Galsky Discusses Ongoing Combination Immunotherapy Trials in Bladder Cancer

Matthew Galsky, MD

The treatment landscape of bladder cancer has undergone a transformation in the last few years, most notably with the approval of 5 checkpoint inhibitors. With all of these new options, Matthew Galsky, MD, said that the question now is whether immunotherapy is more beneficial as a monotherapy or in combination.

IMvigor130 (NCT02807636) is a phase III randomized study that is currently evaluating first-line atezolizumab (Tecentriq) as a single-agent and in combination with platinum-based chemotherapy in patients with locally advanced or metastatic bladder cancer. This study aims to determine the efficacy of the single-agent PD-L1 inhibitor in the first-line setting or in combination with platinum-based chemotherapy compared with placebo and chemotherapy.

The CheckMate-901 study (NCT03036098) is a phase III, randomized, open-label study of nivolumab (Opdivo) plus ipilimumab (Yervoy) or standard chemotherapy versus standard chemotherapy alone in patients with previously untreated unresectable or metastatic urothelial carcinoma. Nivolumab is currently FDA approved as a treatment for patients with unresectable or metastatic urothelial carcinoma following progression on a platinum-containing therapy.

CheckMate-901 has a more complex randomization compared with IMvigor130, said Galsky. Patients who are cisplatin-eligible and -ineligible will be randomized to either arm A, which is nivolumab plus ipilimumab, or arm B, which is gemcitabine/cisplatin or gemcitabine/carboplatin. Arms C and D are for additional cisplatin-eligible patients who will receive nivolumab plus gemcitabine/cisplatin or gemcitabine/cisplatin, respectively.

Both IMvigor130 and CheckMate-901 are ongoing and actively recruiting.

OncLive: Can you provide some background information on these trials?

In an interview with OncLive^®, Galsky, professor of medicine, hematology, and medical oncology, Mount Sinai Hospital, discussed these studies, as well as the future for chemotherapy in bladder cancer.Galsky: The first-line treatment of [patients with] metastatic bladder cancer has been chemotherapy for the past several decades—either cisplatin-based in eligible patients, or carboplatin-based for those who are cisplatin-ineligible. We know that chemotherapy has a response rate of about 30% to 50% in patients with metastatic bladder cancer, particularly with cisplatin-based therapy. A small proportion of those patients will have durable responses, but for the majority of patients, the responses are relatively short-lived and, ultimately, patients progress.

Historically, we haven't had any global standard treatments for patients who would progress on first-line chemotherapy in bladder cancer, but the development of immune checkpoint inhibitors has changed all of that. Now, 5 PD-1/PD-L1 inhibitors are approved for the second-line treatment of [patients with] metastatic bladder cancer, progressing despite first-line chemotherapy. This has raised a major question in the field—should we move these drugs earlier in the course of treatment? Since they seem to not be cross resistant with chemotherapy and have nonoverlapping toxicity profiles, should we combine them with chemotherapy?

This had led to 2 large international randomized trials. These trials are addressing the question of whether we should combine immunotherapy with chemotherapy or use immunotherapy alone in patients with metastatic bladder cancer.

The IMvigor130 study is randomizing patients between standard chemotherapy, regardless if they are eligible for cisplatin. If they are eligible for cisplatin, they will receive gemcitabine and cisplatin, and if they are ineligible, they receive gemcitabine and carboplatin. [This study is] randomizing between that standard chemotherapy arm, and that same chemotherapy with atezolizumab or single-agent atezolizumab. This 3-arm randomization will answer the question of whether we should give immunotherapy alone, chemotherapy alone, or the combination.

The second key question that arises is based on data in the platinum-resistant setting, as well as data from other solid tumors: should we be giving combination immunotherapy? That is, CTLA-4 blockade plus PD-1/PD-L1 blockade. We know from other solid tumors, such as melanoma, kidney cancer, and lung cancer, that combination immunotherapy might increase the response rate compared with single-agent therapy, and these responses also tend to be quite durable.

This has been studied in the platinum-resistant setting in bladder cancer with combination CTLA-4 and PD-1 blockades, showing response rates that seem to be a little bit higher than what is achieved with PD-1 blockade alone. This leads to the question of whether we should be giving doublet immune checkpoint blockade in the first-line setting to patients with metastatic bladder cancer.

Looking ahead, how do you see the role of chemotherapy changing in bladder cancer?

The CheckMate-901 study is testing this concept. It is a little bit more of a complex randomization in this study because the randomization is handled differently depending on whether patients are cisplatin-eligible. The primary endpoint of this study is based on the cisplatin-ineligible population. For those patients, they are randomized to standard chemotherapy versus the combination of ipilimumab plus nivolumab. For platinum-eligible patients, there is a 3-arm randomization for patients to get ipilimumab plus nivolumab, standard chemotherapy, or standard chemotherapy plus nivolumab. Again, this is a trial poised to change the standard of care for first-line treatment of patients with metastatic bladder cancer.I see a potential scenario where chemotherapy plays a lesser role in the treatment of patients with bladder cancer, but I do not suspect that it is going away. I suspect that in at least some patients, the combination of chemotherapy and immune checkpoint blockade—if the clinical trials will read out like we think they will—will be standard of care, at least for some patients.

What would you say the takeaway is so far from this research?

Beyond these 2 trials, is there anything else happening in the space that you are particularly excited about?

The question of whether chemotherapy alone will have any role in the treatment of bladder cancer in the future is very interesting. It is possible that it won't.The takeaway from the first-line trials in metastatic bladder cancer is that the questions that are being asked right now are very practical, straightforward questions, but they are questions that can only be answered in the context of a large randomized clinical trial. Is the future [of this 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.There are 2 trials that I discussed at the 2018 ASCO Annual Meeting that were neoadjuvant immune checkpoint blockade studies. Those trials assess immune checkpoint blockade—either PD-1 or PD-L1 blockade—in the neoadjuvant setting in patients with muscle-invasive bladder cancer. Historically, chemotherapy has been the standard in terms of neoadjuvant therapy followed by cystectomy in patients with cisplatin-eligible muscle-invasive bladder cancer. For patients who are considered cisplatin-ineligible, we have not had any standard preoperative therapy, and patients are treated with surgery alone.

With all of these potentially practice-changing studies, what is your outlook for this treatment landscape?

These are very important proof-of-concept studies testing whether single-agent immune checkpoint blockade can be administered in this setting. Both trials utilize pathologic complete response rate (pCR) as the primary endpoint. The pCR rate with just 2 to 3 doses of immune checkpoint blockade prior to cystectomy was similar to what we achieve with combination cisplatin-based chemotherapy. These studies are incredibly intriguing, and they will inform further studies that have the potential to transform care. Of course, as single-arm studies, they are not practicing changing, but they will impact further studies that may change practice in the future. For a period of more than 20 years, there was 1 single drug approved in the United States to treat [patients with] bladder cancer. Within a period of 2 years—between 2016 and 2017—there were 5 drugs approved. Clearly, there is momentum in terms of drug development in this disease. That momentum has almost certainly translated into patient benefit, and the hope is that this momentum will continue with additional therapies that are not cross resistant to ultimately offer our patients even longer and better survival.