Sacituzumab Govitecan Induced Responses in Pretreated Metastatic Urothelial Carcinoma

Scott T. Tagawa, MD

Scott T. Tagawa, MD

Sacituzumab govitecan (IMMU-132), an antibody—drug conjugate (ADC), induced an objective response rate (ORR) of 29% in patients with heavily pretreated metastatic urothelial carcinoma, according to findings from the phase II TROPHY-U-O1 trial presented at the 2019 ESMO Congress.

Although many new treatments have emerged for patients with metastatic or advanced urothelial carcinoma, not all patients benefit from these advances. The use of ADCs provide hope for patients who relapse following treatment with chemotherapy or immune checkpoint inhibitors.

In the single-arm, open-label phase II clinical trial, 35 patients were enrolled in the first cohort of the 2-cohort study. Patients were treated with 10 mg/kg sacituzumab govitecan on days 1 and 8 of a 3-week cycle and continued treatment until unacceptable toxicity or disease progression. To be included on trial, patients had to have progressed previously on a platinum-based therapy or checkpoint inhibitor (n = 100; cohort 1) or were ineligible for platinum-based therapy and progressed on prior checkpoint inhibitor (n = 40; cohort 2).

This first stage of TROPHY-U-O1 included a prespecified futility stopping rule if 4 or fewer patients achieved responses out of the first 35 patients. However, the Trop-2—directed ADC induced 2 complete responses and 6 partial responses (PRs) by the time of the analysis. Two additional PRs are pending confirmation. At a median follow-up of 4.1 months, 74% of patients achieved a reduction in tumor size. These results were consistent with prior findings with the ADC.

Sacituzumab govitecan also appears well tolerated with a predictable toxicity profile. All-grade treatment-related adverse events (TRAEs) included alopecia, neutropenia, leukopenia, anemia, febrile neutropenia, decrease in lymphocyte count, diarrhea, urinary tract infection, fatigue, and abdominal pain.

In an interview withTargeted Oncology, Scott T. Tagawa, MD, Richard A. Stratton Associate Professor in Hematology and Oncology; associate professor of clinical medicine & urology at Weill Cornell Medicine; and associate attending physician, New York-Presbyterian—Weill Cornell Medical Center, discussed the findings from the TROPHY-U-O1 trial presented at the 2019 ESMO Congress and shared his thoughts on the next steps for sacituzumab govitecan.

TARGETED ONCOLOGY: What was the rationale for TROPHY-U-O1?

Tagawa:We’ve made some clinical advances for patients with advanced or metastatic urothelial carcinoma, but unfortunately only a minority benefit. With platinum-based chemotherapy, about 1 in 10 do well and are potentially cured. About 2 or 3 out of 10 will benefit from immune checkpoint inhibitor therapy, and they can do really well for a long period of time. Most times, there is not a lot of toxicity, but unfortunately the majority of patients don’t benefit. We are looking for new ways of treating those patients. One of those ways appears to be ADCs.

TARGETED ONCOLOGY: Why are you investigating sacituzumab govitecan specifically?

Tagawa:When we are looking for an ADC, there are different principles that we look for. One of them is the antigen or target, [so we look at] where it is expressed, if it is restricted to a certain target or not, or if it is overexpressed in a certain target. Sacituzumab govitecanhas a target of Trop-2. Trop-2 happens to be overexpressed in urothelial carcinoma, as it is in a number of other epithelial tumor types. It’s not only expressed in the tumors, but it is overexpressed in the tumors and particularly in the more aggressive tumors. There is somewhat selective delivery of the agent, depending on which ADC and in this case, SN38. The thing that is a little bit different with sacituzumab govitecanis the way that it is put together and the way it is designed. There are many more molecules of the toxin per antibody than most other ADCs. The other thing that is different is it is a little bit less toxic than some of the other ADCs. The linker is a little weaker. It’s designed to get the drug, SN38, into the actual tumor cells but also around the tumor cells, so it is higher concentration near or around the tumor cells than in the rest of the body, but it is a weaker linker.

TARGETED ONCOLOGY: What was the design of the trial?

Tagawa:This was a 2-cohort, open-label study. We presented the interim results of 1 cohort. The main cohort was those patients that received both platinum-based chemotherapy and immune checkpoint inhibitors, and any number of additional lines of therapy, but at least those 2. Cohort 2, which is exploratory, is designed to look at patients who are platinum-unfit who have received immune checkpoint inhibitors. [At the 2019 ESMO Congress,] we presented the results of the first group, so the larger group, designed to have 100 evaluable patients to have adequate power to rule out a low response rate. It was designed as a 2-stage, so the initial 35 patients were a go/no-go with a futility analysis. Basically, if we didn’t have more than 4 responses within the first 35 patients, we would halt enrollment at that period of time. We analyzed those patients and presented those results.

TARGETED ONCOLOGY: What did those results show?

Tagawa:In terms of the patients that were included, it was fairly a heavily pretreated [population]. This was fourth-line therapy at median, so there was a range from third- and seventh-line therapy. About two-thirds had visceral metastases, about 25% had liver metastases, but good performance status was required for trial entry.

The primary endpoint was response and 29% of the patients, so far, have responded. It’s very early, so it’s possible that it’s more amongst these that have a declining percent of tumor but haven’t quite crossed the threshold because it is quite early. That being said, it is very much in line with prior results, which were in a slightly different era, but 45 patients with pretreated metastatic urothelial carcinoma with a 31% response rate, so it’s very similar to those prior data.

TARGETED ONCOLOGY: Was the tolerability consistent with expectations?

Tagawa:Across different tumor types, we know that the dose-limiting toxicity of this drug happens to be myelosuppression, and we saw potentially two-thirds with some level of neutropenia including some grade 3 and grade 4 neutropenia with 11% febrile neutropenia. Diarrhea is the other concern where the majority, meaning more than half, had some diarrhea, although grade 3 was rare. The good thing was because even though it was not grade 3, grade 2 diarrhea is chronic and [could be] a quality-of-life issue. Even grade 1 can be chronic, but what is notable about this drug for the most part for those patients that get diarrhea, it is usually short-lived for a small number of days per cycle. Their overall quality of life, I hope at least, is not impacted in the long run.

TARGETED ONCOLOGY: What are the next steps with this research given that this trial is a phase II study?

Tagawa:We will look at the available results presented this year as well as at the 2019 ESMO Congress in about 80 patients with about a 30% response rate. Those are quite promising, but it is single-arm and not randomized. We have 2 main steps. The first is to complete this trial, which is designed purely for urothelial carcinoma, to get 100 evaluable patients, and to analyze the data to say with how much confidence we can say what the response rate is and gain additional information about the toxicity profile in this setting that is post-platinum as well as post-immune checkpoint inhibitors. Hopefully, that could lead to accelerated approval. We will have to see what the FDA says, but that would be great to get into patients while we’re waiting for the phase III trial that is planned. Hopefully that will be launched next year, which will hopefully be a confirmatory phase III trial randomized against the standard of care.

TARGETED ONCOLOGY: Is there anything else you would like to note about these data?

Tagawa:There are some interesting components of this cohort. If we look at those patients with grade 4 neutropenia or febrile neutropenia, it was quite striking that 65% had a polymorphism in UGT1A1. That’s higher than expected for an unselected patient population, but maybe this is why there was a little more neutropenia despite a higher rate of prophylactic granulocyte-colony stimulating factor (G-CSF) in this study where 9 out of 35 patients had the first cycle of prophylactic G-CSF.

It’s an interesting observation. We know that from the larger data set of many hundreds of patients that received it that it’s still a small percentage with a polymorphism, but we know it is associated with worse neutropenia, not necessarily diarrhea, and that may be 1 of the explanations for what we saw on this trial.

TARGETED ONCOLOGY: Would you say this might preclude patients receiving it, or could they potentially receive the agent after a dose reduction?

Tagawa:I think we need more data, so it is unclear if, in that patient population setting, we can give the same dose with growth factor or should we dose reduce up front like we might do with irinotecan. It’s not metabolized in the exact same way as irinotecan, which is why I think there is less diarrhea and no major increased diarrhea in the setting of UGT1A1 polymorphisms, but there are not quite enough patients. Right now, everyone is allowed in the trial that is not known to have a polymorphism, and they are being tested. I think the larger data set, particularly the breast data set, which has published larger data sets in this setting, we will see overall what the risk benefit is in a refractory setting. For the patient sitting in front of me, I clearly would like to offer the drug when it is more appropriate with a dose reduction or with growth factor, but I think that depends on the individual patient.

References:

1. Tagawa STT, Balar A, Petrylak DP, et al. Initial results from TROPHY-U-01: a phase 2 open-label study of sacituzumab govitecan in patients with metastatic urothelial cancer (mUC) after failure of platinum-based regimens or immunotherapy. Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA55.
2. 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). doi: 10.1200/JCO.2019.37.7_suppl.354.