Sacituzumab Govitecan Produces Finite Efficacy After Enfortumab Vedotin in Bladder Cancer Subsect

Limited efficacy was observed when sacituzumab govitecan was given after enfortumab vedodin in metastatic urothelial carcinoma.

Investigators highlighted a “limited efficacy” when adding sactituzumab govitecan-hziy (Trodelvy) after enfortumab vedotin-ejfv (Padcev) for patients with metastatic urothelial carcinoma, according to a poster presented at the 2024 American Society of Clinical Oncology (ASC) Annual Meeting.¹

There was an objective response rate (ORR) of 11% (95% CI, 5.2-20) and a median progression-free survival (PFS) of 2.1 months (95% CI, 1.9-2.5) in 82 patients who received EV before SG. The efficacy was not as favorable as what was reported based on the small number of EV-pretreated patients in cohort 1 of the TROPHY-U-01 trial (NCT03547973), raising questions about this sequencing approach.

“In our large real-world cohort of advanced, heavily pretreated mUC patients with prior exposure to EV (n = 82), treatment with SG resulted in limited efficacy compared to previous reports,” the investigators stated in their poster.

Previously reported data showed that the TROP-2–targeted antibody-drug conjugate SG demonstrated efficacy in patients with mUC who received prior platinum-based chemotherapy and immune checkpoint inhibitor therapy in cohort 1 of the open-label phase 2 TROPHY-U-01 study.² In all 113 patients, the ORR was 28% (95% CI, 20.2-37.6) and the clinical benefit rate was 38% (95% CI, 29.1-47.7). With a median follow-up of 10.5 months, the median PFS was 5.4 months and the median overall survival (OS) was 10.9 months.

Among 10 patients on the trial who had received prior EV, there was a 30% ORR with SG, but more data are needed in this population considering that the National Comprehensive Cancer Network guidelines now consider EV plus pembrolizumab (Keytruda) the sole preferred first-line regimen for patients with stage IV disease whether they are cisplatin eligible or ineligible.³

In the retrospective cohort of 82 patients who were treated with SG between April 2021 and November 2023 at Memorial Sloan Kettering Cancer Center, the median age was 71 years (range, 47-83), 57 (70%) were male, and 30 (37%) had upper tract primary disease. Sixty-one (81%) had ECOG performance status (PS) of 0 or 1, and 14 (19%) had ECOG PS of 2 or 3. Liver metastases were present in 50%, lung metastases in 67%, bone metastases in 62%, and brain metastases in 13%. They had received a median of 3 prior lines of treatment (range, 1-8) and 56 (68%) received sacituzumab govitecan as the next line after EV. Most of the patients had received single-agent EV; only 10% had been treated with EV plus pembrolizumab.

Nine patients (11%) had a partial response, and none had a complete response to SG. Twenty percent (n = 16) had stable disease (95% CI, 11.9-30.4) for a disease control rate (DCR) of 31% (95% CI, 21.1-42.1). At the time of follow-up, the median PFS was 2.1 months (95% CI, 1.9-2.5) and the median OS was 6.0 months (95% CI, 4.5-6.9).

The efficacy of SG appeared to be improved when it was sequenced directly after EV, with an ORR of 13% and DCR of 40% among these patients compared with 8% and 12% (P = .024), respectively, in those who did not receive the drugs in direct sequence. Direct sequencing was also associated with improved PFS (HR, 0.46; 95% CI, 0.24-0.88; P = .019) but not improved OS (P = .053).

Outcomes with SG were not associated with prior response to EV. Patients with liver metastases had worse PFS outcomes with SG (P = .002), as did those with an ECOG PS of 2 or 3 (P = .011). In 22 patients (27%) who received SG at a reduced dose, investigators did not observe an adverse association with response (P = .8), nor with PFS (P = .7) or OS (P = .9). Granulocyte colony–stimulating factor (G-CSF) was given as prophylaxis to 57 patients (70%). Grade 3/4 neutropenia occurred in 36% of patients, along with 36% grade 3/4 anemia, and 4% grade 3/4 thrombocytopenia.

The investigators stated the need for more data on the sequencing of EV and SG considering their increasing use in this setting.

Of note, subsequent to the submission of this poster, Gilead, the developer of sacituzumab govitecan, announced on May 30 that results from the confirmatory phase 3 TROPiCS-04 study showed that sacituzumab govitecan did not improve OS vs single-agent chemotherapy in patients with mUC who had previously received a platinum-based chemotherapy and PD-1/PD-L1 inhibitor.⁴ According to the company, a higher level of deaths were associated with AEs observed with sacituzumab govitecan, mainly those related to neutropenic complications and infection. Given this update from Gilead, there is uncertainty regarding the next steps with sacituzumab govitecan in urothelial carcinoma.

References

1. Sternschuss M, Toumbacaris N, Das JP, et al. Clinical outcomes of sacituzumab govitecan (SG) after prior exposure to enfortumab vedotin (EV) in patients with metastatic urothelial carcinoma (mUC). J Clin Oncol. 2024;42(suppl_16):4581. doi:10.1200/JCO.2024.42.16_suppl.4581
2. Tagawa ST, Balar AV, Petrylak DP, et al. Updated outcomes in TROPHY-U-01 cohort 1, a phase 2 study of sacituzumab govitecan (SG) in patients (pts) with metastatic urothelial cancer (mUC) that progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI). J Clin Oncol. 2023;41(suppl_6):526. doi:10.1200/JCO.2023.41.6_suppl.526
3. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 4.2024. Accessed June 2, 2024. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
4. Gilead provides update on phase 3 TROPiCS-04 Study. News release. Gilead Sciences. May 30, 2024. Accessed May June 2, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/5/gilead-provides-update-on-phase-3-tropics-04-study