Expert Talks Immunotherapy, Unanswered Questions in Metastatic Bladder Cancer

The treatment landscape of patients with metastatic bladder cancer may be drastically changing in the future, as two large trials are investigating the use of immunotherapy in the second-line setting for these patients.

CURE sat down with Matthew Galsky, M.D., professor of medicine at the Icahn School of Medicine at Mount Sinai, to discuss these trials and how the role of chemotherapy may change down the line.

Can you give some background on the use of immunotherapy in patients with metastatic bladder cancer?

The first-line treatment of metastatic bladder cancer has been chemotherapy for the past decade, either cisplatin-based chemotherapy in patients who are eligible for cisplatin or carboplatin-based chemotherapy in patients who are cisplatin ineligible. Chemotherapy, we know, has a response rate of about 30 to 50 percent in patients with metastatic bladder cancer. Particularly with cisplatin-based chemotherapy, a small portion of those patients will have durable responses, but for the majority of the patients, the responses are relatively short-lived, and ultimately patients progress.

Historically, we haven't had any global standard treatments for patients who progress on first-line chemotherapy in bladder cancer. But the development of immune checkpoint inhibitors has changed all of that, and now five PD-1 and PD-L1 inhibitors are approved for the second-line treatment of metastatic bladder cancer (that is) progressing, despite first-line chemotherapy.

So, this has raised a major question in the field, which is: Should we move these drugs earlier in the course of treatment? Because they seem to be non-cross resistant with chemotherapy and have non-overlapping toxicity profiles, should we combine them with chemotherapy? It has really led to two key questions that are being addressed in two large, international, randomized trials. One question is should we combine chemotherapy with immune checkpoint blockade, or should we give immune checkpoint alone to patients with metastatic bladder cancer?

The IMvigor study is randomizing patients between standard of care chemotherapy, regardless if they're ineligible for cisplatin or not, so if they're eligible for cisplatin they receive gemcitabine and cisplatin, if they're ineligible, they receive gemcitabine and carboplatin, randomizing that between the standard of care chemotherapy arm, that same chemotherapy with the PD-L1 inhibitor [Tecentriq (atezolizumab)], or single-agent (Tecentriq). So, it's a three-arm randomization, which will really answer the question: should we be giving immunotherapy alone, chemotherapy alone or the combination to this patient population?

The second key question that arises is based on data from the platinum-resistant setting, and of course, data from other solid tumors is: Should we be giving combination immunotherapy that is (a combination of) CTLA-4 blockade plus PD-1 or PD-L1 blockade? We know from other solid tumors such as melanoma, kidney cancer and recently lung cancer that combination immunotherapy might increase the response rate compared to single-agent chemotherapy. These responses tend to be quite durable. So, this has been studied in the platinum-resistant setting in bladder cancer with combinations CTLA-4 blockade and PD-1 blockade, showing response rates that seem to be a little bit higher than what's achieved with PD-1 blockade alone, leading to the question, should we be giving doublet immune checkpoint blockade in the first-line setting to patients with metastatic bladder cancer?

So, the CheckMate-901 study is testing this concept. It's a little bit of a more complex randomization in this study because the randomization is handled differently depending on whether patients are cisplatin eligible or ineligible. The primary endpoint of this study is based on the cisplatin-ineligible population, and for those patients, they're randomized to standard of care chemotherapy versus the combination of [Yervoy (ipilimumab)] plus [Opdivo (nivolumab)]. For cisplatin-ineligible patients, there's a three-arm randomization, randomizing patients to (Yervoy) plus (Opdivo) versus standard of care chemotherapy, versus standard of care chemotherapy plus (Opdivo). So again, a trial poised to change the standard of care for first-line metastatic bladder cancer.

What is the current status of the trials?

Both of the trials are ongoing and actively recruiting. It will take a little while before the accrual is complete and until patients are followed until the primary endpoint is met.

Moving forward, can you see chemotherapy moving out of the treatment realm for bladder cancer?

I see a potential scenario where chemotherapy plays a lesser role in the treatment of bladder cancer, but I don't suspect it's going away. I suspect in at least some patients the combination of chemotherapy and immune checkpoint blockade, if the clinical trials read out how we think they might read out. That will be standard of care at least for some patients.

I think the question of whether or not chemotherapy alone will have any role in the treatment of bladder cancer in the future is a very interesting question. I think it's possible that it won’t.

What would say the takeaway is right now from these studies?

The takeaway from the first-line trials in metastatic bladder cancer is that the questions that are being asked right now are very practical questions, very straightforward questions, but questions that can only be answered in the context of a large randomized clinical trial. That is, is the future (of bladder cancer treatment) single-agent immunotherapy, doublet immunotherapy, combinations with chemotherapy or chemotherapy alone? We can speculate about that all we want, but the only way to determine those answers definitely is through prospective clinical trials.