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Vial Presents: Challenges in Bladder Cancer Trials with Dr. Guru Sonpavde

guru sonpavde

Dr. Guru Sonpavde, Genitourinary Oncology Director, at the Advent Health Cancer Institute, sits down with Rich McCormick, VP of Oncology, to discuss current challenges in bladder cancer trials. Follow Vial on LinkedIn to stay up to date on our latest conversations!

Rich McCormick: Hello. My name is Rich McCormick. I’m the Vice President of Oncology here at Vial. Happy to be joined today by Dr. Sonpavde to discuss some next-level topics related to urothelial carcinoma, and also bladder cancer. Dr. Sonpavde, welcome, would you like to introduce yourself?

Dr. Guru Sonpavde: Thank you, Richard, for the invitation. So I’m Dr. Guru Sonpavde. I’m the GU, Genitourinary Oncology Director, at the Advent Health Cancer Institute in Orlando, Florida. I just moved here in August of 2022 from Dana Farber, and before that, I was at UAB in Birmingham, Alabama.

Rich McCormick: Congratulations on your new position.

Dr. Guru Sonpavde: Thank you.

Rich McCormick: Alright, I have some questions prepared for you today. So being that you’ve served in this oncology space for over 20 years I’m sure you’ve seen some really challenging cases. Would you mind walking us through your most challenging malignancy to treat, and why that’s the case?

Dr. Guru Sonpavde: So among GU cancers, I have focused, more on bladder cancer in my career, and I would say that bladder cancer is a very challenging malignancy to treat. It’s got a rapid progressive course. It does tend to metastasize frequently when patients have muscle invasive disease, even following radical cystectomy or chemo radiotherapy. Once it is metastatic, it is again, an aggressive disease. You tend to need systemic therapy, early to, in order to even, have a chance of controlling the disease. A big proportion of patients don’t get second-line therapy, and then subsequent third-line therapy, just because of the rapidity of progression and decline in performance status. So this is really a challenging disease.

Rich McCormick: Mm-hmm, very good. Thank you.

So you’ve recently published a piece regarding a phase two trial of CV301 which is a vaccine, in combination with atezo for advanced urothelial carcinoma. Could you just walk us through some of the details within that paper, and explain to us how that trial played out?

Dr. Guru Sonpavde: So CV301 was actually a disappointing agent in this study. This is a poxvirus vaccine. This is a second-generation poxvirus vaccine that was engineered to target different antigens present on the bladder cancer cell specifically CEA and MUC1, and also had a costimulatory triple molecule, ICAM-1, LFA-3, and B71. And this was thought to be a promising product, and this trial was done in combination with atezolizumab in the first-line setting of metastatic cisplatin-ineligible urothelial carcinoma, as well as in the second-line setting in patients progressing post-platinum based chemotherapy.

And these were essentially two separate phase two cohorts, two-stage phase two cohorts, trying to achieve a certain minimum threshold of response rate. And unfortunately, both of these cohorts did not meet the minimum bar required to go onto the second stage of these phase two trial cohorts. So it was a disappointing response rate, and so, one of the things, I think, the messages from this trial was that maybe we should pay more attention to biomarkers to select patients, optimally for trials with agents such as this. Maybe these patients were very advanced, and had a poorer performance status, very advanced disease, and maybe we did not give the agent a chance to, or a fair chance to work. So I think this was a learning experience, but the combination was unfortunately disappointing.

Rich McCormick: You had mentioned the challenges of treating patients with bladder cancer. For a patient that has had a radical resection, what are your thoughts on immunotherapy, versus monitoring sort of the signs, you know, that may indicate that that cancer has reoccurred?

Dr. Guru Sonpavde: Right, so adjuvant nivolumab, a PD-1 inhibitor, was approved for high-risk, muscle-invasive urothelial carcinoma following surgery, so either radical nephroureterectomy, or radical cystectomy. And these were patients who had had neoadjuvant chemotherapy, but also included patients who had not had neoadjuvant chemotherapy, but had high-risk, extra-vesicle, and muscle-invasive disease, of course.

So this trial was positive. It showed an improvement in the primary endpoint of disease-free survival in all comers, as well as in PDL-1 high patients. The benefit was more robust in the PDL-1 high patients, so in the U.S., the FDA approved adjuvant nivolumab in all comers based on the improvement in the overall population. The hazard ratio was approximately 0.7, and in the PDL-1 high population, the hazard ratio was about 0.55. And actually [00:05:00] in Europe, that agency approved it only in the PDL-1 high population. So there’s a difference in the way this therapy was approved in the adjuvant setting. We don’t have survival yet from this trial, so this has been the criticism so far, that we have not seen an improvement in survival. However, we hope that this level of improvement in disease-free survival does translate to improvement in survival, especially in the setting of an adjuvant-immune checkpoint inhibitor, where the benefits tend to be durable, as opposed to chemotherapy.

So at the moment, I have incorporated this into my practice, so adjuvant nivolumab is offered in patients that qualify based on, the definition of high-risk disease with or without neoadjuvant chemotherapy. One of the, questions that gets asked in this setting is, would you use minimal residual disease as has meant using CTDNA, tumor-informed CTDNA profiling to select patients who have MRD for adjuvant nivolumab? So the answer to that is that we don’t know quite, but in the setting of adjuvant nivolumab, a different phase III trial, it seemed that there was a benefit, mostly confined to the MRD-positive patients for adjuvant nivolumab, while in the overall population, adjuvant nivolumab did not improve disease-free survival.

So it’s an attractive platform, but I think we need more data to adopt it on a more broad scale. But I have used it selectively in patients where we’re trying to avoid potentially unnecessary adjuvant therapy, especially the older, frail patients with comorbidities, where you’re concerned about toxicities of adjuvant immunotherapy.

Rich McCormick: Great, thank you for expanding on that. So some of the symptoms of bladder cancer are often mistaken for what end up being benign indications. When would you recommend a healthcare provider pursue sort of a more detailed workup on a patient, to see if there is something more serious happening?

Dr. Guru Sonpavde: Yes, I agree that the symptoms of bladder cancer, the early symptoms can be difficult to pick up, and it is quite frequent, frequently that we see that these patients are treated for a urinary tract infection and just overactive bladder, things like that, yeah, before the bladder cancer is discovered. So I think that these patients, as you know, present usually to a primary care provider. Sometimes to a urologist, but frequently to a primary care, family internal medicine physician. So I think that internists need to be vigilant about these symptoms. We’re not seeing that the initial presentation of symptoms, we need to jump up and do things like a cystoscopy at the initial presentation, but I think we need to have a high index of suspicion.

The symptoms don’t resolve over the next one or two weeks after presentation. That would be a good time to consider and actually refer patients to the urologist for a more thorough investigation, including a cystoscopy. I think that a high index of suspicion is critical, because this is an aggressive disease. So if you miss the earlier stages of non-muscle-invasive or superficial disease, this disease can progress rapidly to muscle-invasive disease, and even metastatic disease.

So I think that primary care providers especially need to be vigilant. Urologists are more in tune with these symptoms, and tend to do an earlier investigation with a cystoscopy, an office cystoscopy, and a urine cytology, and other imaging to detect the malignancy. But I think the primary care providers are where I think that more vigilance is probably necessary.

Rich McCormick: Great, thank you. What about, what about patients maybe that are not symptomatic? Is there a point in life where a patient should be routinely screened for the likes of bladder cancer?

Dr. Guru Sonpavde: That’s a good question. So there is not a routine role for like urine cytology or cytoscopy for example. Now, one situation where routine screening is advised is in patients with a known genetic familial predisposition syndrome, like Lynch syndrome. So Lynch syndrome is known to be associated with colorectal cancer. Not many people know about the association with bladder cancer or upper urinary tract cancer. So in a family, in a patient known to have the germ line, the genetic predisposition Lynch syndrome, it is advised that screening with urine cytology ultrasounds starting at age 35 to 40 is a good idea because of the chance of urinary tract cancer in patients with the genetic syndrome called Lynch syndrome.

But broadly, beyond that, there is not a well-defined role for that, but I think it’s it’s a good idea to be vigilant in patients especially patients who are smokers, or past smokers, which has a known association with bladder cancer.

Rich McCormick: That’s interesting. So in terms of clinical trials, so enrolling within the oncology space is, you know, it is challenging in all indications, really, but specific to [00:10:00] bladder and urothelial, what sort of advice would you give to oncologists to how to go about including, you know, clinical research in the discussions for the treatment of their patients?

Dr. Guru Sonpavde: I think clinical trials have to be considered a standard of care, and one of the things that maybe the message is not gotten out thoroughly is that we often define therapies as standard of care, and then we define research as a separate category. But I think that research and clinical trials need to be a component of standard of care, and perhaps even a preferred component, because that’s how we make advances. We also, in terms of the trials themselves, sometimes trials offer very promising treatments that have a reasonable chance of becoming a standard of care in the future.

But I think that the way to present it in my judgment is to present research and clinical trials as a standard of care, and not just the other option. Oh, we also have research, and that’s not the way to present it, I think. I think it should be presented as a standard of care.

Rich McCormick: That’s interesting. How much does the conversation change between a phase I type of first-in-human as an option, versus maybe a later-phase study where there’s more safety data? Like, how would you navigate that conversation with a patient?

Dr. Guru Sonpavde: That’s a good question. I think that both trials are of interest, and, you know, when patients come to major academic centers, a tertiary academic center, they are really looking for, promising new options. These patients tend to be those who have tried standard options out in the community, and they’re coming to the major center, an academic center, looking for new options. So, in my judgment, the major center’s, role is mostly to offer new, promising drugs in phase I and phase II trials. Phase III trials definitely have a role, a big role to get, drugs out into the clinic, and show that the newer treatments are better than the older treatments.

But I feel that those need to be done mostly in the community, in a real-world setting, where you can show that these new agents, or combinations, or regimens are improving outcomes compared to the older standards of care. So I think that this is a situation where you wanna have a bigger component of the community setting, the real-world setting, as opposed to just being done in academic centers.

So I think that both of these play a role. It just, I would, I would say that the emphasis in a tertiary center needs to be the phase one, phase two trials.

Rich McCormick: Interesting. Thank you for that. So Dr. Sonpavde, that takes us through all the questions that we had prepared for today. So we would really just like to thank you for your time. Taking time out of your busy schedule to meet with us today, and it was very insightful. And, and we appreciate that, and have a great day.

Dr. Guru Sonpavde: Thank you. Thank you, Richard. 

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