Sacituzumab Govitecan Displays Activity in Advanced/Metastatic Endometrial Cancer

Alessandro Santin, MD

Encouraging efficacy was seen when patients with heavily pretreated advanced endometrial cancer received sacituzumab govitecan-hziy (Trodelvy) in the phase 2 TROPiCS-03 (NCT03964727) basket study, according to findings published in the Journal of Clinical Oncology.¹

At a median follow-up of 5.8 months (range, 0.7-19.3), patients treated with the TROP-2–directed antibody-drug conjugate (n = 41) experienced an objective response rate (ORR) of 22% (95% CI, 11%-38%) with a median duration of response (DOR) of 8.8 months (95% CI, 2.8-not estimable); all responses were partial. The median time to response was 2.8 months (range, 1.4-5.8) and patients also experienced stable disease (44%) or progressive disease (20%). The clinical benefit rate (CBR) was 32% (95% CI, 18%-48%).

“This is the first publication demonstrating the clinical activity of [sacituzumab govitecan] in uterine cancer,” the study’s first author Alessandro Santin, MD, said in a news release.² Santin is a professor of obstetrics, gynecology, and reproductive sciences at Yale School of Medicine and clinical research team leader for Gynecological Oncology as well as cochief of the Section of Gynecologic Oncology at Yale Cancer Center in New Haven, Connecticut. “I have been working with this antibody-drug conjugate in my lab since the beginning of its development. This is a major ‘bench-to-bedside’ accomplishment for [patients with] uterine cancer,” he added.

Additionally, patients achieved a median progression-free survival (PFS) of 4.8 months (95% CI, 2.8-9.8); the 6- and 12-month PFS rates were 36% (95% CI, 20%-52%) and 19% (95% CI, 6%-38%), respectively. Investigators also noted that 61% of patients experienced a reduction in target lesion diameters from baseline with durable responses. They added that overall survival (OS) data were not mature at the time of data extraction.1

Enrollment and Trial Criteria for TROPiCS-03

The multicohort, open-label TROPiCS-03 basket study evaluated the efficacy and safety of sacituzumab govitecan in patients with metastatic solid tumors including cohorts of those with small cell lung cancer, non–small cell lung cancer, head and neck squamous cell carcinoma, and endometrial cancer. The proof-of-concept stage of the study enrolled approximately 40 patients per cohort with potential for an expansion phase if efficacy criteria were met.

The endometrial cancer cohort enrolled patients with advanced or metastatic disease who experienced disease progression following treatment with platinum-based chemotherapy and anti–PD-(L)1–directed therapy; a protocol amendment was added to include anti–PD-(L)1–directed therapy given either sequentially or in combination with platinum-based chemotherapy because the standard of care had changed. However, 6 patients in the endometrial cancer cohort included in the TROPiCS-03 analysis did not previously receive anti–PD-(L)1–directed therapy.

Additional inclusion criteria for the endometrial cancer cohort were an ECOG performance status of 0 or 1, measurable disease by CT or MRI per RECIST 1.1 criteria, and creatinine clearance of at least 30 mL/min. Patients were not eligible for the trial if they had carcinosarcoma, uterine leiomyosarcoma, and/or endometrial stromal sarcomas. Patients were enrolled from August 30, 2021, to December 28, 2022, and the primary end point of the study was ORR by investigator assessment per RECIST 1.1 criteria. Secondary end points included CBR, DOR, PFS, and OS, among others.

Patients received 10 mg/kg of sacituzumab govitecan via intravenous infusion once daily on day 1 and 8 of a 21-day cycle until disease progression, unacceptable toxicity, study withdrawal, or death.

The median age of patients at study entry was 68 years (range, 44-83) and most patients were White (51%), had an ECOG performance status of 1 (56%), and did not have microsatellite instability–high disease (78%). Patients had serous (42%), endometrioid (49%), or other (10%) histology and received 1 (7%), 2 (32%), 3 (39%), or more than 3 (22%) prior anticancer regimens; prior therapies included chemotherapy (100%), hormonal therapy (12%), immunotherapy (85%), targeted agents (63%), or other agents (2%).

Subgroup Analysis Findings and Safety

TROP-2 expression was examined in 39 evaluable patients and the median TROP-2 expression H-score was 115 (range, 0-245). The median PFS was similar among patients with evaluable TROP-2 expression at 4.2 months in those with a Trop-2 expression H-score equal to or above the median vs 5.0 months in those with a Trop-2 expression H-score below the median (HR, 0.9; 95% CI, 0.4-2.0; P = .8). The relationship between best tumor volume change from baseline vs tumor Trop-2 H-score also did not reveal a correlation (P = .873).

“Altogether, these observations suggest that Trop-2 expression has limited correlation with efficacy of sacituzumab govitecan,” Santin and coauthors of the article wrote.

Regarding safety, the most common any-grade treatment-emergent adverse effects (TEAEs) included diarrhea (56%), nausea (54%), and fatigue (51%). Grade 3 or higher TEAEs occurred in 80% of patients treated with sacituzumab govitecan as well. Two patients discontinued treatment because of TEAEs with one patient discontinuing due to febrile neutropenia and one due to weight decrease.

“Sacituzumab govitecan showed an encouraging ORR of 22% in a heavily pretreated patient population with advanced/metastatic endometrial cancer; the trial is ongoing with 29% of patients still on treatment. Evaluation of efficacy by TROP-2 expression showed that there may be limited association between response to sacituzumab govitecan and TROP-2 expression,” Santin and coauthors wrote in conclusion.

References

1. Santin AD, Corr BR, Spira A, et al. Efficacy and safety of sacituzumab govitecan in patients with advanced solid tumors (TROPiCS-03): analysis in patients with advanced endometrial cancer. J Clin Oncol. Published online July 31, 2024. doi:10.1200/JCO.23.02767
2. Masciadrelli M. Treatment for recurrent uterine cancer advances to next research phase. Yale Cancer Center. Published July 31, 2024. Accessed August 15, 2024. https://www.yalecancercenter.org/news-article/treatment-for-recurrent-uterine-cancer-advances-to-next-research-phase/