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Professor of Medicine
Division of Hematology/Oncology
Department of Medicine
Lineberger Comprehensive Cancer Center
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Matthew I. Milowsky, MD, has disclosed that he has received consulting fees from BioClin Therapeutics and funds for research support paid to his institution from Acerta, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean, Clovis, Constellation, Incyte, Innocrin, Inovio, Jounce, MedImmune, Merck, Roche/Genentech, Seattle Genetics, Syndax, and X4 Pharmaceuticals.
Professor of Medicine, Medical Oncology
Director, Prostate and GU Medical Oncology
Director, Prostate Cancer Translational Research Group
Yale Cancer Center
New Haven, Connecticut
Daniel P. Petrylak, MD, has disclosed that he has received consulting fees from Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Exelixis, Incyte, Janssen, Lilly, Pfizer, Pharmacyclics, Roche, Seattle Genetics, and UroGen; has received funds for research support from Ada Cap, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis, Endocyte, Genentech, Innocrin, Lilly, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche, Sanofi, Seattle Genetics; and has ownership interests in Bellicum.
Chief, Genitourinary Oncology Service
Division of Solid Tumor Oncology
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
Jonathan E. Rosenberg, MD, has disclosed that he has received consulting fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Merck, Pharmacyclics, Pfizer, Roche/Genentech, and Seattle Genetics; funds for research support from Astellas, AstraZeneca, Bayer, QED Therapeutics, Roche/Genentech, and Seattle Genetics; and honoraria from Chugai.
In this commentary, bladder cancer experts Daniel P. Petrylak, MD; Jonathan E. Rosenberg, MD; and Matthew I. Milowsky, MD, answer questions on the use of immunotherapy posed by the audience during a live CCO Webinar in June 2020.
Do you routinely check audiometry prior to prescribing cisplatin? How do you interpret the results?
Daniel P. Petrylak, MD: I do check it, particularly for patients with known hearing issues, but not necessarily routinely. I will monitor the audiometry as needed. Overall, with cisplatin, I am more concerned about cardiac issues than auditory issues.
Jonathan E. Rosenberg, MD: I treat audiometry similarly, in that I don’t routinely check it at baseline and instead use it only with patients where there is some concern. On occasion, I will put patients with baseline audio impairment on a monitoring program where they are monitored every 2 cycles.
Matthew I. Milowsky, MD: Overall, to assess patients for cisplatin eligibility, I use the criteria set forth by Galsky and colleagues:
In addition, other factors can preclude cisplatin use and/or carboplatin use, including coexisting medical problems with impaired performance status.
For patients with bladder cancer who are cisplatin ineligible but otherwise eligible for platinum agents, would your standard regimen be gemcitabine plus carboplatin followed by avelumab maintenance? What if they were PD-L1 positive?
Daniel P. Petrylak, MD: That’s an interesting question. The phase III JAVELIN Bladder 100 data showed a benefit for maintenance avelumab after first-line platinum-based chemotherapy and led to the FDA approval of avelumab as maintenance therapy for patients with urothelial cancer (UC) that has not progressed with first-line platinum-containing chemotherapy. However, there are no comparative data for the sequencing of avelumab and chemotherapy. Also, in that study, the improvement in survival with maintenance avelumab was conserved regardless of whether patients were PD-L1 positive or negative. In my experience, if patients receive carboplatin-based chemotherapy in the first line and are PD-L1 negative, they will likely receive an immune checkpoint inhibitor as subsequent therapy after progression. Now, with the JAVELIN Bladder 100 data, maintenance avelumab can also be considered. In the absence of comparative data for immuno-oncology maintenance vs sequential therapy, the patient’s preference is a key deciding factor.
For PD-L1–positive patients who are ineligible for cisplatin-based therapy, both pembrolizumab and atezolizumab are FDA-approved options in addition to carboplatin/gemcitabine. A randomized trial is needed to understand the role of avelumab maintenance after platinum-based chemotherapy vs first-line pembrolizumab or atezolizumab for these patients. Again, right now, I think it comes down to patient choice until we have more data.
Matthew I. Milowsky, MD: I am reminded of when many clinicians opted for immune checkpoint inhibitors instead of carboplatin/gemcitabine in the first line, followed by the FDA recommendations to be more selective about which patients are candidates for this approach, so I think we gave up chemotherapy a little too quickly. I agree that we have insufficient data as to when or if to use maintenance avelumab with chemotherapy vs first-line immune checkpoint inhibitor therapy for patients who are cisplatin ineligible and that the patient’s preference is important.
In my clinical practice, I am increasingly using carboplatin/gemcitabine to treat patients who are not candidates for cisplatin but are still fit enough to receive chemotherapy, and now with the addition of avelumab maintenance. Patients who benefit most from upfront chemotherapy like this are often symptomatic, have more aggressive disease features, and need a response quickly.
Given the positive results for maintenance avelumab in the JAVELIN Bladder 100 trial, what changes do you expect in clinical practice? Would you consider a patient who progresses on avelumab maintenance after chemotherapy to have the same third-line options as patients who progress on other checkpoint inhibitors?
Daniel P. Petrylak, MD: As mentioned, the phase III JAVELIN Bladder 100 data showing a benefit for maintenance avelumab for patients in response after first-line chemotherapy are very intriguing, and I expect maintenance avelumab will increasingly be accepted as a standard of care in this setting. It makes sense to administer a checkpoint inhibitor earlier in the disease state, prior to progression. It also makes sense that OS is longer when patients are treated with a small volume of disease vs larger volume seen at progression.
Regarding progression, a patient who has received avelumab would already have received a platinum agent, per the approved indication for bladder cancer, so I would move on to the standard third-line options that we have.
Matthew I. Milowsky, MD: Formally speaking, enfortumab vedotin is approved in the post-platinum/post–immune checkpoint inhibitor space, so it would be entirely reasonable to recommend this next to a patient whose disease progressed on avelumab maintenance. Alternatively, erdafitinib is approved for patients with FGFR2 or FGFR3 alterations after progression following platinum-based chemotherapy, so I think is another reasonable approach for patients with FGFR alterations.
The data to date from IMvigor130 are unclear. If there is an OS benefit, would it be appropriate to start adding atezolizumab to platinum chemotherapy as first-line treatment?
Jonathan E. Rosenberg, MD: The phase III IMvigor130 trial is exploring the use of atezolizumab with or without platinum-based chemotherapy vs placebo plus platinum-based chemotherapy as first-line therapy for patients with metastatic UC. In the initial analysis, the final PFS data were presented and showed a statistically significant improvement in PFS with the addition of atezolizumab to chemotherapy (HR: 0.82; P = .007) in the intention-to-treat population. However, the interim OS analysis showed a trend toward an improvement with the addition of atezolizumab, but the data are not yet mature. Whether I would consider adding immuno-oncology therapy to first-line chemotherapy will depend on the magnitude of the survival benefit once the data are mature, which should become more clear in subsequent analyses of IMvigor130. The main question for me is whether the benefit is the same from starting an immune checkpoint inhibitor at the end of chemotherapy (eg, JAVELIN Bladder 100) as it is from starting a checkpoint inhibitor at the beginning of chemotherapy (eg, IMvigor130).
We do not have any direct evidence for this, but if the OS data from IMvigor130 are positive, it would be helpful to have a trial looking at the timing for immunotherapy with either starting with first-line therapy vs as switch maintenance after chemotherapy. At the moment, I am not changing my clinical practice based on the results from IMvigor130. However, if a clinically meaningful OS benefit were to become apparent, I would consider this approach. But to date, that has not been the case.
Matthew I. Milowsky, MD: I agree. These data are not sufficient to change my practice as well.
Daniel P. Petrylak, MD: Yes, and I am interested in additional novel combinations as maintenance therapy as well. It is possible that some antibody–drug conjugates, like enfortumab vedotin, combined with immune checkpoint inhibitors may have a role up-front as maintenance therapy or even as frontline therapy as was seen in the EV-103 trial. It will be interesting to see what the future holds for combination therapy.
For a patient with locally advanced, muscle-invasive bladder cancer who either isn’t a candidate for surgery or declines surgery, would you start with chemotherapy or immunotherapy? Or would you start with chemoradiation instead of systemic therapy?
Matthew I. Milowsky, MD: This is a complicated question. A patient who is not a candidate for surgery and has locally advanced disease may benefit from combined modality therapy, which is typically well tolerated and may be effective at controlling local disease. This is an individualized decision that depends on the particular patient’s coexisting medical problems. In my practice, I like to use bladder-preservation regimens that can be extrapolated to treat patients with more locally advanced disease. I find they are well tolerated and can control locally advanced disease well.
For a patient with bladder cancer and progression on platinum chemotherapy, what is your current standard for a second-line checkpoint inhibitor?
Daniel P. Petrylak, MD: I typically give pembrolizumab given the demonstrated survival benefit in the phase III KEYNOTE-045 clinical trial.
Matthew I. Milowsky, MD: I do the same.
Jonathan E. Rosenberg, MD: As do I, in general.
If patients with bladder cancer have FGFR3 mutations and progress on platinum chemotherapy, would it be better to give them pembrolizumab or erdafitinib?
Matthew I. Milowsky, MD: Personally, I would generally give them pembrolizumab as second-line therapy, with the known OS benefit demonstrated in the Keynote 045 study. I would also always consider referral for clinical trials if available. For a patient has an FGFR2/3 alteration and has already received pembrolizumab as second-line therapy after chemotherapy, I need to choose between erdafitinib and the antibody–drug conjugate enfortumab vedotin, which targets nectin-4. From a tolerability standpoint, enfortumab vedotin may be easier, even though erdafitinib is an oral agent. However, tolerability varies among different patients, and to date, there are no biomarkers to predict adverse events with either agent in this population. In addition, different co-existing medical issues may make one therapy preferable over another for individual patients and this needs to be taken into account when selecting therapy. Currently, my preferred sequence is an immune checkpoint inhibitor, followed by enfortumab vedotin, and then erdafitinib (for patients with an FGFR2/3 alteration), although we do need more data to aid in sequencing decisions.
Daniel P. Petrylak, MD: Yes, I agree. For example, I would consider erdafitinib before enfortumab vedotin for patients with preexisting neuropathy, which they could experience as a result of carboplatin. I try to consider each patient’s risk of adverse events when I am making decisions on sequencing these agents.
What are your thoughts on the correlation between FGFR alterations and poor responses to immunotherapy?
Matthew I. Milowsky, MD: The data are mixed on this question. The presence of FGFR alterations may be associated with a non–T-cell–inflamed phenotype that may be predictive of decreased response to immune checkpoint blockade, however this may be balanced by lower expression of resistance markers such as stromal/TGF-β signaling. At present, these data are not ready for clinical decision-making until we have additional data from randomized trials.
Jonathan E. Rosenberg, MD: This is a very exciting time in bladder cancer treatment. Novel agents like avelumab are being used in earlier lines of treatment as maintenance therapy. Exciting data are emerging regarding targeted therapies and antibody–drug conjugates. I hope we continue to see this rapid rate of FDA approvals that we have seen during the last 4 years.
Matthew I. Milowsky, MD: I agree. The rapid developments during the past several years are extraordinary. With the avelumab data from JAVELIN Bladder 100, it is even more important to continue evaluating novel therapies like enfortumab vedotin, erdafitinib, and novel combinations in different clinical disease states. The landscape of bladder cancer treatment is transforming, with patients living longer and, potentially, even being cured.
Daniel P. Petrylak, MD: I am struck by the contrast between the survival improvements we have discussed here and the experience of patients with bladder cancer in 2012-2013, where they could expect to live only 6-12 months after failing primary chemotherapy. The challenge now is to rationally design future clinical trials to incorporate the deepening understanding of the biology of bladder cancer. But these trials are necessarily large and take years to read out. Yet, checkpoint inhibitors like pembrolizumab and atezolizumab are being moved earlier into the new adjuvant setting in clinical trials, and newer drugs like enfortumab vedotin, sacituzumab govitecan, and erdafitinib may be moving to even earlier in our treatment paradigm. We need to design trials to obtain answers in the shortest amount of time possible.
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