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Sacituzumab Govitecan for Advanced Urothelial Cancer: Petros Grivas, MD, PhD

Petros Grivas, MD, PhD.

Recently, the FDA granted accelerated approval to sacituzumab govitecan (Trodelvy®, Immunomedics), an antibody-drug conjugate, for patients with locally advanced or metastatic urothelial cancer whose disease progressed following treatment with platinum-containing chemotherapy and a programmed cell death protein 1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor. In this interview with Oncology Data Advisor, Dr. Petros Grivas, Associate Professor and Clinical Director of the Genitourinary Cancers Program at the University of Washington Medicine, Fred Hutchinson Cancer Center, and Seattle Cancer Care Alliance, and one of the lead investigators of TROPHY-U-01, on which the approval was based, discusses the challenges of urothelial cancer management, the benefits of sacituzumab govitecan, and the future of treatment for patients with this disease.

What are some of the most challenging aspects of treating patients with advanced urothelial cancer?

Petros Grivas, MD, PhD: Advanced urothelial cancer is a universally lethal disease, and patients—even those who derive benefit from treatment—eventually experience progression and may succumb to the disease. With a few exceptions, most of the small proportion of patients having long-term remissions, which is the goal, unfortunately have cancer progression. There's definitely an unmet need to find more safe and effective therapies for patients with advanced urothelial cancer. In that regard, we are very fortunate to have a number of new agents approved in the last five years: for example, immune checkpoint inhibitors, a fibroblast growth factor receptor (FGFR) inhibitor (erdafitinib), and two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. This is a really important development because those agents can help patients experience tumor response and stay progression-free for a time period.

Of course, the ultimate goal is for patients to live longer and better overall, although the major hurdle is the nature of the disease, which is very aggressive and becomes resistant to therapy. A major challenge is to try to induce long-term remission with a great quality of life in more patients. Many patients are senior in age and may also have other medical conditions and suboptimal functional status that can interfere with our ability to give them therapies. Another challenge is access to the therapy. Sometimes, patients may not have access to therapy equally, especially if you think about the world globally. I think it's important to address those barriers in terms of finding a safe and effective therapy, providing equitable access to care, and accounting for other medical conditions that patients may have, such as cardiovascular, kidney, or pulmonary disease. Overall, urothelial cancer management has many challenges, and it is great to help our patients through innovative clinical trials, as well as to optimize access to those.

What is the significance of the approval of sacituzumab govitecan for patients with advanced urothelial cancer?

Dr. Grivas: As I mentioned before, despite the amazing advances in the field, clearly most patients still experience progression and resistance to prior therapies, which requires the urgent need for additional safe and effective treatments. We cannot have enough new therapies in this disease. We definitely need more options and having these new opportunities for treating our patients is key. In that regard, I think the approval of sacituzumab govitecan aligns with that goal because it provides another great option for patients, especially for those who have progression on prior chemotherapy and immunotherapy. It offers this opportunity to offer another treatment, and based on the data so far, we have seen very good responses lasting for a period of time in many patients, with an overall manageable safety profile.

How does sacituzumab govitecan compare with other treatment options for advanced urothelial cancer?

Dr. Grivas: Sacituzumab govitecan has not been directly compared to other agents so far in trials; this work is ongoing. The FDA approval was accelerated based on the results of Cohort 1 of the TROPHY-U-01 trial, which was a single-arm phase 2 study of sacituzumab govitecan at the dose of 10 mg/kg given intravenously on Days 1 and 8 of a 21-day cycle. This trial showed an overall response rate of 27% with sacituzumab govitecan in heavily pretreated patients. If you think about the patient population, this response rate is impressive, because many of those patients had many prior therapies. The randomized phase 3 TROPiCS-04 trial is currently comparing sacituzumab govitecan to salvage chemotherapy—either single agent taxane in the United States or vinflunine in Europe. This trial has been launched, and we're very excited to have a large randomized phase 3 trial to see whether this antibody-drug conjugate that was just FDA approved is superior to taxanes or vinflunine, in terms of overall survival.

The design of TROPiCS-04 is very similar to that of the EV-301 trial, which showed overall survival benefit with enfortumab vedotin, another antibody-drug conjugate, versus salvage chemotherapy. For example, TROPiCS-04 allows patients with prior therapies, including enfortumab vedotin, chemotherapy, and checkpoint inhibitors. It's also important to note that there has been no comparison between the two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. However, I want to point out that these drugs have very different molecules with different targets (Nectin-4 versus Trop-2), different linkers, and different payload toxins. There is, in theory, no overlapping resistance based on their mechanism of action. I think these antibody-drug conjugates can be sequenced one after the other, and we'll also have to see the safety and efficacy of their potential combination.

Do you have any words of advice for members of the cancer care team using sacituzumab govitecan to treat their patients with advanced urothelial cancer?

Dr. Grivas: I think it's very important for all of us to get experience and be well-educated, and I would definitely welcome everybody to read the publication of TROPHY-U-01 Cohort 1, which led to the approval of this agent, published in the Journal of Clinical Oncology. I would say that this drug has a different toxicity profile compared with enfortumab vedotin. For example, sacituzumab govitecan does not have much

of the neuropathy that enfortumab vedotin has, and probably has less skin rash. However, it can cause more neutropenia, but only 10% of it was febrile neutropenia, and it's usually manageable with either growth factor, dose reduction, or dose hold. Sacituzumab govitecan also caused diarrhea in about 65% of patients, but it was usually grade 1 or 2, with only 10% grade 3. Diarrhea usually happens around the day of administration of the drug and can generally be managed with educating patients about hydration and nutrition and administering antidiarrheal medications. I think it's important to get familiarity with this drug, to read the label and package insert, and definitely have an open channel of communication with the folks who give this drug in order to get insights into their perspectives. Personally, I'm very excited to see this agent approved, and I'm looking forward to more options for our patients with advanced urothelial cancer.

Is there anything else you'd like to add today?

Dr. Grivas: I would also add that the approval of sacituzumab govitecan was based on Cohort 1 of the TROPHY-U-01 trial. However, the other cohorts (2, 3, 4, and 5) are all actively open and enrolling patients. We definitely welcome colleagues to refer patients to this phase 2 trial with single-agent sacituzumab govitecan. Cohort 2 is particularly for patients who had progression on prior checkpoint inhibitor given in the frontline setting and are not fit for platinum; sacituzumab govitecan is being administered as second-line therapy after progression on a checkpoint inhibitor in that Cohort 2. Cohort 3 is evaluating the combination of sacituzumab govitecan plus pembrolizumab, an anti–PD-1 agent, in the platinum-refractory second-line setting. This is a very exciting study, and we're looking forward to continuing it and also generating more data in the TROPiCS-04 phase 3 trial.

About Dr. Grivas

Petros Grivas, MD, PhD, is the Clinical Director of the Genitourinary Cancers Program and an Associate Professor in the Division of Medical Oncology at the University of Washington Medicine. He is also a medical oncologist at Seattle Cancer Care Alliance and an Associate Professor in the Clinical Research Division at Fred Hutchinson Cancer Research Center. Dr. Grivas specializes in the treatment of patients with genitourinary malignancies, including bladder, prostate, and testicular cancers, and his research has been instrumental in the FDA approvals of several new agents for these diseases.

For More Information

Loriot Y, Balar AV, Petrylak DP, et al (2020). TROPHY-U-01 cohort 1 final results: a phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI). Ann Oncol (ESMO Virtual Congress Abstracts), 31(suppl_4): S1142-S1215. Abstract LBA24. DOI:10.1016/j.annonc.2020.08.2253

Grivas P, Tagawa ST, Bellmunt J, et al (2021). TROPiCS-04: study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy. J Clin Oncol (Genitourinary Cancers Symposium Abstracts), 39(suppl_6). Abstract TPS498. DOI:10.1200/JCO.2021.39.6_suppl.TPS498

Powles T, Rosenberg JE, Sonpavde G, et al (2021). Primary results of EV-301: a phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol (Genitourinary Cancers Symposium Abstracts), 39(suppl_6). Abstract 393. DOI:10.1200/JCO.2021.39.6_suppl.393

Tagawa ST, Balar AV, Petrylak DP, et al (2021). 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. J Clin Oncol. [Epub ahead of print] DOI:10.1200/JCO.20.03489

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 


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