence Friedlander, MD
Terence Friedlander, MD
The bladder cancer community has generated excitement with 5 monotherapy approvals for PD-1/PD-L1 inhibitors within the last year, including nivolumab (Opdivo), durvalumab (Imfinzi), avelumab (Bavencio), atezolizumab (Tecentriq), and pembrolizumab (Keytruda).

Now, ongoing clinical trials are aiming to further advance the treatment paradigm by investigating targeted agents, as well as immunotherapy-based combinations.

For example, a 2-part, first-in-human, dose-escalation/expansion study explored the fibroblast growth factor receptor (FGFR) inhibitor BGJ398 in patients with non–small cell lung cancer (NSCLC) and other solid tumors, including urothelial carcinoma, who harbored the FGFR genetic alteration. Findings showed that there were 7 partial responses, 6 confirmed, with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified squamous NSCLC and FGFR3-mutant bladder/urothelial cancer. The targeted therapy was also associated with a manageable safety profile.

Additionally, a phase I/II safety and pharmacology study is investigating the combination of atezolizumab with Bacille Calmette-Guérin (BCG) in patients with high-risk, non-muscle invasive bladder cancer (NCT02792192).

“These PD-1/PD-L1 agents are being tested across the board in bladder cancer,” said Terence Friedlander, MD. “There is a lot more to come besides PD-1. This is just the beginning; it’s not the end of the story. [There are] combinations with IDO inhibitors, adenosine A2a receptor antagonists, OX40 agonists, and CTLA-4 inhibitors—just a number of other immune partners. [There are also] combinations with chemotherapy, radiation therapy, and targeted agents.”

Friedlander, an assistant clinical professor in the Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco, lectured on the continuous change occurring in the bladder cancer landscape during the 2017 OncLive® State of the Science SummitTM on Genitourinary Cancers. In an interview, he spoke about the targeted therapies emerging in the field, as well as immunotherapy combinations that are travelling through the pipeline.

OncLive: Please summarize the key points of your discussion.

Friedlander: The major focus of my talk was on immunotherapy, because there has been just a number of new agents approved and there is a lot of excitement in the field right now about using these drugs. We discussed why immunotherapy might work, and 1 of the major take-home points is that bladder cancer is very mutated compared with other agents. That has to do with other exposures, including tobacco, environmental, and industrial exposures that cause a lot of damage to the bladder lining and can cause the cancer to form. That presents a lot of targets for both the immune system to see an attack and target for targeted therapy.

In terms of immune therapy, we spoke about where these drugs are approved and where an oncologist treating a patient with bladder cancer can use them in 2017. The first group that these drugs are approved in are metastatic patients who are not eligible for cisplatin, which is the mainstay of chemotherapy for these patients. While it works and there is a decent response rate, it’s not a good long-term solution. The average survival is only 1 to 1.5 years for patients who just receive chemotherapy. For patients who are ineligible for cisplatin—which is defined as poor renal function, poor performance status, neuropathy, or hearing loss—the agents atezolizumab and pembrolizumab are both approved. They are given, essentially, as monotherapy every 3 weeks.

What we are seeing that is true across the board in bladder cancer is about 20% to 25% of patients are responding to these drugs. When they respond, it’s great because they are long-term responses, in general; they tend to be durable and measured in years for most patients. The other piece is that responses happen quickly. You can do a scan and see a patient responding in as short as 6 weeks. That is exciting and encouraging; it is sort of winning the lottery with these patients because you’re getting an agent that provides long-term control of the cancer. Overall, the toxicity rates look fairly good; there is only about a 10% or 15% rate of grade 3/4 toxicity. It is sort of like a trifecta of efficacy, long-term responses, and tolerability. 


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