TROPHY-U-01 Results Lead to Accelerated Approval of Sacituzumab Govitecan (Trodelvy) for Pretreated Metastatic Urothelial Carcinoma - Scott Tagawa

May 1, 2021

Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (Trodelvy) is a TROP-2–directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC.

Scott Tagawa, MD joins Alicia Morgans to discuss the FDA approval of SG based upon the clinical trial where the data was recently published in Journal of Clinical Oncology "TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors."  Dr. Tagawa discusses Sacituzumab govitecan, this is an active drug with a manageable safety profile with the most common toxicities of neutropenia and diarrhea. Sacituzumab govitecan has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior platinum-based combination chemotherapy regimens and checkpoint inhibitors. The results from this study supported accelerated approval of sacituzumab govitecan in this population. 


Scott T. Tagawa, MD, Associate Professor of Clinical Medicine, Clinical Urology, Medical Director, Genitourinary Oncology Research Program, Weill Cornell Medicine, New York, NY

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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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. I'm so excited to talk today with Dr. Scott Tagawa, who is a Professor of Medicine at Weill Cornell New York-Presbyterian in New York, and who has been involved with the development of sacituzumab govitecan since the beginning. Sacituzumab govitecan was recently approved for patients with metastatic urothelial carcinoma, and we are here to talk a little bit about that approval, which really meets, of course, an unmet need in patients who do not have a cure for metastatic urothelial carcinoma and continue to need any therapy that we can give them that is both effective and tolerable. Thank you so much for being here with me today, Dr. Tagawa.

Scott Tagawa: Thanks so much for the invitation. Let me start off with a little bit of background about the drug. Sacituzumab govitecan is an antibody drug-conjugate with the target of Trop-2. Trop-2 is a cell-surface protein, overexpressed in a number of different epithelial malignancies, including urothelial carcinoma. It was recently Food and Drug Administration (FDA)  approved for triple-negative breast cancer and looked interesting in early drug development for urothelial carcinoma.

Actually, in the initial phase 1 dose-escalation study, there were six patients that were treated with urothelial carcinoma. We noticed an early signal, published by my colleague, Bishoy Faltas, where four out of the six patients had improvement in their tumors on radiographs, two out of six with a RECIST partial response (PR) that led to a basket study that enrolled patients with urothelial carcinoma with about a 30% response rate. And that led to the TROPHY-U-01 study, which is a dedicated urothelial study enrolling patients in cohort 1 with prior exposure and progression, despite platinum-based chemotherapy and immune checkpoint inhibitors, without a limit to the number of prior therapies that could be given.

Overall, we ended up enrolling 113 patients. That sample size was designed to be able to exclude a response rate of less than 12%. We ended up enrolling patients that were meeting a fourth-line therapy, about two-thirds had visceral metastasis, about half of those, or third overall, that had liver metastasis, with the primary endpoints of blinded independent central reviewed RECIST response. And overall, a 27% response rate was seen. And that, in combination with the overall tolerability profile and duration, led to the FDA approval.

Alicia Morgans: Fantastic. So, antibody-drug conjugates are something that I think is really, obviously, being approved in urothelial carcinoma, seem to be highly effective. And it's interesting. This is a different payload than other antibody-drug conjugates that we have in this space. Can you comment a little bit on the payload for this particular drug, and maybe comment on how that might affect the side effect profile? What do you monitor for? What are you looking for? And how do you help patients get this drug safely and effectively?

Scott Tagawa: Sure. Well, of higher relevance in the world of urothelial carcinoma with enfortumab vedotin (EV) approved and other antibody-drug conjugates in the space being developed, what I would note is that both the target as well as the toxin are different. So we would hypothesize that there would not be overlapping, at least not a 100% overlapping, cross-resistance. Interestingly, what I did not mention before, is that 10 patients in the TROPHY-U-01 study cohort 1 had prior exposure to enfortumab vedotin, and the response rate was basically the same. So 30% responded, around the same response rate as the overall patient population, two out of those three had primary progression on EV. So that is small numbers, but in line with the hypothesis that because of the target and the toxin, there would be differences in the toxicity profile.

I do think that probably a combination of the construct, as well as the toxin, lead to the adverse events (AE) profile of sacituzumab govitecan. So it is a little bit of a different conceptual framework for the construction of the antibody-drug conjugate (ADC), so there is a higher drug to antibody ratio and kind of a looser conjugant, so it was designed to release in the tumor as well as in the stroma. And the toxin is a little bit weaker than the average prototypical ADC construct with SN-38 as the toxin, which is the active metabolite of irinotecan, and because of that, I think most clinicians will recognize myelosuppression and diarrhea as something to watch out for with irinotecan. And that is also seen with this.

It's a little bit different, but in phase 1, we know that myelosuppression was dose-limited toxicity and in the TROPHY-U-01 study, it was less than half, that had neutropenia, but high-grade neutropenia was the most common AE of high grades, of grade 3 and 4, and approximately one in 10 did have febrile neutropenia. So something to look out for.

Interestingly, this patient population that was enrolled, for whatever reason, only 40% had wild-type UGT1A1, and we know, across the board, not just in urothelial carcinoma, but across the board, those with a homozygous alteration in UGT1A1 do get more neutropenia. So it is something to just be aware of. It's not in the label that we have to watch out for it, but if it's noticed, it's something that, I would say, requires additional monitoring.

Diarrhea happened in about two-thirds, luckily, 40% overall was grade 1, and generally speaking intermittent, so related to dosing. So several days after dosing, there may be some increase in stool number and/or watery consistency. Generally not getting to grade 3, but I do think that it is something to look out for because one of the reasons that grade 3 is not so common is because of supportive care and early recognition. So it is something that can happen, less so than with irinotecan, but those, myelosuppression and diarrhea, would be two main things I would suggest looking out for.

Alicia Morgans: Great, thank you. If clinicians are thinking about getting this drug, treating their patients, what is the treatment schedule that they can expect?

Scott Tagawa: So, this is given on day 1 and day 8 of a 21-day schedule, so two on a one-off. Officially, the label is prior platinum and a prior immune checkpoint inhibitor. So as I am describing this to patients, my most common platinum-based regimens are in combination with gemcitabine and generally a day 1, day 8, q21 day regimen. So I say, "remember that chemo that we gave you in the past, where it was 2 weeks in a row with 1 week off?" That's kind of how I explain that to patients. Like with other drugs, if someone is not appropriate for therapy on day 8 or day 1 of the next cycle, then obviously we can hold the dose. So for instance, if there was persistent neutropenia, then doses could be held.

There was granulocyte colony-stimulating factor (G-CSF) allowed in the trial. So 18% had cycle 1 G-CSF, not necessarily prophylactic. Cycle 1 could have been later to not make cycle 2 delayed. That was kind of just how it was defined. I know my colleagues in the breast cancer world use a lot of G-CSF, I think more than we do in the genitourinary cancer world, other than maybe dose-dense MVAC.

Alicia Morgans: Okay, great. If you had a final thought for folks who are interested in this drug as a new option for their patients, and certainly for patients who are watching and who are interested in new therapies, what is your take-home message on this approval?

Scott Tagawa: I think that the best thing for our patients, at least in this country, with advanced urothelial carcinoma, is we have another option. Another option that has a better than historical control response rates with overall tolerability. I had mentioned there were patients that can remain on this drug for more than a year, so I think that is the best thing. The other thing is that it doesn't look like there is any specific prior therapy or disease characteristics, like liver metastasis or anything else, that makes this drug not able to work. So I don't think that patients need to have five lines of therapy to receive this drug, but patients that are in an unreasonable shape that have had five lines of therapy or less, exaggerating a little bit, might still be able to benefit.

Alicia Morgans: Absolutely. And really importantly, there is not any cross-resistance with enfortumab vedotin, which is another antibody-drug conjugate approved in this space. So another option for therapy, really just adding to our list and giving ways for people to control cancer that really can be very challenging, especially if there are liver mets or widespread metastatic disease. So thank you so much for sharing this. Congratulations to you and your team on this approval, and congratulations to the patients who now have yet another option for metastatic urothelial carcinoma. Thank you for your time.

Scott Tagawa: Thank you very much.