Sacituzumab Govitecan Shows Early Promise in Urothelial Carcinoma

Scott Tagawa, MD

Sacituzumab govitecan seemed to effectively achieve its goal of delivering the potent toxin SN-38 to tumor cells and sparing normal cells in patients with advanced urothelial carcinoma, said Scott T. Tagawa, MD.

In results of a phase I/II study (NCT01631552) presented at the 2019 Genitourinary Cancers Symposium, the antibody-drug conjugate (ADC) demonstrated clinical activity in patients with advanced urothelial carcinoma, including those who were previously treated with checkpoint inhibition and those with visceral disease.

In 45 patients, the objective response rate (ORR) was 31.1% (95% CI, 18.2-46.6), including a complete response rate of 4% and a partial response rate of 27%. Median progression-free survival (PFS) and overall survival (OS) were 7.3 months (95% CI, 5.0-10.7) and 16.3 months (95% CI, 9.0-31.0), respectively.

In patients with visceral involvement, investigators reported an ORR of 27.3%. Those who were previously treated with a checkpoint inhibitor had an ORR of 23.5%. Further, the median duration of response was 12.9 months, with 50% of responses ≥12 months. Three patients were still on therapy with response ongoing at the time of data cutoff.

The safety profile of the agent proved consistent with previous reports, said Tagawa, the lead author of the study. The most frequent treatment-associated adverse events (AEs) across all grades were diarrhea (69%), nausea (67%), fatigue (58%), and neutropenia (51%). The most frequent grade ≥3 AEs observed were neutropenia and anemia, while the most frequent serious AEs were febrile neutropenia and diarrhea in 2 patients each.

OncLive: What is the mechanism of action of sacituzumab govitecan?

What was the design and findings of the phase I/II study looking at this agent?

In an interview with OncLive, Tagawa, Richard A. Stratton Associate Professor in Hematology and Oncology, associate professor of clinical medicine and urology at Weill Cornell Medicine, associate attending physician, NewYork-Presbyterian/Weill Cornell Medical Center, discussed the potential of sacituzumab govitecan in advanced urothelial cancers and reflected on progress made in prostate cancer.Tagawa: Sacituzumab govitecan, also known as IMMU-132, is an ADC; it targets Trop-2, which is a cell-service antigen on multiple epithelial cells. Trop-2 is overexpressed in several different cancers, urothelial carcinoma in particular. The ADC takes that antibody with a link to SN-38, which is the toxin and the active metabolite of the chemotherapeutic drug irinotecan. It is, at least in in vitro studies, probably too potent to give in a free fashion. Therefore, like with other ADCs, we hope to deliver a more potent chemotherapy agent or toxin to the right cells and avoid the wrong cells. This ADC gets more SN-38 into the tumor cells and tumor areas by the way it is designed. You will see a higher concentration in those areas than in the rest of the body.It was what we would call a basket trial, so the initial phase I portion enrolled a number of different patients across different tumor types in a dose-escalation study. During that study, it was determined that the optimal dose would be 10 mg/kg on day 1 and day 8 of every 21-day schedule. In that study, there were 6 patients who had advanced heavily pretreated urothelial carcinoma who had responses to sacituzumab govitecan. Not all 6 had responses, but in general, they did better than the other patients. One of the phase II arms that came out of that, including other cancers, was [its use in patients with] advanced urothelial carcinoma.

Therefore, the presentation [from the 2019 Genitourinary Cancers Symposium] is on those specific patients with urothelial carcinoma who were treated [with the ADC] in the phase II portion of the study. Forty-five patients who received the ADC had received a median of 2, but up to 6, lines of prior therapy. Overall, the results looked better than what we would expect with standard chemotherapy or a historical control arm. We saw about a 30% ORR versus a historical ORR of about 12% with standard chemotherapy.

What are the next steps for this research?

That was in the setting of overall good tolerance. The patients with advanced urothelial carcinoma were not so different from [patients with] other tumor types in that there was myelosuppression and grade 3/4 neutropenia; however, there were very few incidences of febrile neutropenia. There were no nonlaboratory grade 3/4 AEs. Diarrhea was seen in 9% of the patients at the grade 3 level.These are good preliminary data, but it is limited to only 45 patients. Also, only the minority of the patients in the study had received both platinum-based chemotherapy and a PD-1 inhibitor [as a prior line of treatment]. We have launched what is called TROPHY-U-01 (IMMU-132-06; NCT03547973), [which is looking at the use of this agent in] patients with advanced urothelial carcinoma who have had both platinum-based chemotherapy and an immune checkpoint inhibitor. There is no limit on number of lines of prior therapy. We hope to confirm the ORR we saw in the phase II study. This trial also has a separate cohort of patients who are cisplatin ineligible who have received a prior immune checkpoint inhibitor, but that will be an exploratory cohort. There was also a trial-in-progress poster for this study presented at the 2019 Genitourinary Cancers Symposium.

Moving beyond urothelial carcinoma, there were some intriguing data with the use of darolutamide in patients with prostate cancer. Where do you see this drug fitting into the treatment paradigm?

Overall, in urothelial carcinoma, we have moved from having only platinum-based chemotherapy and have taken a major step forward with immune checkpoint inhibitors. Unfortunately, it is still the minority of patients who have benefit from immunotherapy, but it is nice to have more than 1 ADC that has shown promise, as well as targeted agents.It is fairly clear with the initial data that the patient population in the ARAMIS trial (NCT02200614) is not that big of a clinical patient population. Although they have high-risk disease and rising prostate-specific antigen levels, you can scan them with more effective imaging techniques, and they have metastatic disease. I do not believe that the requirement for that drug to work is seeing something on a computerized tomography scan or a bone scan. Darolutamide sets the stage for exploring additional uses of that drug, and we know there are other phase III trials that are waiting to be read out with that drug.

What are your thoughts on the use of radium-223 dichloride (Xofigo) in this space?

Because we do not have head-to-head comparative studies yet, we do not know for certain yet, but it appears that there are properties different than enzalutamide (Xtandi) and apalutamide (Erleada). There may be some clinical differences, too. I do not think we will really be able to tell, but we will look at the toxicities and make some inferences. The nice thing is that there are more studies coming down the pike that are looking specifically at the different AE profiles of those drugs in a head-to-head fashion.Radium-223 is a great drug, but it has some problems. It is a great drug because it targets the bone, and for men with metastatic prostate cancer, bone tends to be the most common site of issues that could lead to symptoms or ultimately death, so it is nice to have a drug targeting the bone. The downside is that it only targets the bone. The tendency might be to want to combine radium-223 with other therapies. We have seen, retrospectively, that combining this [agent] with essentially any androgen receptor (AR) inhibitor is beneficial, but then the ARROW-223 study (NCT02412878) showed some problems with fractures; this trial looked at upfront abiraterone acetate (Zytiga) and radium-223. We have yet to see data with enzalutamide.

What trends are you seeing with recent advancements made in prostate cancer treatment?

What is nice is that we can also safely combine radium-223 with chemotherapy. The phase I/II DORA trial (NCT03574571), [in which investigators] randomized men to receive the combination of radium-223 plus docetaxel, showed some efficacy in terms of PFS versus docetaxel alone. Likely because of the dosing of the regimen, it also looked to be safer.We have had very precise treatments for a long period of time. With castration in whatever form—surgical, medical, estrogen—we have been able to target a very precise pathway that happens to be the dominant pathway in most of our patients' tumors. It is nice to see more potent AR-targeted drugs, and there is role for additional ones if we can get around the challenge of resistance.

We also want to look at additional targets. We are starting to understand biomarkers a little bit better. There are some factors where we can say, "In the presence of these, certain drugs are less likely to work." That is not quite as good as saying a drug will work, but at least in the settings where we have more than 1 option, we can look at that. We also have pembrolizumab (Keytruda) FDA-approved for patients with microsatellite instability—high tumors, even though it is indicated for a very small subset. Those are examples of existing therapies out there that we can find a role for [in the paradigm]. PARP inhibitors are also out there and [physicians] may want to use those agents off-label, but we have prospective studies looking at those additional targeted drugs in a specific patient population.

Radiolabeled prostate-specific membrane antigen and ligands are the next wave of drugs that I think will get approval [from the FDA]. There are now several prospective studies; there used to only be retrospective studies. We have several trials accruing that may lead to initial label. What I am looking forward to is being able to optimize the way that these drugs are delivered in terms of dosing and combinations, as well as optimizing the patient population who can receive them. Once those therapies are hopefully approved, we can use them better.

Tagawa S, Faltas BM, Lam ET, et al. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): results from a phase I/II study. J Clin Oncol. 2019;37(suppl 7S; abstr 354). meetinglibrary.asco.org/record/170545/abstract.