Expert Discusses Urothelial Carcinoma Approval

Patients with metastatic urothelial carcinoma have another option for treatment, as the Food and Drug Administration (FDA) approved Keytruda (pembrolizumab) in the first- and second-line settings.

The PD-1 inhibitor was specifically approved in the second-line setting for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In the frontline setting, the FDA granted an accelerated approval to frontline Keytruda for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

Keytruda joined other approved immunotherapy agents in the urothelial carcinoma armamentarium, including Bavencio (avelumab), Imfinzi (durvalumab), Tecentriq (atezolizumab) and Opdivo (nivolumab).

Can you discuss the significance of the recent FDA approval of Keytruda?

In an interview with CURE, Arjun V. Balar, M.D., a lead investigator on pivotal Keytruda research in bladder cancer, and an assistant professor, Department of Medicine, and director, Genitourinary Medical Oncology Program, NYU's Perlmutter Cancer Center, discussed the impact of the approval of Keytruda and other immunotherapy agents in urothelial carcinoma, as well as the next steps with these treatments.It comes down to which approval we’re talking about, whether it is the second line or the first line. For the second line, at that point, Keytruda becomes the 5th drug approved for the second-line treatment of bladder cancer. From that perspective, it adds to our armamentarium in terms of options that we can provide our patients. It's similar in terms of the class of drug. It’s a PD-1 antibody, allowing it to work on the PD-1 axis, making the response and safety very similar to other agents in its class.

Now that we have more options for immunotherapy treatments, how do you determine which immunotherapy to use for patients?

What other remaining questions regarding these agents still need to be addressed?

What do you anticipate for the future of these agents?

What's unique about Keytruda in the second-line setting is that it was approved on the basis of a randomized phase 3 trial that definitively demonstrated its improved survival versus standard of What is particularly unique about both Tecentriq and Keytruda in the frontline setting is that these are the first FDA-approved drugs for a population of patients who have never had an FDA approved drug. These are the first treatments that have ever been approved for patients who are ineligible for cisplatin. In my opinion, what is particularly unique about these two approvals is that about 50 percent to 70 percent of our patients with metastatic bladder cancer are cisplatin ineligible. This means that these approvals greatly impact a majority of patients with metastatic bladder cancer, which is quite unique and exciting. I think that is the main challenge right now. Within one year, we’ve had five different drugs that have been approved in various settings. It’s been difficult for the research community and the bladder cancer community to parse out the differences between these agents. The response rates, the durability of responses, and the survival rates appear to be very similar. However, again, the caveat is it’s a mix of phase 1, phase 2 and now a phase 3 study. In my opinion, I don’t think we can make any comparisons about survival because survival between phase 1, 2 and 3 studies can be marginally different for a variety of reasons. In terms of the response, durability of responses and the safety of the drugs, I think they are quite comparable and that it probably the most we can say at this point.From these drugs so far, I think what we need to see is in the frontline setting. The major unanswered question is if Keytruda and Tecentriq are better than standard of care chemotherapy. We need a randomized phase 3 trial. There are two notable studies that are currently ongoing, the atezolizumab study, which is IMvigor-130, and then the Keytruda phase 3 study where it is compared against chemotherapy, which is KEYNOTE-361. Both of those trials will answer the question of does PD-1 blockade improve survival versus chemotherapy in the frontline setting. Now that we have these approvals, the challenge is that based on Keytruda and Tecentriq, up to 25 percent of patients are responding to treatment. What that means is the next generation of trials need to improve on that response rate.

We need to use immunotherapy as a backbone and to develop novel combinations. Perhaps those combinations are with radiation, chemotherapy, targeted therapy, or other immuno-oncology drugs to increase that response rate in terms of immune responses. That is the next generation of trials that we need to focus on.

I think that is particularly unique in the second-line setting.

In terms of the frontline setting, Keytruda is now just one of two drugs that is approved for patients who are ineligible for cisplatin. In this case, these are both accelerated approvals, whereas Keytruda’s second-line approval is a full approval. Both accelerated approvals are on the basis of response and durability of responses in the first-line setting.