Sacituzumab Govitecan Does Not Significantly Improve OS in Pretreated Urothelial Carcinoma

Treatment with sacituzumab govitecan-hziy (Trodelvy) did not significantly improve overall survival (OS) or progression-free survival (PFS) over physician’s choice of chemotherapy in patients with pretreated advanced urothelial carcinoma, according to findings from the final analysis of the phase 3 TROPiCS-04 study (NCT04527991) presented during the 2024 ESMO Asia Congress.1

The median OS with the antibody-drug conjugate (ADC; n = 355) was 10.3 months (95% CI, 9.1-11.8) vs 9.0 months (95% CI, 7.5-9.7) with physician’s choice of chemotherapy (n = 356; HR, 0.86; 95% CI, 0.73-1.02; P = .087), missing the study’s primary end point. The OS rates in the respective arms at 12 months were 44% (95% CI, 39%-49%) and 37% (95% CI, 32%-42%). The hazard ratios of OS consistently favored sacituzumab govitecan over chemotherapy in the majority of prespecified subgroups.

Moreover, the median PFS with sacituzumab govitecan was 4.2 months (95% CI, 3.8-4.5) vs 3.6 months (95% CI, 2.9-4.2) with chemotherapy (HR, 0.86; 95% CI, 0.72-1.03). The 12-month PFS rate in the ADC arm was 14.5% (95% CI, 10%-19%) vs 9% (95% CI, 5%-14%) in the chemotherapy arm.

A higher objective response rate (ORR) was observed with the ADC vs chemotherapy, at 23% (95% CI, 18%-27%) and 14% (95% CI, 10%-18%), respectively (stratified odds ratio [OR], 1.84; 95% CI, 1.24-2.73). Of those who responded to sacituzumab, 5% had a complete response (CR) and 17% had a partial response (PR); 43% had stable disease (SD) and 21% experienced progressive disease (PD). In this arm, the median duration of response (DOR) was 7.2 months (95% CI, 6.3-8.4). Of those who responded to chemotherapy, 3% achieved a CR and 11% experienced a PR; 48% had SD and 22% experienced PD. The median DOR in this arm was 6.5 months (95% CI, 5.2-8.3). The clinical benefit rates (CBRs) in the sacituzumab and chemotherapy arms were 30% (95% CI, 25%-35%) and 21% (95% CI, 16%-25%), respectively (stratified OR, 1.68; 95% CI, 1.19-2.37).

“TROPiCS-04 showed that sacituzumab govitecan is active in advanced urothelial carcinoma but did not demonstrate significant improvement of physician’s choice of treatment,” Petros Grivas, MD, PhD, in the Department of Medicine in the Division of Hematology/Oncology at the University of Washington, Fred Hutchinson Cancer Center, in Seattle, Washington, said in a late-breaking presentation of the data. “Several reasons may have contributed to the results beyond efficacy, e.g. early deaths due to toxicity with sacituzumab govitecan, a higher number of patients randomized but not treated with physician’s choice of treatment, [and] subsequent therapies, including enfortumab vedotin [Padcev].”

Patients with locally advanced or metastatic urothelial carcinoma have limited therapeutic options after they experience PD on a frontline regimen. Although the paradigm has evolved over the past few years with the emergence of novel options that have helped improve survival, more effective approaches are needed. Data from the phase 2 TROPHY-U-01 study (NCT03547973) showed that sacituzumab govitecan alone and plus pembrolizumab (Keytruda) led to ORRs ranging from 28% to 41% in patients with pretreated advanced urothelial carcinoma.2-4

The global, open-label, randomized, phase 3 TROPiCS-04 study enrolled patients with histologically confirmed urothelial carcinoma who had metastatic or locally advanced disease and progressed on or following platinum-based and PD-(L)1 therapy.1 Patients had an ECOG performance status of 0 or 1.

Study participants (n = 711) were randomized 1:1 to receive 10 mg/kg or sacituzumab govitecan on days 1 and 8 every 21 days or physician’s choice of treatment given on day 1 every 21 days; the latter arm could have received paclitaxel at 175 mg/m2, docetaxel at 75 mg/m2, or vinflunine at 320 mg/m2. Treatment continued until disease progression or intolerable toxicity. Patients were stratified based on Bellmunt risk score (0-1 vs 2-3), previous platinum agent (cisplatin vs carboplatin), and setting of chemotherapy (neoadjuvant vs locally advanced unresectable or metastatic).

OS served as the trial’s primary end point, and secondary end points comprised PFS, ORR, DOR, and CBR per blinded independent central review and investigator. Investigators also evaluated health-related quality of life and safety.

“Granulocyte–colony stimulating factor [G-CSF] primary prophylactic use for neutropenia was not required per study protocol, but investigators were encouraged to consider prophylaxis in patients with risk factors for febrile neutropenia, per ASCO guidelines for use of growth factors,” Grivas noted. After a recommendation issued by an independent data monitoring committee, a memorandum was sent to participating clinical sites in September 2022 strongly recommending primary prophylaxis beginning in cycle 1 for these patients.

The data cutoff date for the final analysis was March 8, 2024, and the median follow-up was 9.2 months (range, 0-33.7).

The median patient age in the ADC and chemotherapy arms was 67.5 years (range, 30-89); most patients were male (80% vs 78%), from Europe (65% vs 73%), had an ECOG performance status of 1 (63% vs 62%), had a Bellmunt risk score of 0 or 1 (74% vs 75%), had metastatic disease at the time of enrollment (93% vs 90%), had their primary tumor located in the lower urinary tract (62% vs 65%), and had metastatic disease in the liver (30% vs 29%). Most patients had previously received 1 to 2 prior anticancer regimens (68% vs 71%); 32% and 29% of patients, respectively, had received 3 or more prior regimens. Cisplatin was the most recent prior platinum therapy received for most patients (60% vs 57%), and most received platinum-based therapy in the locally advanced unresectable or metastatic setting (83% vs 83%).

In the ADC arm, 98% of patients received treatment. The median duration of treatment was 3.0 months (range, 0-26.6) and the median number of cycles received was 5 (range, 1-33). Ninety-six percent of patients discontinued treatment most commonly because of PD (69%). In the chemotherapy arm, 95% of patients received treatment. The median duration of treatment was 2.1 months (range, 0-20.7) and the median number of cycles received was 4 (range, 1-30). Ninety-four percent of patients discontinued most commonly due to PD (65%). Moreover, 50% of those in the ADC arm and 49% of those in the chemotherapy arm received subsequent anticancer therapy; subsequent enfortumab vedotin was received by 19% and 21% of patients, respectively.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99% of those in the sacituzumab arm and 95% of those on the chemotherapy arm; they were related to treatment for 97% and 88% of patients, respectively. Grade 3 or higher TEAEs were experienced by 77% of those in the ADC arm and 51% of those in the control arm; they were treatment related for 67% and 35% of patients.

Serious TEAEs occurred in 52% and 33% of patients, respectively; they were related to treatment for 34% and 18% of patients, respectively. TEAEs led to discontinuation or death for 15% and 7% of patients, respectively, on the ADC arm; on the chemotherapy arm, these respective rates were 15% and 2%.

“Sixteen events with sacituzumab govitecan were infections in the setting of neutropenia, of which 14 occurred within the first month of treatment,” Grivas noted. “Patients who experienced fatal infections with neutropenia had a higher burden of risk factors for medical complications compared with the overall [ADC] group.” Such risk factors included being 65 years of age or older (81%), having undergone prior cystectomy (56%), previously undergoing a major urinary tract procedure (81%), prior receipt of radiotherapy (50%), or having received at least 3 prior anticancer regimens (50%).

In the ADC arm (n = 349), the most common treatment-related AEs included fatigue (any grade, 54%; grade ≥3, 12%), anemia (46%; 13%), alopecia (38%; 0%), diarrhea (52%; 15%), neutropenia (48%; 35%), nausea (41%; 3%), reduced appetite (23%; 3%), vomiting (22%; 3%), leukopenia (19%; 10%), peripheral neuropathy (3%; 0%), and febrile neutropenia (12%; 12%).

In safety-evaluable patients, 37% of those in the sacituzumab arm (n = 349) received any prophylaxis vs 26% of those in the chemotherapy arm (n = 337). In the ADC arm, 21% of patients received G-CSF primary prophylaxis and 15% received secondary prophylaxis; these respective rates were 22% and 4% in the chemotherapy arm. Moreover, 30% and 10% of patients in the respective arms received a therapeutic.

“The incidence of grade 3 or higher neutropenia with or without primary prophylaxis G-CSF was 32% and 48%, respectively,” Grivas noted.

He concluded by saying that the safety data were in line with the known safety profile of sacituzumab govitecan across tumor types with the exception of increased rates of neutropenic complications. “Increased incidences of grade 3 or higher neutropenic events, infections secondary to neutropenia, andgrade 5 TEAEs were observed with sacituzumab govitecan vs physician’s choice of treatment,” he concluded.

In October 2024, Gilead announced that the US indication for sacituzumab govitecan in adult patients with pretreated, locally advanced or metastatic urothelial cancer would be voluntarily withdrawn.5 The decision was made in conjunction with the FDA and followed the April 2021 accelerated approval of the ADC in this population,6 which had been based on data from TROPHY-U-01. TROPiCS-04 was the confirmatory study.

Disclosures: Dr Grivas reported serving in a consulting or advisory role for Merck, Bristol Myers Squibb, AstraZeneca, EMD Serono, Pfizer, Janssen, Roche, Astellas Pharma, Gilead Sciences, Inc., Fresenius Kabi, CG Oncology, Strata Oncology, ImmunityBio, Asieris Pharmaceuticals, AbbVie, Bicycle Therapeutics, Replimune, and Daiichi Sankyo. Research funding was provided by Bristol Myers Squibb, Merck, QED Therapeutics, Mirati Therapeutics, EMD Serono, G1 Therapeutics, Gilead Sciences, Inc., Acrivon Therapeutics, ALX Oncology, and Genentech.

References

1. Grivas P, Powles T, Vulsteke C, et al. TROPiCS-04: a randomized phase 3 study of sacituzumab govitecan vs chemotherapy in pretreated advanced urothelial carcinoma. 2024;35(suppl 4):S1505-S1507. doi:10.1016/j.annonc.2024.10.830
2. Tagawa ST, Balar AV, Petrylak DP, et al. 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. 2021;39(22):2474-2485. doi:10.1200/JCO.20.03489
3. Loriot Y, Petrylak DP, Kalebasty AR, et al. 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: updated safety and efficacy outcomes. Ann Oncol. 2024;35(4):392-401. doi:10.1016/j.annonc.2024.01.002
4. Grivas P, Pouessel D, Park CH, et al. Sacituzumab govitecan in combination with pembrolizumab for patients with metastatic urothelial cancer that progressed after platinum-based chemotherapy: TROPHY-U-01 cohort 3. J Clin Oncol. 2024;42(12):1415-1425. doi: 10.1200/JCO.22.02835
5. Gilead provides update on US indication for Trodelvy in metastatic urothelial cancer. News release. October 18, 2024. Accessed December 17, 2024. https://www.gilead.com/company/company-statements/2024/gilead-provides-update-on-us-indication-for-trodelvy-in-metastatic-urothelial-cancer
6. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA. April 13, 2021. Accessed December 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer