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The antibody-drug conjugate (ADC) sacituzumab govitecan showed encouraging efficacy with a manageable toxicity profile in heavily pretreated patients with advanced endometrial cancer, researchers reported.

is a basket study designed to evaluate the efficacy and safety of sacituzumab govitecan, a trophoblast cell-surface antigen 2–directed ADC, in patients with metastatic solid tumors. A recent analysis of patients in the endometrial cancer cohort of TROPiCS-03 was reported in the by Alessandro D. Santin, MD, of Yale University School of Medicine in New Haven, Connecticut, and colleagues.

Santin, who is clinical research team leader in Gynecologic Oncology, discusses the findings in the following interview.

What does the study add to the literature?

Santin: Findings from TROPiCS-03 showed for the first time encouraging efficacy of sacituzumab govitecan with a manageable toxicity profile in a heavily pretreated population with advanced endometrial cancer in progression after chemotherapy and immune checkpoint inhibitors (ICIs).

Nearly two-thirds (61%) of the advanced, recurrent endometrial cancer patients in progression after chemotherapy or ICIs enrolled in the TROPiCS-03 phase II trial demonstrated a reduction in target lesions, with 22% of them fulfilling the criteria of a partial response. The median time to response was 2.8 months.

In patients who responded to the treatment, their cancers remained stable for an average of 8.8 months without progressing. As the trial continues, 29% of patients are still on treatment.

How would you characterize the safety profile of sacituzumab govitecan?

Santin: Sacituzumab govitecan had a manageable safety profile in this study. Although more than 70% of patients had grade 3 or higher treatment-related adverse events, these were well managed with dose interruptions, dose reductions, and supportive care measures for neutropenia, nausea/vomiting, and diarrhea, in line with the established guidelines.

The incidence of treatment discontinuation due to adverse events was low, at 5%. The results were consistent with the safety profile previously seen with sacituzumab govitecan in endometrial cancer and other solid tumors.

Why is there a high unmet need for novel treatment options in patients with advanced endometrial cancer?

Santin: Limited treatment options exist for patients with advanced disease after progression on platinum-based chemotherapy and ICI therapy. Accordingly, advanced endometrial cancer-targeting TROP2 may represent a novel, effective treatment option for these patients.

How do the results of the TROPiCS-03 study compare with other studies of advanced endometrial cancer?

Santin: In the , 827 patients with advanced endometrial cancer who had progressive disease after platinum-based chemotherapy were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or single-agent chemotherapy (416 patients).

With single-agent chemotherapy in the second line, the overall response rate (ORR) was 15%, median progression-free survival (PFS) was 3.8 months, and median duration of response (DOR) was 5.7 months. Results for the lenvatinib-pembrolizumab arm were 32%, 7.2 months, 18.3 months, and 14.4 months, respectively.

Of note, the patients in this trial had not received checkpoint inhibitor therapy and the majority were treated in the second line. Despite the fact that the patient population in TROPiCS-03 was more heavily pretreated than in KEYNOTE-775, sacituzumab govitecan demonstrated a higher ORR, PFS, and DOR than chemotherapy in KEYNOTE-775.

Other agents that have been evaluated in recurrent/advanced endometrial cancer in the post-platinum setting include bevacizumab, letrozole plus everolimus, trastuzumab deruxtecan (for HER2+ cancer), and abemaciclib plus letrozole, but the trials of these drugs were conducted before approval and widespread use of checkpoint inhibitors in endometrial cancer.

To our knowledge, the TROPiCS-03 trial provides the first data in this setting.

What are the treatment arms of the planned randomized phase III study?

Santin: On the basis of the results from the TROPiCS-03 trial, a randomized, open-label, phase III study of sacituzumab govitecan versus treatment of physician's choice (either doxorubicin or paclitaxel) in endometrial cancer patients who have received prior platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy (ASCENT-GYN-01) is planned. This trial is expected to begin in the third or fourth quarter of 2025.

What is your main message for practicing oncologists?

Santin: Sacituzumab govitecan demonstrated encouraging efficacy with a manageable toxicity profile in a heavily pretreated population with advanced endometrial cancer in progression after chemotherapy and immune checkpoint inhibitors. Sacituzumab govitecan is clinically active against both type I and type II endometrial tumors.

Read the study here and expert commentary about it here.