Sacituzumab govitecan-hziy, a Trop-2directed antibody-drug conjugate with an SN-38 payload, has carved out a role in the treatment landscape for patients with locally advanced or metastatic urothelial cancer following accelerated approval by the FDA.
Sacituzumab govitecan-hziy (Trodelvy), a Trop-2directed antibody-drug conjugate (ADC) with an SN-38 payload, has carved out a role in the treatment landscape for patients with locally advanced or metastatic urothelial cancer following accelerated approval by the FDA.1
Specifically, the indication applies to patients whose disease has progressed following treatment with platinum-containing chemotherapy and either a PD-1 or a PD-L1 inhibitor. The decision was based on efficacy and safety data from the phase 2 TROPHY U-01 trial (NCT03547973), a multicohort, open-label clinical study.2 The agent elicited a confirmed objective response rate of 27.7% (95% CI, 19.6%-36.9%) comprising a 5.4% complete response rate and 22.3% partial response rate among 112 treated patients. The median duration of response was 7.2 months.
In an interview with OncologyLive®, Scott T. Tagawa, MD, MS, professor of medicine and urology at Weill Cornell Medicine and attending physician at NewYork-Presbyterian/Weill Cornell Medical Center, discussed the evolving treatment landscape of urothelial cancer that comes with the introduction of sacituzumab govitecan.
In terms of what was available before the approval, [treatment options were limited to] platinum-based chemotherapy, immune checkpoint inhibition, either PD-1 or PD-L1 inhibition, FGFR inhibition with a kinase inhibitor, and then, most recently, enfortumab vedotin-ejfv [Padcev], which was the first ADC [to receive] accelerated approval for urothelial carcinoma, and then full approval and a broadened [label].
[The difference with sacituzumab govitecan] has to do with the target, meaning Trop-2, which is a different target than other available drugs. The target is more important in terms of differentiation in the toxin, and for sacituzumab govitecan SN–38, which is the toxin, is a bit weaker than some of the toxins used in ADCs. The construct is designed to release the toxin inside the tumor but also near the tumors [in the microenvironment], so the linkers are not quite as tight.
[In data from] the primary trial that led to the approval, 10 patients received enfortumab vedotin prior to enrollment in the trial, and in a subset analysis the response rate was the same whether they were exposed to the agent or not. Although there were not a tremendous number of patients who have received both [enfortumab vedotin and sacituzumab govitecan], now there are dozens of patients who have.
The response rate demonstrated that this drug was effective for patients with pretreated, advanced urothelial carcinoma. The available data are from the nonrandomized TROPHY-U-01 trial, which had 5 cohorts, and cohort 1 was the main confirmatory population, [which included patients who were] post platinum-based chemotherapy, post-immune checkpoint inhibitor.
Myelosuppression, specifically neutropenia, is one of the major AEs to watch out for and it is relatively easily managed with dose reductions or delays if warranted. Neutropenia is something that occurred in a large percentage of this patient population; incidence was a little less than 50% in this data set, but high-grade neutropenia was reported for more than a third of patients, which translated into a 10% febrile neutropenia rate.
The other major AE is diarrhea. Approximately 10% of patients experienced grade 3 or 4 events, and grade 1 or 2 events were reported in more than half the patients. It’s important to note to the prescribers, as well as to the patients, that in my experience, diarrhea didn’t tend to persist throughout the course of therapy, but was more intermittent and related to dosage. Because it’s reasonably common, I make sure that my patients have an over-the-counter antidiarrheal at home. A small percentage of patients may need to go on prescription-strength drugs and/or have reduction in dose. But largely, because of the limited number of days and reasonably effective management with over-the-counter medicines, it’s an OK trade-off for what the response rate is in this refractory patient population.
The landscape is shifting, and we hope to move these agents upstream. We’re looking not just for improvements in survival and quality of life, but increased cures in the either non–muscle invasive setting or muscle-invasive setting in combination with local therapy.
There are things that are clear and ongoing right now: The pivotal TROPiCS-04 trial [NCT04527991]—the data of which are hopefully positive and will lead to full approval of sacituzumab govitecan for pretreated, urothelial carcinoma, and then, more importantly, the first approval of the drug outside of the United States.
I briefly mentioned that the TROPHY-U-01 trial has a number of other cohorts. Another cohort that many of us are excited about seeing what happens is cohort 3. Here, investigators looked to see what happens if you combine sacituzumab govitecan with pembrolizumab [Keytruda]. We already know that that combination is safe now we’re waiting to see what happens in terms of efficacy. The cohorts not randomized against each other, but present different single-arm trial data.