Today we are discussing immunotherapy approaches for the treatment of advanced urothelial cancer with Dr. Petros Grivas, MD, PhD, a medical oncologist who focuses on genitourinary cancers at the Seattle Cancer Care Alliance and the University of Washington. Grivas is an associate professor and clinical director of the Genitourinary Cancers Program at the University of Washington, and associate member of the Fred Hutchinson Cancer Research Center in Seattle.
Cancer Network: There have been at least five Food and Drug Administration (FDA) approvals of immunotherapies, and specifically of immune checkpoint inhibitor antibodies, for urothelial cancer. Could you briefly go through the agents now available for treatment and which patients are eligible?
Dr. Grivas: I would start by saying that we have experienced a revolution in the treatment landscape for advanced urothelial cancer in the last few years and this has led to the FDA approval of five distinct immune checkpoint inhibitors that inhibit the PD1/PDL1 axis of the immune system. These five agents are pembrolizumab, atezolizumab, durvalumab, avelumab and nivolumab.
All of these agents are approved for patients who have advanced urothelial cancer, meaning locally advanced/unresectable or metastatic disease and have progressed despite treatment with platinum-based chemotherapy. These agents are approved by the FDA in what we call the “salvage setting” after prior platinum-based chemotherapy.
One of those agents, pembrolizumab, has shown overall survival benefit, as a primary endpoint of a phase 3III trial, compared to salvage chemotherapy in patients who progressed on platinum-based chemotherapy. The other agents were approved based on phase II trials. It is worth mentioning that another agent, atezolizumab, was also tested in a phase III trial that showed that in “all-comers," meaning in the entire study population, there was overall survival benefit compared to salvage chemotherapy.
However, this was not the primary endpoint; the primary endpoint was overall survival in the subset of patients who had higher PD-L1 expression and this particular primary endpoint was not met in this IMvigor211 trial.
So overall, we have five agents approved in this particular salvage setting, and one of them has Level 1 evidence based on NCCN [National Comprehensive Cancer Network] guidelines based on the phase III Keynote 045 trial, that compared pembrolizumab vs salvage chemotherapy. However, all of these therapy options are approved and available in this setting, but there is no data to use one after progression on another checkpoint inhibitor.
Moreover, in the first-line setting, especially for cisplatin-unfit patients, meaning patients who cannot safely receive cisplatin in the first-line, chemotherapy-naïve for advanced disease setting, two of these agents are FDA approved: atezolizumab and pembrolizumab based on single arm, phase II studies (IMvigor 210, cohort 1, for atezolizumab, and Keynote 052 for pembrolizumab). These agents were initially approved regardless of tumor tissue PD-L1 expression.
However, more recently, around May and June of 2018, there were discussions with the FDA and EMA (European Medicines Agency) in Europe that ultimately led to the modification of the label of these two agents in the first-line setting. The chemotherapy naïve cisplatin-unfit patients that restricted the use of these two checkpoint inhibitors to patients with high PD-L1 expression based on the companion corresponding assay for each agent.
For example, for pembrolizumab, this is the Agilent/Daco 22C3 assay, and for atezolizumab, the Ventana SP142 assay. However, in the US based on FDA clarification, if a patient is very frail and unfit for carboplatin, so not a good fit for any platinum-based chemotherapy, there is no need to check PD-L1 expression in these patients and they could get either approved checkpoint inhibitor in the first-line setting regardless of PD-L1 expression.
These are the approved agents, but there are a plethora of ongoing clinical trials that are looking at combination therapies in advanced urothelial cancer, while also looking at biomarkers. There is also evaluation of those and other immune checkpoint inhibitors in earlier disease settings, including the adjuvant and neoadjuvant settings as well as the non-muscle invasive bladder cancer setting.
Cancer Network: You mentioned cisplatin-based chemotherapy has been the standard of care for urothelial carcinoma. In the context of the labels for the approved checkpoint inhibitors, how do you view the role of these agents in treatment? Are there also other options for the same line of therapy? How do you choose an immunotherapy vs a different type of treatment for patients?
Dr. Grivas: There are a few points to make here. Number one is that in the front-line setting in the locally advanced/unresectable or metastatic urothelial cancer, the standard of care is cisplatin-based chemotherapy. Of course, we always want to do clinical trials and this is the optimal way to go regardless of treatment setting. But in the absence of trials, cisplatin chemotherapy, usually gemcitabine-cisplatin, or less frequently, accelerated, dose dense MVAC [methotrexate, vinblastine, doxorubicin, cisplatin] is used in this first-line setting.
The patients who cannot get cisplatin have the option of getting non-cisplatin chemotherapy and usually many of those patients end up getting carboplatin/gemcitabine or a checkpoint inhibitor, pembrolizumab or atezolizumab, which, as we just discussed, are approved in this first-line “chemotherapy naive for advanced disease” setting for cisplatin unfit patients. The decision depends on the fitness, candidacy, eligibility for cisplatin, and the availability of clinical trials. Right now, in advanced urothelial cancer we have chemotherapy and immunotherapy as approved options.
We don't have any other agents approved yet, however, we have many ongoing clinical trials looking at antibody drug conjugates. Agents like enfortumab vedotin and sacituzumab govitecan, which are being tested in very interesting phase II and III trials, with prior, early-phase, trial data looking very promising.
There are also targeted therapy trials, including inhibitors against FGF receptor, PARP, HER2, and other molecular targets. I think that these trials are very interesting, and hopefully we will have more agents approved in the future. Until then, I think clinical trials is the optimal way to go.
To summarize, cisplatin-based chemotherapy upfront is the standard of care for fit patients. For cisplatin-unfit patients we have either other chemotherapy, for example carboplatin/gemcitabine, or the two approved checkpoint inhibitors as first line therapy, based on the details we discussed above.
If a patient is progressing on platinum-based chemotherapy, a clinical trial is again the way to go. Outside of clinical trials, we have the five FDA-approved checkpoint inhibitors, with pembrolizumab having Level 1 evidence in this salvage therapy setting.
Cancer Network: You mentioned that there are clinical trials of combinations and there are trials testing these immunotherapy agents in earlier disease settings, and also biomarkers. Of all of these questions that you and your colleagues are addressing with respect to checkpoint inhibitor antibodies, are there one or two questions that you could highlight?
Dr. Grivas: I think there are multiple, very interesting clinical trials, really a huge list, and I don’t want to leave anything out. But overall, the main questions we are trying to answer are in the first-line setting, is chemotherapy or immunotherapy the way to start for advanced urothelial cancer?
In that context, there are four large, phase III trials asking this question of chemotherapy vs immunotherapy in the front-line setting. Two of these trials are asking an additional question, which is whether the combination of chemotherapy and immunotherapy is better than chemotherapy or immunotherapy alone. I think these trials may potentially impact the treatment landscape.
There are also two very important “switch maintenance” trials. One is a phase III trial that is testing an anti-PDL1 agent, avelumab), after 4 to 6 cycles of front-line platinum-based chemotherapy, with no progression. Patients get randomized to avelumab and best supportive care vs best supportive care alone.
There is also a phase II trial that has a very similar design that is randomizing patients to pembrolizumab vs placebo with a crossover design after front-line platinum-based chemotherapy to evaluate this “switch maintenance” question, whether this sequencing of therapies is of benefit. As I mentioned, there are numerous other trials with a plethora of agents, checkpoint inhibitors plus chemotherapy, radiation therapy, targeted therapies, antibody drug conjugates, vaccines, other immune related molecules, cytokines, epigenetic modulators, anti-angiogenesis agents, etc., that are all very interesting.
These trials are trying to build upon what we have already seen with checkpoint inhibitors and are trying to prospectively evaluate the clinical utility of biomarkers. The question is, could we try to select the right patients for the right treatment in the future? Because “one size may not fit all” and patient selection is critical. So far, with the exception of tumor tissue PD-L1 in the front-line setting, we do not have clinically useful biomarkers in advanced urothelial cancer.
There is definitely the opportunity to try to identify clinically useful biomarkers to select patients, but this requires multi-center collaborations and prospective validation of candidate biomarkers across clinical trials. This is something very hard to do, but we should all push through. Candidate biomarkers span across tumor tissue, urine and blood-based biomarkers, which are interesting and worth exploring further.
Cancer Network: Thank you so much for joining us today Dr. Grivas.
Dr. Grivas: My pleasure. Hopefully we will experience many more advances in the near future in the field of urothelial cancer with new agents and biomarkers.
Grivas has done consulting with Genentech, Merck & Co., Pfizer, Bristol-Myers Squibb, AstraZeneca, Biocept, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Driver Inc., QED Therapeutics, Heron Therapeutics, and Janssen within the past 2 years. He was previously involved in an educational, unbranded program with Genentech and Bristol-Myers Squibb. His institutions have received research support from Genentech, Bayer, Merck & Co., Mirati, OncoGenex, Bavarian Nordic, Pfizer, AstraZeneca, Clovis Oncology, and Immunomedics.