Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States.

I am so excited to have here with me today two good friends and colleagues, Dr. Neeraj Agarwal, who is a Professor of Medicine and a GU Medical Oncologist at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, and Dr. Petros Grivas, who is an Associate Professor of Medicine and a GU Medical Oncologist at the University of Washington in Seattle. Thank you both so much for being here with me today.


Neeraj Agarwal: Thank you for having me. It's such a pleasure, Alicia. Thank you.

Petros Grivas: Thank you so much, Alicia, for having Neeraj and me today.

Alicia Morgans: Wonderful. Guys, I wanted to talk with you about some breaking news, sacituzumab govitecan has recently been approved by the FDA for use in patients with metastatic urothelial carcinoma.

I'd love to hear your thoughts on this and let's start with you, Dr. Grivas, letting us know a little bit about the trial that led to the approval, and the patients who can most benefit from this therapy at this point, in terms of the label.


Petros Grivas: Absolutely, Alicia. We are very excited and thrilled to see that the FDA has approved sacituzumab govitecan, an antibody-drug conjugate against Trop-2, linked to a metabolite of irinotecan, called SN-38, in the management of patients with advanced urothelial cancer previously treated with platinum-based chemotherapy and a checkpoint inhibitor.

So the results of the TROPHY-U-01 trial, specifically cohort one, in which trial Dr. Scott Tagawa was one of the PIs and also Dr. Agarwal was also an investigator along with other colleagues, supported the approval of this agent, and the TROPHY-U-01 trial was a single-arm, especially a cohort one and cohort two. Let's focus on cohort one, single-arm sacituzumab govitecan, this antibody-drug conjugate, in patients with prior platinum-based chemotherapy and a checkpoint inhibitor. But, other therapies were allowed, and if you think about the median number of prior therapies, this was three, but the range was between one and eight prior therapies.


So, we are talking about the heavily pretreated patient population and if you think about risk factors, about 84% of patients had at least one major risk factors overall. Based on those elements, this is a heavily pretreated population and with poor prognostic factors. So, the overall response rate with such a population was 27%. And the median response duration was about seven months, median PFS around six months, and with promising, I would say, a median overall survival signal, which in this particular phase two trial, was about 11 months.


Obviously, when we talk about PFS in the single-arm phase two study, we will have to be cautious because of selection bias. Some of those patients are, what we call professional trial patients, always going to different trials. Having said that, I think the data is very promising, and I would probably use the term impressive and the response rate with single-agent chemotherapy is about 10%. So, when you almost triple that, I think it's meaningful. And in terms of toxicity, which was always the other side of the coin, right? We have to think about the toxicity profile, something different than the other antibody-drug conjugate that is approved, enfortumab vedotin. Sacituzumab can cause classical neutropenia, however, only 10% of patients or less had febrile neutropenia and usually, this is managed. The neutropenia is managed with dose reductions and or growth factors. So I think it's manageable toxicity.


Diarrhea seems to be another common adverse event with sacituzumab, mostly goes to grade one, grade two. I think 10% or less had grade three. And again, it's usually situational around the administration of the drug. Day or day eight on a three-week cycle, as sacituzumab was given. And, it's usually managed with hydration, education of the patient, nutritional elements, and diarrhea medications. And just to make the point that this  drug conjugate is given on day one, and day eight of this 21-day cycle and it's an interesting structure, it targets Trop-2. And as I mentioned before, it's linked to the SN-38, sacituzumab govitecan Govitecan. So, if you think about that, it's a completely different mechanism of action, but other antibody-drug conjugates, like enfortumab vedotin.


Alicia Morgans: Great. Well, thank you for that tour de force discussion of that. That was very, very helpful hearing about the trial design, the response rates, and the adverse events. I'd love to hear from you Dr. Agarwal, in terms of your clinical experience with this drug and how you choose the right patient, as this drug is now approved. Who is the right patient to get this treatment?

Neeraj Agarwal: Absolutely. So first of all, it has been a pleasure to accrue on this trial, under the leadership of Dr. Scott Tagawa and Dr. Petros Grivas, which is going to be published very soon and has brought very exciting news for our patients with metastatic bladder cancer, who until recently had very few treatment options. So, coming back to your question, regarding the side effects I think, yes, we see diarrhea. We see myelosuppression and neutropenia. I think those are the two side effects I would like to highlight. Myelosuppression or neutropenia is very well managed with growth factors in my experience. And, if growth factors are not able to improve myelosuppression, I think dose reduction is the next strategy I would utilize for our patients. For diarrhea, again, a very small number of patients, less than 10% or around that number had grade three diarrhea. Otherwise, again, well managed with conservative management, being diarrhea is not a very uncommon side effect to us oncologists and so is neutropenia.

So I think growth factors for neutropenia and anti-diarrheal medications for diarrhea and, obviously we can always go for dose reduction, but I think bigger news here is the nonoverlapping nature of these toxicities with another antibody-drug conjugate, enfortumab vedotin and I'm more excited about that part. Both are getting different chemotherapy payloads, and both have different side effect profiles. And I think the news could not have been better for our patients because we can actually use both drugs in our patients who were until just two, three years ago, had very limited treatment options.


Alicia Morgans: That is a fantastic thing and to be able to give patients not one, not two, but multiple three and four lines of therapy is definitely something I think we are going to just strive for and certainly have the opportunity to do now that we have another approval for metastatic urothelial carcinoma patients. So, as the two of you think about this and are excited about this news, this new approval, what would your final message be to the audience? Dr. Grivas?

Petros Grivas: Number one, I think it's very exciting to see the data published, and as Dr. Agarwal mentioned that this is going to happen very soon or with the data from cohort one of the TROPHY-U-01 trial being in print. I want to pass the message that it's really, really important to have options for this patient population. We cannot have enough. And I think in urothelial cancer, we have made strides in the last five to 10 years with the advent of immunotherapy, with targeted therapies and with antibody-drug conjugates, like enfortumab vedotin, and sacituzumab govitecan. You know that sometimes the discussion is being very limited to one or the other, enfortumab vedotin versus sacituzumab. I don't think it's a dilemma here. I think we need both drugs as Dr. Neeraj very nicely said. We can use both drugs sequentially.

There is also a combination trial I think that is being done at Dana-Farber, which will be interesting to see. I think the optimal sequence will be defined down the road, but definitely, it's important to have options for the patients, and potentially these antibody-drug conjugates could be used in conjunction with immunotherapy. And I think that is something that is already shown with the promising data with enfortumab vedotin plus pembrolizumab and also in the context of the TROPHY-U-01 trial cohort three that is being evaluated currently as an ongoing evaluation of sacituzumab govitecan plus pembrolizumab. So we are going to have data with a combination very soon and I'm hopeful that with these clinical trials, we're going to keep moving the needle forward as we did with the sacituzumab approval.


And also, I want to point out that as Dr. Agarwal is part of this and Dr. Tagawa, of course, we're actually now in the process of opening a phase three trial called TROPiCS-04, which is very important to accrue, and this is a phase three trial comparing sacituzumab govitecan at the same dose, 10 milligrams per kilogram, day one, and day eight on a 21-day cycle versus taxane or vinflunine. So the design of the TROPiCS-04 is very similar to the EV301 trial that was presented by Professor Powles at ASCO GU. So, accelerated approval and a phase three trial. Very, very good news.


Alicia Morgans: Fantastic. And Dr. Agarwal what is your message?

Neeraj Agarwal: I think the news is so exciting for our patients. Patients with advanced metastatic bladder cancer, for whom we only used to talk about cisplatin or carboplatin based chemotherapy just five years ago now we can offer them immune checkpoint inhibitors avelumab maintenance therapy right after completion of chemotherapy without having to wait for disease progression, novel antibody-drug conjugates, such as enfortumab vedotin and sacituzumab govitecan with non-overlapping toxicities, non-overlapping targets. I think this is really exciting and speaks of the tremendous advancements in science and technology which have happened over the last decade.

Alicia Morgans: I completely agree. And as I reflect on this landscape and just marvel at the approval after approval and the adjustments in the landscape that are optimizing outcomes for our patients and really ensuring that the drugs that we have been used in the right order in the right patient and the right combinations, I just really encourage our patients with urothelial carcinoma, and certainly their clinicians, to try as they can to stay up to date because the advances are coming fast and furious and it is only with the implementation of these advances and giving them to our patients that we can actually make the differences that we know we have the opportunity to do. So, thank you so much, both of you, for all of your work and efforts, and thank you for your time today and your expertise.

Neeraj Agarwal: Thank you. It was a pleasure.

Petros Grivas: Thank you so much, Alicia, for having Niraj and me. I agree with you, an exciting time for urothelial cancer and of course, our patients who are the reason for what we do.