Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials -Pedro Barata

August 29, 2018

(Length of Discussion: 21 min)

Petros Grivas and Pedro Barata discuss how a recent study they performed applies to the field of metastatic urothelial cancer regarding the use of checkpoint inhibitors in a patient population outside the context of the clinical trial and the main objectives, results, and conclusion of that study as well as implications for the field.


Pedro Barata, MD, MSc, Tulane University, Department of Hematology and Medical Oncology

Petros Grivas MD, Ph.D. a medical oncologist at Seattle Cancer Care Alliance with expertise in genitourinary cancers such as bladder cancer, prostate cancer, and testis cancer.  He is the Clinical Director, of the Genitourinary Cancers Program at the University of Washington Medicine and an Associate Professor of the Department of Medicine, Division of Oncology at the University of Washington School of Medicine.

Read the full video transcript

Petros Grivas: Hello, I am Petros Grivas. I'm a medical oncologist and clinical director of the Genitourinary Cancers program at the University of Washington and the Fred Hutchinson Cancer Research Center. I am an associate professor in this institution, and today we're discussing with my colleague and friend, Dr. Pedro Barata, about the recent study we performed and applies to the field of metastatic urothelial cancer regarding the use of checkpoint inhibitors in a patient population outside the context of the clinical trial, and the main objectives, results, and conclusion of that study as well as implications for the field.

 would like to ask you to introduce yourself and then we'll discuss about this study.

Pedro Barata: Sure. Hello, everyone. Thank you, Dr. Grivas, for chit chatting a little bit about our study here. I'm an assistant professor at Tulane University in New Orleans, Louisiana. I'm focusing on genitourinary tumors including prostate, bladder, and kidney cancer. Today, we're going to talk a little bit about a study that I've conducted with Dr. Grivas as my mentor a few months ago, which is actually reports on efficacy and safety, atezolizumab for patients who were treated with this checkpoint inhibitor outside clinical trials. In the context of the checkpoint inhibitors being approved in advanced bladder cancer, namely five of them, the big question is we had a fair amount of patients who were receiving these therapies outside clinical trials. In particular, we have a reasonable number of patients who are treated with atezolizumab in the setting of metastatic urothelial carcinoma.

Basically what we did, we wanted to report outcomes and response to atezolizumab. In addition to that, we also want to understand better what happens to these patients who, unfortunately, progress on this therapy or seem to not benefit from it anymore. We basically conducted a retrospective study at our oncology institution, the Cleveland Clinic, and we identified 79 patients who were treated with at least one dose of atezolizumab 1200 mg every three weeks, and this happened between May 2016 and April, last year.

As I said, we identified 79 patients with baseline characteristic, pretty much concordant with what we would expect for these patient population in this setting, so median age 72, most men, good performance status, and more commonly with cancer in the bladder, two-thirds or so were treated previously with surgery. Importantly, 75% of these patients, so three-fourths of patient core were actually received atezolizumab on the second line or more in the advanced setting.

Starting on efficacy, we basically had 18% of partial responses to atezolizumab, whereas, 29% of these patients revealed stability of their disease. We did not find any complete response, and on the other hand, a little bit more than half of the patient actually eventually had progressive disease as best response to treatment.

In other words, these patients were atezolizumab for a median of 2.7 months which reflects a median progression-free survival of above 3.2 months. Just have in mind that, again, 25% of these patients receive atezolizumab in the frontline setting, and so we kind of separate PFS for that, as well, and PFS for those patients receiving atezolizumab in second-line was actually 2.8 months. We also are interested in reporting on safety. Approximately 40, 42% of patients had any kind of adverse events. Among those we highlight two patients who developed a hyperbilirubinemia, although no toxic deaths were reported with this checkpoint inhibitor in this context.

Furthermore, we also were interested in reporting what happened to these patients afterwards. Importantly, at time of data cutoff, 29% were still on atezolizumab, whereas, 80% or so stop atezo and move on to a different systemic therapy. Importantly, 40%, actually, were not in clinical studies to actually receive any kind of therapy and they were referred to hospice or eventually died. A few of them lost to follow up with single agents here.

The main conclusion of this paper is actually that patients who progress on atezolizumab outside of clinical trials were unlikely to receive subsequent systemic therapies in the context of the numbers I just shared with you and the benefit of these treatments appeared somewhat limited in this cohort. How can we improve these numbers and how can we actually offer other strategies or can explore other strategies to actually make people live better and live longer?

Petros Grivas: Thank you very much, Pedro, for the very detailed outline of the paper. I think it's, as you mentioned, a relevant study because it attempts to evaluate efficacy, safe tolerability, and subsequent therapy data in a population of patients who are outside the context of a clinical trial more closer set to the real world. However, as you pointed out, this population was treated in a tertiary, very specialized cancer center like the Cleveland Clinic, which definitely may introduce some selection bias in terms of the patients who are able to get there. At the same time, it opens a lot of questions regarding the implication of the results, which I think are very, very meaningful and I think very important to take into account in clinical trial design and also in clinical practice.

In your opinion, what's your sense regarding the efficacy and safety across the different FDA-approved immune checkpoint inhibitors, especially in the platinum refractory, platinum-resistant setting. Do you sense ... Do you use these agents and you experience similar to what is reported in our study and also in the clinical trials?

Pedro Barata: Right. Great questions, Dr. Grivas, as usual. I'll say, you know, we actually were not surprised at all with the results, efficacy and safety data on atezolizumab that we reported, right? Just to have in mind that we report a PFS of 3.2, but if we want to adjust, we individualize the core of patients were treated with atezo, in second-line and beyond. Patients had a median PFS of close to three months, 2.8 to be precise. I think this compares favorably with both studies with atezo, both phase two, IMvigor 210, and the phase three, IMvigor 211, where they actually were a PFS of 2.1 or so. In the same token, the median overall survival of our core, which is reported to be 7.8 months was actually in line with what we saw in both the core two and IMvigor 210 and the phase three trial with atezolizumab in the same setting where we compare it with physicians' chemotherapy of choice.

I'll say, efficacy-wise, it's pretty comparable, so no surprises here. Similarly, safety-wise, I think, and Dr. Grivas, you can expand on that, but basically I would say that these agents are pretty safe. We expect significant side effects to occur; I'll say in the less than 20%. Most of the patients, they are able to tolerate this treatment with minor, if any, side effects. Again, we didn't detect any toxicity signals that will make us as concerned about the administration of atezolizumab, right? Regarding the use of atezo versus the other four checkpoint inhibitors in this setting out, I would say ... We are data driven, right? I actually was taught by Dr. Grivas about that, as well.

In the context of multiple phase two trials and a phase three trial for pembrolizumab and phase two trials for the other four agents, where atezolizumab is included, so far the phase three trial that showed the survival benefit in favor of checkpoint inhibitor was with pembrolizumab. Not that I believe there's a significant difference between the checkpoint inhibitors. I think more work needs to be done, but the outcomes seem to be pretty similar among different checkpoint inhibitors. The reality of it is we do have phase three data that supports the use of pembrolizumab if we are data driven. Not that I anticipate to see differences among different checkpoint inhibitors, but if we want to use data to support our decision process, I'll say we tend to use more pembrolizumab because of that.

Petros Grivas: I think it's a great discussion, and as you mentioned, is extremely difficult to compare across studies. We always have limitations doing that because of different patient populations and different characteristics, of course, the incident caveat of pursuing that in the trial comparison. At the same time, you mentioned there have been comparable efficacy and safety, as well as discontinuation rates data across the different trials with all the checkpoint inhibitors. Many colleagues in the community believe that these agents have comparable efficacy and safety. It seems to be the reality. At the same time, if you go by the level of evidence, as you mentioned, then you have a phase three trial that met the primary endpoint versus chemotherapy in the platinum-resistant setting based on the KEYNOTE-045 trial.

At the same time, it's interesting that the IMvigor 211 trial did not meet the primary endpoint of overall survival compared to chemotherapy with atezolizumab. However, this primary endpoint was only in the subset of patients with a higher PD-1 expression, what they call the PD-L1 positive patients based on the specific VENTANA SP142 assay. However, interestingly, in the overall population, on all comers, there was a basically significant difference favoring atezolizumab potential for survival. However, this was not the primary endpoint of the study. I think overall it's important to dissolve that clinical trial design, statistical design, in that case here, hierarchical design, might have played a role and also I think that all of biomarkers have to be defined as we have discussed before. It's really difficult and very hard to define prognostic versus predictive biomarker based on the single arm phase two study. This is assay-dependent as in that case, so it was very difficult to do, to have that conclusion until if randomized phase three launch trial takes place.

Having said all this, I think immune checkpoint inhibitors as a class of drugs have definitely revolutionized the treatment landscape of advanced urothelial cancer, as you said, and this is an important message. Many patients who could not get chemotherapy before or they were too frail for aid, or they did not opt to do that, now they have options. That's very, very positive methods across immune checkpoint inhibitors, and there are five of them approved in the platinum-resistant setting. Two of them are approved by the FDA in the first-line setting in cisplatin unfit, ineligible patients. As you mentioned that there's a plethora of clinical trials going on, and I think the future is probably going to evaluate a several combinations of immunotherapy agents along with other therapies, targeted therapies. There are other drugs like FGF receptor inhibitors, PARP inhibitors, other signaling pathway inhibitors that are being evaluated. It's a very exciting field as well as chemotherapy immunotherapy combinations.

One question I have for you is in this really exciting and dynamic field with new data coming almost every month or so, what do you think are the implication of this particular study in the timing of subsequent therapies and the clinical trial design so far, we're continuing checkpoint inhibitors until clinical deterioration in the platinum-resistant setting. What are your thoughts regarding the timing of those subsequent clinical trials and subsequent therapies?

Pedro Barata: Right. The question is great. I'm not sure if I'll be able to respond 100%, but I'll do my best. As we've seen over and over in cancer research active therapies are approved later on just because the end points are much weaker to get. Once these therapies are proven to be active in patients, we tend to study to investigate these therapies earlier and earlier. I don't think it's surprising at all that we actually are seeing data, good data, as you mentioned, with checkpoint inhibitors in the frontline setting for instance with both, atezolizumab and pembrolizumab so far, but we are seeing other studies investigating checkpoint inhibitors as single agent or in combination with other therapies early on. I think that's what's going to happen. I think one good point about our study is that it shows that we do need to do more. The reason why I say that because only a minority of patients, for one reason or the other, is actually able to receive some subsequent therapies. It tells us that only a minority of patients are actually fit to first be enrolled in clinical trials. Even if we have therapies approved in the refractory setting, only a minority of patients will be able to actually benefit from those therapies.

We were seated together at ASCO meeting this year and we saw interesting data with new therapies with novel mechanism of action and FGFR inhibitors or antibody drug conjugates with promising activity data presented there. I think the way the field is moving is actually we'll see check inhibitors being used early on. I agree with you, maybe combined with other immunotherapies or maybe we'll see ... At time of progression on one checkpoint inhibitor, we might see a combination of immunotherapies to explore possible mechanisms of resistance to immunotherapy and to kind of resensitize tumors. I also see these novel therapies or novel mechanism of actions. As they show to be active, maybe they will be combined a little bit later on with immunotherapy such as atezolizumab or other checkpoint inhibitors.

Petros Grivas: Thank you very much, Dr. Barata, for your detailed presentation. I think it's a really, really exciting field. I think we all see really continuous and dynamic data presentations at ASCO that you sit in other meetings regarding urothelial cancer. The field is moving so forward that I'm hopeful that in the next few years we're going to have a number of new agents to accompany and increase our current armamentarium with immune checkpoint inhibitors and chemotherapy. The questions will become more relevant regarding combinations, sequencing of therapies, timing of sequencing, and also discovery and validation of relevant biomarkers can help us, hopefully in the future, select our patients.

With that note, I think, overall this study did show consistent data with these immune checkpoint inhibitors in a clinical setting outside the clinical trials. Again, as you mentioned, I agree with you more studies are needed and maybe registries are also important to capture efficacy but also rare but sometimes severe immune-related adverse events that may happen with a variety of immunotherapy agents, checkpoint inhibitor and other classes. I think it's important because, as you mentioned, these agents are usually very well tolerated. However, it's of utmost importance to have education for providers, oncologists, the primary care physicians, emergency room physicians and others as well as patients for better awareness, education, and proper management of any related adverse events so we can have the optimal management of them and optimal outcomes and care of all the patients.

Overall, I would like to thank you for your time and looking forward to more collaborations and interactions.

Pedro Barata: Thank you, Dr. Grivas. It was a pleasure. Thank you for hosting and presenting this study. I'll also look forward for future collaborations with you and your group that you are leading. Thank you so much.
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