Transcript:Daniel P. Petrylak, MD: Hello, and thank you for joining this OncLive Peer Exchange® titled “Immunotherapy Use in Advanced Urothelial Carcinoma.” The advent of novel immunotherapies has revolutionized the field of oncology and is a particularly welcome addition to multimodality treatment of bladder cancer. Aggressive bladder cancers are challenging to treat, and until the recent availability of checkpoint inhibitors, patients with progression of metastatic disease on platinum-based therapy had few options. In this OncLive Peer Exchange® discussion, we’ll discuss what we know today about integrating immune therapy into the current treatment strategy, and emerging data that we anticipate will shape the way forward.

I am Dr. Daniel Petrylak, and I am a professor of medicine, medical oncology and urology, director of Prostate and GU Medical Oncology, and director of Translational Prostate Cancer Research at Yale University Cancer Center in New Haven, Connecticut. Participating today on our distinguished panel are: Dr. Dean Bajorin, attending physician at Memorial Sloan Kettering Cancer Center and professor of medicine at the Weill Cornell Medical College in New York, New York; Dr. Arjun Balar, assistant professor of medicine and director of the Genitourinary Medical Oncology Program at the Laura and Isaac Perlmutter Cancer Center of NYU Langone Medical Center in New York, New York; Dr. Robert Dreicer, associate director for Clinical Research and deputy director of the University of Virginia Cancer Center; and professor of medicine and urology at the University of Virginia School of Medicine in Charlottesville; Dr. Elizabeth Plimack, chief for the Division of Genitourinary Medical Oncology, director of Genitourinary Clinical Research, and associate professor for the Department of Hematology/Oncology at Fox Chase Cancer Center, Temple Health in Philadelphia, Pennsylvania; and Dr. David Quinn, medical director of USC Norris Cancer Hospital, head of a section of Genitourinary Medical Oncology, and associate professor of medicine in the Division of Oncology at the Keck School of Medicine of USC in Los Angeles, California. Thank you for joining us. Let’s begin.

So, segment 1 is rapidly evolving paradigms for the treatment of muscle-invasive bladder cancer. First, I’d like Dean to provide an historic perspective on the treatment of advanced bladder cancer and the potential for immune therapy in this setting. What’s known about the genetics and the heterogeneity of bladder cancer?

Dean F. Bajorin, MD: I think what we’ll do is start with advanced disease, or metastatic disease, because that’s really what most of our audience are seeing on a regular basis. What we know in terms of advanced disease for patients who have metastatic disease is that we typically will split them into 2 different populations of patients. Cisplatin historically has been the foundation for metastatic disease treatment. We know that it’s potentially curative, and there are a number of combinations that we all use—MVAC, gemcitabine plus cisplatin, etc. And we know that depending on the subset, the average or the median survival is roughly around 14 to 15 months in those patients. Long-term survival, however, depending on the subset, is 5% to 15%. But, in terms of long-term survival, this is a highly lethal disease even with the best of therapy that we have. Then, we have the patients who really don’t qualify for cisplatin-based therapy, and that’s a substantial population of patients, actually—the elderly, those who have renal insufficiency, cardiac disease, etc, and those who actually have problems with hearing. For most of those patients, we’re using carboplatin-based regimens, and the typical one that we will use will be carboplatin plus gemcitabine. There has been a randomized trial showing that, that should be a, if not the, standard of care historically. But, if you look hard and fast at the data, median survival is about 9 months with those patients. And, historically, we really don’t see any long-term survival in those patients at all.

And then, we get into second-line therapy. Since for most of the patients, their disease will have progressed after first-line therapy, historically, that’s been the space for the use of chemotherapy. In the United States, up until recently, we had absolutely no approved treatment for that state of disease. The NCCN guidelines and other guidelines recommended taxanes and even pemetrexed, for example. But if you look at the response rate, it was 10% or less, the median survival is roughly around 6 to 8 months, and long-term cures were simply unseen. And so, the metastatic disease setting is an area of critical unmet need and is poised for new therapies.

Then, we have the second disease state moving down, muscle invasive disease without metastasis. Standard of care really evolves around a management that includes cystectomy or management that is with bladder preservation approach. So, probably the gold standard that we all talk about is neoadjuvant chemotherapy followed by cystectomy and pelvic lymph node dissection. We know that chemotherapy can play a major role there, as does the cystectomy, and that can be curable. But if we look at the patients who don’t respond well to chemotherapy and have residual disease after this type of approach, we know that they actually don’t do well, that they actually have a high likelihood of relapse and death from disease.

And then, we have the patients who we may consider bladder preservation in, and that’s usually considered trimodality therapy where we do an aggressive transurethral resection. We give the combination of chemotherapy and radiation. We preserve the bladder as best we can, and the data are typical in that around 50% of patients will survive roughly 5 years and that about 35% of patients will be able to preserve that bladder and it will be highly functional.

The last group are the patients in whom cystectomy is warranted, but do not qualify for cisplatin-based neoadjuvant chemotherapy. Cystectomy alone would be the standard of care there. And in fact, that survival actually can be quite limited as well. And so, there is another area of critical unmet need, both in the perioperative setting and in combined therapies. The third disease state that we are now seeing more commonly on the medical oncology side is the old superficial disease—the non-muscle invasive disease, the Ta, the T1, carcinoma in situ. We typically don’t see them, and there are subsets that do better and subsets that do worse.

The one that has actually drawn the attention of the medical oncologists and new therapies are the so-called BCG-unresponsive patients. The standard of care is resection for high-grade disease, and then BCG is given 6 weeks successively with maintenance for the majority of patients, and that can be highly curative. But the patients who do not respond well early on within that first 6 months or 1 year, those patients actually do quite poorly, and that is an unmet need. In fact, the FDA has identified that as an area in which drug development is really necessary. And, in fact, it doesn’t even warrant randomized trials because of the high lethality of that patient population.

So, then we get into the issue of BCGs, highly active immune therapy. Point of fact, actually, bladder cancer in general is highly active in terms of its sensitivity to early immune therapy, as we know from years ago. In terms of the question asked about the high number of mutations and clonality, we know from studies, now that we have the TCGA and other studies, that there is a substantial number of mutations that we see in this disease. In fact, the mutation rate is right up there with non—small cell lung cancer and melanoma; a high number of mutations. And, if we actually look at studies that look at the primary tumor in metastatic disease, there’s even more mutations in the metastatic disease setting. In fact, we expect that there is an evolutionary clonality of these mutations over time. Metastatic disease might be quite sensitive based on that mutation rate.

I think we’re well poised in terms of areas of unmet needs in all 3 of these disease states: the metastatic, the muscle invasive, and the non-muscle invasive. We have a disease that has a high mutation rate. It’s poised for sensitivity to immune therapy. And then, we also have a history of immune therapy being active. If we look at biopsies, we see, for example, there’s tremendous lymphocytic infiltration, so we know that some of these tumors are highly recognized with regard to immunotherapeutic interventions.

Robert Dreicer, MD, MS: Let me just add one thing. From a societal perspective, 10% to 15% of all bladder cancers in the United States don’t get treated at all, and part of this is a reflection of the difficulty, the tolerability of therapy. So, as we talk about the immune-based therapies, there’s the potential to actually reach a large group of patients who are undertreated.

Dean F. Bajorin, MD: And a disease in the elderly, they really need tolerable therapy.

Daniel P. Petrylak, MD: Absolutely, and it’s a very, very heterogeneous disease as well.

Transcript Edited for Clarity