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Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing the recently published TROPHY-U-01 data. This is a phase two open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma, progressing after platinum-based chemotherapy and checkpoint inhibitors. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and with me today is Zach Klaassen, Assistant Professor in The Division of Urology of The Medical College of Georgia.

This is the citation for this recent publication led by Dr. Scott Tagawa and published in The Journal of Clinical Oncology. As highlighted on this slide, there has been rapid development in the advanced bladder cancer space, particularly over the last five years, we've seen the introduction of atezolizumab and avelumab in 2016 and 2017. These indications for both atezolizumab and pembrolizumab have more recently changed, but we have seen other options outside of immune checkpoint inhibitors, including erdafitinib, as an FGFR inhibitor, as well as enfortumab as a nectin based approach. However, we continue to search for new treatment approaches given the fact that even with these null developments, prognosis remains generally poor in advanced urothelial carcinoma.

Sacituzumab govitecan is a Trop-2-directed antibody-drug conjugate. Trope-2 is a transmembrane glycoprotein that is highly expressed on epithelial cancer cells. And as you can see in the figure here, we have a humanized Anti-Trop-2 antibody, which is bound to an SN-38 payload. And this is a metabolite of a topoisomerase 1 inhibitor, and thus it is related to irinotecan and provides drug delivery.

So initial phase one and phase two data are highlighted here. They showed the efficacy of this treatment approach in patients with advanced epithelial cancers who had received at least one prior line of systematic therapy. And so subsequent subgroup analyses of these data and further study in advanced urothelial carcinoma suggested a clinical activity within an objective response rate of over 30%.

As a result, this launched the hypothesis for the TROPHY study. This hypothesis is that sacituzumab govitecan would have a significant anti-tumor activity, measured using objective response rate, comparing favorably to historical controls who received cytotoxic chemotherapy. This forms a component of the overall TROPHY urothelial study approach. This paper focuses on cohort one, which includes patients with metastatic urothelial carcinoma, who progressed after both prior platinum-based chemotherapy and checkpoint inhibitors. Cohort two looks at those who are ineligible for platinum and received checkpoint inhibitors, and cohort three looks at checkpoint naive patients who have progressed after platinum-based therapy. In each case, treatment is the same and the primary outcome is the objective response rate.

So this study enrolled patients with locally advanced unresectable or metastatic urothelial carcinoma. They had to have disease progression following both platinum and checkpoint inhibitors, and platinum was allowed to be in the neoadjuvant setting if there was recurrence and progression of disease within 12 months. Patients had to have measurable metastatic disease according to RECIST criteria, good performance status of zero to one, adequate organ function, as well as be following a washout period subsequent to their prior lines of therapy.

The treatment was administered on days one and eight of 21-day cycles. And the treatment was continued until unacceptable toxicity, a loss of benefit, or withdrawal of consent. Patients were allowed to receive growth factors or transfusions as necessary, as well as anti-emetic premedication, which was recommended.

The assessment was performed with cross-sectional imaging at baseline, and then every six weeks for 12 cycles, followed by every nine weeks thereafter. If there was evidence of response, confirmatory imaging was mandated four to six weeks after this. The best objective response was assessed using RECIST criteria by a blinded independent central review, and safety was continually assessed during clinic visits. The primary endpoint was objective response by blinded independent central review. Whereas secondary objectives included the duration of response by central review, progression-free survival according to central review, as well as objective response rate as assessed by the investigator, overall survival, and safety outcomes.

The authors employed a Simon two-stage design with the goal to reject the null hypothesis that the objective response rate will be less than 10% with 90% power. Relying on a hundred accrued patients and a postulated objective response rate of 24%, the 95% confidence interval would thus exclude 15%. And in keeping with their two-stage design, they had a pre-planned interim analysis at 35 response-evaluable patients, and the study was to continue if at least 10 of those patients had responses and to be terminated if nine or fewer had responses.  The objective response rate was calculated with 95% confidence intervals, determined using the Clopper-Pearson method, and time-to-event outcomes were evaluated using the Kaplan-Meier method.

At this point in time, I will hand it over to Zach to take us through the results of TROPHY-U-01.

Zachary Klaassen: Thanks, Chris. So this is a figure looking at the CONSORT diagram for this study, and there were 151 patients enrolled that had locally advanced or unresectable or metastatic urothelial carcinoma who had progressed after prior platinum-based and checkpoint inhibitor-based therapies. Ultimately, there were 113 patients that received SG.  And in terms of the efficacy and safety analysis, there are 113 patients, as you can see at the bottom there are 16 patients that continued treatment, including 103 that discontinued treatment primarily for progressive disease.

This is table one, looking at the patient demographics and baseline characteristics. Given the size of the table, I've divided it into two halves to allow easier viewability. Looking at the age, the median age was 66 years, 23% of patients were greater than 75 years of age. Most of these patients were males at 78%, and most of them were white at 74%. Looking at ECOG performance status, the majority of patients were ECOG performance status one at 72%, and the majority of patients at 96% had metastatic urothelial cancer. There were 66% of patients that had visceral metastasis, most commonly to the lung in 43% of patients, and to the liver in 34% of the patients. 95.6% of patients had prior therapy in the metastatic setting, and 99% of patients had prior checkpoint inhibitor therapy. Interestingly, as Chris mentioned, this landscape has gotten quite diverse and they did have patients that had prior enfortumab vedotin at 8.8% and erdafitinib at 1.8%. In terms of lines of prior metastatic regimens, 50% had greater than or equal to three lines of prior regimens, and the median time since diagnosis of metastatic cancer was 24.1 months. So, a heavily treated population with more than a two-year timeframe from the time of metastasis diagnosis.

This table looks at the summary of treatment efficacy. In terms of best response, there were 5% of patients had a complete response, 22% of patients had a partial response, 34% of patients had stable disease and 19% of patients had progressive disease. In terms of the objective response rate, there were 27% of patients had an objective response, with a 95% confidence interval of 19% to 37%. In terms of clinical benefit rate, which the authors describe as complete response, plus partial response, plus stable disease greater than or equal to six months, 37% of patients had a clinical benefit rate with a 95% confidence interval of 28% to 47%. The median time from onset of response was 1.6 months, and the median duration of response was 7.2 months with a 95% confidence interval of 4.7 to 8.6 months.

This is the forest plot showing the objective response rate in different subgroups. You can see the subgroups on the left with the objective response rate on the right, and taking a broad overview, you can see that across the majority of these subgroups there was a benefit for SG therapy. Looking specifically at the number of prior therapies for metastatic disease, number of prior chemotherapies, baseline visceral metastasis, and involvement of the liver, there was a benefit for SG and all of these subgroups, regardless of the number of therapies, number of metastases, prior therapies, and visceral metastases.

This figure looks at tumor response to sacituzumab govitecan, looking at the waterfall plot for diameter change from baseline of target lesions. You can see here, the authors have highlighted that 77% of patients had a reduction in their target lesion diameter with only a handful of patients having a more than 40% change in their diameter. This looks at tumor response via the spider plot of tumor response by week, the responders are in blue and you can see that the majority of people that did respond have a durable response with several of these patients having a remarkable response within the first few weeks of therapy.

This is the swimmer plot of the response and duration, and you can see here that 30 out of 31 were still alive at the date of cutoff, and four patients were still receiving an ongoing response in therapy. This is the Kaplan-Meier analysis of progression-free survival. You can see that the median progression-free survival was 5.4 months with a 95% confidence interval of 3.5 to 7.2 months. This is the analysis by overall survival, with a median overall survival of 10.9 months, and a 95% confidence interval of 9.0 to 13.8 months. This is the Kaplan-Meier analysis of duration of response, with a median duration of response of 7.2 months and a 95% confidence interval of 4.7 to 8.6 months. months.

This table looks at the most common treatment-related adverse events of any grade or grades greater than or equal to three, and I'll focus on the grades greater than or equal to three and four. We can see here that the most common adverse event in this more severe adverse event group was neutropenia, 22% of people with grade three, and 12% of people with grade four. Also, we saw that there was 14% of patients had grade three anemia as well as 9% of patients that had grade three diarrhea.

So several discussion points from the TROPHY-U-01 trial. Sacituzumab govitecan demonstrated a clinically and statistically significant objective response rate of 27% in these patients with pretreated metastatic urothelial carcinoma when given after progression on platinum-based chemotherapy and immunotherapy compared to the historic controls. Importantly, as we showed in the forest plot, there was a benefit seen across multiple subgroups. And we know, as Chris mentioned in the introductory slides, there are several options now available in this heavily pretreated disease space. As we discussed in previous journal clubs, enfortumab vedotin had an overall survival benefit over single-agent taxane or vinflunine chemotherapy in the EV-301 trial. However, importantly, this cannot be used in patients with uncontrolled hyperglycemia and neuropathy. Erdafitnib has also been in this disease space, however, it is only for patients currently right now with activating mutations or fusions in the FGFR2 or FGFR3 gene.

So in conclusion, sacituzumab govitecan is an active drug with a manageable safety profile with the most common toxicities of neutropenia and diarrhea. Sacituzumab govitecan has a notable efficacy and is compared with historical controls in pretreated metastatic urothelial carcinoma that has progressed on both platinum-based chemo and checkpoint inhibitors. Finally, the results of cohort one of the TROPHY-U-01 trial support fast track designation and accelerated FDA approval for sacituzumab govitecan for the treatment of metastatic urothelial carcinoma, previously treated with platinum-based chemotherapy and checkpoint inhibitor therapy.

Thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussing the TROPHY-U-01 trial recently published in The Journal of Clinical Oncology.