Grivas Discusses Developments in Bladder Cancer

Petros Grivas, MD, PhD

For patients with locally advanced or metastatic bladder cancer who are cisplatin-ineligible, treatment options are limited, making clinical trials invaluable to further developments, explained Petros Grivas, MD, PhD.

“[There is a lot of potential with] combinations of targeted therapies and immunotherapies, or targeted therapy alone in some cases, said Grivas. “Right now, we only have chemotherapy and single-agent checkpoint inhibition [in advanced bladder cancer]. There is definitely room for improvement. These clinical trials provide good opportunities for biomarker discovery and validation, and hopefully, for more agents to come forward for our patients with...urothelial cancer.”

OncLive: What has changed in the management of localized bladder cancer in recent years?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Grivas, director, University of Washington Medicine’s Genitourinary Cancers Program, associate professor of Oncology, University of Washington, Seattle Cancer Care Alliance, discussed the rapidly evolving locally advanced and metastatic bladder cancer field.Grivas: It's an exciting era in the management of bladder cancer, and specifically, in the localized disease setting. Thus far, we have Level I evidence for cisplatin-based neoadjuvant chemotherapy before radical cystectomy and lymph node dissection. However, many patients may not be fit enough to receive cisplatin. Right now, those patients go right to the operating room to get radical cystectomy because there's no good evidence [to support the use of] carboplatin or other agents.

To try to meet this unmet need, we have designed clinical trials with immune checkpoint inhibitors. [Efficacy] is being evaluated by pathologic complete response rates (pCRs). We have data from the ABACUS trial, which was presented at the 2018 ASCO Annual Meeting by Thomas Powles, MBBS, MRCP, MD, of Barts Cancer Centre. The trial showed a 29% pCR rate in patients who received just 2 doses of atezolizumab (Tecentriq) followed by radical cystectomy. If you look at the subset of patients who have PD-L1 expression, the pCR went up to 40%.

Similar data were presented by Andrea Necchi, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and colleagues at the 2018 ASCO Annual Meeting and the 2018 ESMO Congress. In the trial, patients received 3 doses of pembrolizumab (Keytruda) before radical cystectomy and lymph node dissection. In all comers, the pCR was about 40%, and 50% in those with high PD-L1 expression. These data were not practice changing, but they definitely fueled enthusiasm and brought significant attention to neoadjuvant trials with immunotherapy.

We’re looking for these immunotherapy agents—especially for those who are cisplatin-ineligible—to see whether we can offer patients a new treatment down the road. [That’s assuming] these trials confirm the activity and safety of these agents. At the same time, we may be able to build upon the cisplatin backbone. There are new trials looking at cisplatin plus immunotherapy versus cisplatin-based therapy alone. That's something that will probably be looked at in the near future to try to improve outcomes for patients with localized disease.

Is bladder preservation an option for these patients?

We also have patients who come to us after receiving a radical cystectomy. They never had neoadjuvant chemotherapy, or they received it and they still had muscle-invasive residual disease. If those patients are fit for cisplatin and have PT3-4 or node-positive disease, we tend to offer them cisplatin-based adjuvant chemotherapy. However, if they cannot receive cisplatin safely, refuse it, or already received it neoadjuvantly, we have these immunotherapy trials. There are trials [currently] looking at single-agent checkpoint inhibition in the adjuvant setting after radical cystectomy and lymph node dissection.There is a significant effort going into improving upon the data with bladder preservation. We've used concurrent chemotherapy and radiation and chemoradiation as a backbone. We have this intergroup trial with SWOG, NRG Oncology, ECOG, ACRIN, and ALLIANCE looking at chemoradiation alone or chemoradiation plus atezolizumab (Tecentriq) to see whether the combination could improve upon bladder intact disease-free survival and other endpoints. If this trial accrues well, it will give us more data on bladder preservation.

What are some advances that have been made in metastatic bladder cancer?

I cannot emphasize enough the role and importance of biomarkers. In those trials—especially the neoadjuvant trials—we get tissue as well as blood and urine. We get a plethora of biospecimens to do research studies to look at biomarkers. To help biomarker discovery and validation, we have to align more endpoints, and therein, attempts of which biomarkers to look for. As an oncology community, [we need to] get smarter so that we can select the right treatment for the right patient.Metastatic disease is an unmet need in the field of advanced urothelial cancer. We have tried to use frontline cisplatin-based chemotherapy [in this patient population]. Some patients are not fit enough to receive it or they have already received adjuvant or neoadjuvant chemotherapy and relapsed within the year. Chemotherapy-naïve patients can get cisplatin. Usually, we give them cisplatin-based chemotherapy. If they are not fit for cisplatin, then we go with either carboplatin and gemcitabine [or immunotherapy].

We also have 2 checkpoint inhibitors approved in that setting: pembrolizumab and atezolizumab. Recently, the FDA and the EMA restricted the use of those agents to patients with PD-L1—high tumors. Patients undergo a PD-L1 assessment based on the corresponding companion assay that is linked to a particular drug. However, a patient who is too frail or too sick to get any chemotherapy does not need to have a PD-L1 assessment because they have no other options. The FDA recognizes that, but there’s no such disclaimer in Europe; they still have to test PD-L1 there.

Again, the theme is the same. We need more clinical trials to find more treatments for those patients. There are many ongoing trials evaluating very interesting combinations and [making] comparisons between chemotherapy and immunotherapy or the combination thereof.

There are a couple of switch maintenance trials for patients who started with chemotherapy alone and achieved a response or stable disease. These [2 ongoing trials] are looking at checkpoint inhibitors as a way to sustain the benefit they got with chemotherapy. The phase II trial closed to accrual, and results are pending. The phase III trial is still ongoing. We're going to have more data in the next couple of years that could potentially transform the frontline setting.

In platinum-refractory disease, we have 5 FDA approvals of checkpoint inhibitors. The Level I evidence as per National Comprehensive Cancer Network guidelines is with pembrolizumab, because it met the primary endpoint in a phase III randomized clinical trial. The other 4 inhibitors are atezolizumab, nivolumab (Opdivo), durvalumab (Imfinzi), and avelumab (Bavencio). There is a great opportunity in this setting to conduct clinical trials to try to improve upon single-agent checkpoint inhibition, as well as combination therapies.

Which agents have the greatest potential to extend the durability of immunotherapy?

Also, we now have antibody-drug conjugates, which are very promising. Enfortumab vedotin and sacituzumab govitecan are 2 examples. We have targeted therapies with FGFR inhibitors, PARP inhibitors, and HER2 inhibitors, which are being tested in clinical trials. The data with FGFR inhibitors look very promising. Targeted therapies have a future based on proper patient selection; that's where next-generation sequencing plays an important role with tumor tissue. Circulating tumor DNA is an emerging tool to try to profile patients’ cancers to come up with innovative clinical trial designs.It's a great question, and it's very difficult to discern one or two of them. I'm very excited about combinations of PD-L1 inhibitors and vaccines. We have a clinical trial for cisplatin-unfit patients that’s looking at the frontline combination of a checkpoint inhibitor with a vaccine called CV301. The vaccine is trying to prime the immune system against the cancer-related antigen CEA-MUC-1. There are other trials evaluating the combination of immunotherapy with targeted therapies.

There are data with FGFR inhibitors in patients with mutations or fusions of the FGFR gene. One of them has a breakthrough status from the FDA: erdafitinib. There are other FGFR inhibitors out there from multiple companies that look promising and merit investigation in urothelial cancer.

It's exciting to see this emerging landscape. Of course, we also have PARP inhibitors; we're doing a trial with rucaparib (Rubraca), which is approved in other tumor types. We’re evaluating its single-agent activity in patients with urothelial cancer and in all comers, regardless of mutations, in patients with particular genomic scarring mutations in DNA repair genes, and homologous recombination deficiency.

How important is genomic testing in bladder cancer?

Cabozantinib (Cabometyx) and atezolizumab are also being evaluated in urothelial cancer. The combination of ipilimumab (Yervoy) and nivolumab is being tested. There is a plethora of other agents that look promising. It's definitely an exciting opportunity to define more therapies and identify which patients might benefit from particular agents.It’s important not to forget about germline mutations in urothelial cancer, especially upper-tract disease. Many patients carry germline mutations; it may be up to one-third of patients with upper-tract disease. That is why we also keep an eye on family history and the age of diagnosis. When you do somatic mutation testing, have your genetic counselor look for potential hints of germline mutations. Keep in mind somatic mutation testing is not enough to replace dedicated germline testing.