Novel Immunotherapy Combos Shake Up Bladder Cancer Paradigm

Petros Grivas, MD, PhD

Immunotherapy has completely transformed bladder cancer treatment, said Petros Grivas, MD, PhD, and a plethora of ongoing clinical trials evaluating this class of drugs in combination with chemotherapy, other checkpoint inhibitors, and targeted agents, could lead to more options.

"Immunotherapy has completely changed the way we treat [patients with] bladder cancer," said Grivas, clinical director of the Genitourinary Cancers Program, University of Washington (UW) School of Medicine. "There are also several ongoing clinical trials—in metastatic disease, adjuvant, neoadjuvant, and non-muscle invasive disease—with very promising data that I believe possess the potential to impact the landscape even further, even in earlier disease states."

In an interview with OncLive, Grivas, also an associate professor, UW Medicine, and a medical oncologist, Seattle Cancer Care Alliance, and an associate member at the Fred Hutchinson Cancer Research Center, highlighted the evolving role of immunotherapy in bladder cancer and ongoing research slated to further progress along.

OncLive: What is the role of immunotherapy in bladder cancer and how has it evolved in recent years?

Grivas: Immunotherapy has changed the treatment landscape. We have 5 checkpoint inhibitors approved for use in patients with metastatic platinum-refractory urothelial cancer. One of these agents has level I evidence, which is pembrolizumab (Keytruda), and 4 others have been approved in that setting (atezolizumab, nivolumab, durvalumab, avelumab). Two of them are also approved in the first-line setting—atezolizumab (Tecentriq) and pembrolizumab—for patients who have not received chemotherapy for advanced disease.

Patients who have not received chemotherapy for metastatic or locally advanced unresectable disease and are not fit for cisplatin can potentially receive either pembrolizumab or atezolizumab under 2 circumstances in the United States: if the tumor has high PD-L1 expression based on a corresponding companion assay or if they're unfit for any platinum chemotherapy, including carboplatin. These are all very exciting advances. We also have a plethora of clinical trials that I believe have the promise to further change the landscape. Specifically, we have ongoing combination trials in metastatic disease, and it's very exciting to look at these studies in earlier disease states, as well as to evaluate biomarkers.

One trial that has recently read out is the phase III IMvigor130 trial with frontline atezolizumab. Could you highlight the key takeaways from that study?

IMvigor130 is a randomized clinical trial that is evaluating the role of atezolizumab plus a chemotherapy combination—gemcitabine with cisplatin or carboplatin—[arm A] compared with either atezolizumab alone [arm B] or chemotherapy plus placebo [arm C]. This clinical trial has coprimary endpoints of progression-free survival (PFS) and overall survival (OS) in arm A versus arm C in the intent-to-treat population, meaning in all-comers, regardless of PD-L1 expression. There is another primary endpoint of OS in arm B versus arm C, again, in the intent-to-treat population.

The key secondary endpoints are investigator-assessed overall response rates, response duration, and PFS. This is a very large trial; the study was supposed to accrue about 1200 patients.

A recent press release reported that one of the coprimary endpoints, specifically PFS, was met for the combination of chemotherapy/atezolizumab compared with chemotherapy/placebo. We don't have the actual data yet; we just have the press release. Based on that, the OS data are not mature yet. The data, I assume, are going to be presented at an upcoming meeting soon. We need to look at the actual data and specific results [to fully understand the implications of this trial].

Where will future research efforts likely focus?

In my opinion, this is great news but the big question is whether PFS by itself will be enough for regulatory approval or not. I say that because there are 4 large, randomized phase III trials in the frontline setting and 2 important studies evaluating switch maintenance immunotherapy after first-line chemotherapy.

One of them is a phase II study that was already presented at the 2019 ASCO Annual Meeting by Matthew Galsky, MD, et al., which showed that treatment with switch maintenance pembrolizumab versus placebo after first line platinum-based chemotherapy prolongs PFS as per iRECIST criteria. However, the study was small—about 107 patients with a crossover design—and it will be very hard to show an OS difference.

There is also a large phase III switch maintenance trial with avelumab (Bavencio) versus best supportive care in patients who complete 4 to 6 cycles of first-line platinum-based chemotherapy and have no progression. That trial is anticipated to also read out in the near future.

Therefore, we have a total of 6 large trials—4 frontline (Checkmate-901, DANUBE, IMvigor130, KEYNOTE-361) and the 2 switch maintenance studies—that are going to define the landscape of advanced disease. Therefore, the question remains whether the PFS endpoint will be enough for regulatory approval or not. I suppose it's a good question to ask, but I don't think the answer is clear yet.

What immunotherapy-focused trials showed promise at the 2019 ASCO Annual Meeting?

As I mentioned, there were data from the phase II study that randomized 107 patients to receive pembrolizumab versus placebo with a cross-over design as switch maintenance after first-line chemotherapy. The study showed that patients who were randomized to pembrolizumab had higher response rate compared with [those who received] placebo.

This was interesting because there were also responses with placebo, which probably reflect late responses to prior chemotherapy. The primary endpoint was PFS, and this was prolonged with pembrolizumab versus placebo; however, the median difference in PFS between the two groups was about 2 months and there was no significant OS difference presented. This is very promising, but in my opinion, we may probably have to wait until we get the randomized phase III trial with avelumab versus best supportive care, also in the context of the frontline trials, to see what [the role of this] switch maintenance approach [will be].

In the frontline setting, we're still waiting for other phase III trials, such as KEYNOTE-361, which is looking at chemotherapy plus pembrolizumab, versus chemotherapy alone, versus pembrolizumab alone; this trial is very similar to IMvigor130.

Then, we have the CheckMate-901 trial, which is comparing ipilimumab (Yervoy) plus nivolumab (Opdivo) with chemotherapy. This trial also has a second comparison, which is gemcitabine/cisplatin plus nivolumab versus gemcitabine/cisplatin alone, so it also aims to answer the question about chemotherapy with PD-1 inhibitor combination versus chemotherapy alone.

The fourth trial in the frontline setting is the phase III DANUBE trial; it's exploring durvalumab (Imfinzi) plus tremelimumab versus chemotherapy in the frontline setting. We don't have the data yet but I believe all these studies will help define the landscape.

We also saw recently interesting data in the neoadjuvant space. The PURE-01 trial with pembrolizumab alone, as well as the ABACUS trial with atezolizumab alone, showed very promising data in terms of pathologic complete response (pCR) rates with single-agent checkpoint inhibitor in the neoadjuvant setting and promising data on putative biomarkers. This was in patients who were destined to get radical cystectomy and did not get chemotherapy.

These studies are not practice-changing yet, but definitely create high enthusiasm for more immunotherapy trials in the neoadjuvant space; many phase I, II, and III trials are being designed or are ongoing. It's also important to mention the 3 large phase III trials being done in the adjuvant space; one is with atezolizumab versus observation, the other is with pembrolizumab versus observation, and the last is with nivolumab versus placebo. I believe these trials are very interesting, but we don't have results from them yet.

Another point to make is the work being done in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non muscle-invasive disease. There are data from the KEYNOTE-057 trial showing that pembrolizumab was feasible and had a clinical complete response rate of about 40% at 3 months; some of those responses were durable, follow-up is ongoing to assess that durability.

What will be the regulatory fate of pembrolizumab in patients with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer? I believe it remains to be seen. We'll have to see what the regulatory agencies will say and what the durability of response is in this setting. There was another study in the same space, SWOG 1605, with atezolizumab that has not been reported yet, among other studies in NMIBC. Of course, there are also multiple combination trials involving anti-PD-L1/PD-1 agents across disease settings. Moreover, the SN1806 trial is evaluating the role of atezolizumab added to concurrent chemoradiation versus chemoradiation alone in localized MIBC, as a method of bladder preservation, the trial is active and requires accrual.

Is research being done of checkpoint inhibitors in combination with targeted agents?

Absolutely. This topic is relevant also in the context of the recent accelerated FDA approval of erdafitinib in platinum-refractory advanced bladder cancer harboring FGFR2 or FGFR3 activating mutations or fusions, with several ongoing clinical trials. There are data that will be presented soon from the BISCAY trial, which is an interesting, open-label phase Ib study that is evaluating different combinations of durvalumab—an anti—PD-L1 monoclonal antibody—with several targeted therapies, specifically in patients who have metastatic, platinum-refractory, bladder cancer. Depending on what genomic alterations the tumor had, patients were allocated to a particular treatment module.

For example, if they have DNA damage response gene mutations, they received durvalumab plus the PARP inhibitor olaparib (Lynparza). If they had a FGFR [alteration] they received durvalumab plus an FGFR inhibitor or the latter alone; additional modules were available. We have to see what that study shows, but I believe it's one of the first trials that is using genomic-based, biomarker-driven treatment allocation in an adaptive design, evaluating combinations of anti—PD-L1 therapy with targeted therapies. Another focus of attention is the combination of antiangiogenic agents with immune checkpoint inhibitors, which is attractive. There are additional trials assessing interesting combinations as well, e.g. with vaccines, cytokines, different immune-oncology compounds, antibody drug conjugates and other agents.

Beyond PD-L1, what other work is being done with biomarkers in this space?

There is so much going on with biomarkers, and here, at the University of Washington, Fred Hutchinson Cancer Research Center, and Seattle Cancer Care Alliance, we do plenty of biomarker studies across tumor types, but [there are ongoing efforts] specifically for bladder cancer. Globally, just to name a few candidate biomarkers that are out there in the literature, there is PD-L1 protein expression assessed by immunohistochemistry, gene expression profiling, eg luminal versus basal molecular subtypes, DNA damage response gene mutations, tumor mutational burden, T-cell clonality and diversity, and gene signatures in the tumor microenvironment, such TGF-β, ΕΜΤ, interferon-γ, etc.

All of them are under development and they need validation of clinical utility before routine clinical use. I believe the only one that's used in practice is PD-L1 in the first-line setting of cisplatin-unfit patients. Many ongoing trials are looking at several candidate biomarkers and it will be nice to see biomarker analyses down the road; a major challenge is the significant heterogeneity in assays, endpoints, and time points of biospecimen collection across clinical trials that might impede biomarker validation.

What is your take-home message to colleagues working in the bladder cancer space?

Immunotherapy has changed the treatment landscape; it provides an option for patients who were otherwise too frail for any chemotherapy. These patients were going for palliative care alone and now they can potentially receive an immune checkpoint inhibitor. The results [seen so far] are very promising. [The data] have established a new standard of care for platinum-refractory disease and an option for cisplatin-ineligible patients.

There is also a plethora of ongoing clinical trials that need accrual. It's very important for oncologists out there—both in the community and academic centers—to refer patients for clinical trials. Both single agent and combination studies, as well as the extensive biomarker work being done across disease settings are really impressive and the field is rapidly evolving.