Alessandro Santin, MD, discusses the rationale and design of a phase 2 trial of sacituzumab govitecan in patients with persistent or recurrent endometrial cancer; unmet needs for patients with this disease; and key findings from the stage 1 portion of the trial.
Sacituzumab govitecan-hziy (Trodelvy) has emerged as a tolerable antibody-drug conjugate (ADC) with early signs of efficacy in patients with recurrent endometrial cancer whose tumors harbor TROP2, according to Alessandro Santin, MD, who emphasized that this ADC also has clinical implications in tumor types beyond gynecologic cancers.
At the 2023 ASCO Annual Meeting, Santin and colleagues presented preliminary findings from a nonrandomized phase 2 trial (NCT04251416) of sacituzumab govitecan in patients with persistent or recurrent endometrial cancer. In stage 1 of this trial, among 21 evaluable patients with TROP2-overexpressing disease, 1 patient achieved a complete response (CR), and 6 patients achieved a partial response (PR). Of the 50 total patients screened during stage 1, 92% had TROP2 expression in at least 1% of their tumor cells and 62% had TROP2 expression in at least 50% of their tumor cells. Stage 2 of this trial, which is open for enrollment, will enroll 29 additional evaluable patients regardless of TROP2 expression level.1
“The fact that we have seen such an impressive response, with one-third of patients [achieving] a clinical response in this biologically difficult-to-treat group of patients with cancer makes us excited about these encouraging results,” Santin said.
In an interview with OncLive®, Santin discussed the rationale and design of this phase 2 trial; unmet needs for patients with recurrent endometrial cancer, particularly those with uterine serous carcinoma and carcinosarcoma; and key findings from the stage 1 portion of this trial.
Santin is a professor of obstetrics, gynecology, and reproductive sciences, the clinical research team leader of Gynecologic Oncology, and co-chief of the Section of Gynecologic Oncology at Yale Cancer Center in New Haven, Connecticut.
Santin: Endometrial cancer is the most common gynecological cancer in the United States, with 60,000 new cases and approximately 13,000 deaths every year. When patients develop recurrent disease and become resistant to carboplatin and paclitaxel, [which is] our gold standard treatment in the recurrent setting in advanced-stage disease, there are limited options to deal with recurrent disease.
In this trial, most of the patients were resistant to previous chemotherapy, and many were also resistant to lenvatinib [Lenvima] plus pembrolizumab [Keytruda], a new combination approved in the recurrent setting. When patients are resistant to chemotherapy and become resistant to lenvatinib plus pembrolizumab, there are limited [treatment] options. That is why we designed this phase 2 trial with sacituzumab govitecan, an ADC targeting TROP2, [which is] a glycoprotein that is overexpressed in most endometrial cancers and conjugated through a linker with a toxic payload called SN-38, which is a derivative of irinotecan, a [type I] topoisomerase inhibitor.
Our study enrolled patients with recurrent endometrial cancer of any histologic type with measurable disease by RECIST v1.1 criteria. [There was] no limit on previous lines of chemotherapy. This group of patients was heavily pretreated with previous chemotherapy regimens.
Over two-thirds of the patients enrolled in this trial had biologically aggressive endometrial cancer, namely, uterine serous carcinoma and carcinosarcoma. These groups are difficult to treat because of the intrinsic biologic aggressiveness of this histologic type of endometrial cancer [that is] more resistant to chemotherapy.
In the first phase, the plan was to enroll 21 evaluable patients. The first phase of the trial was considered positive, and positivity meant at least 3 clinical responses, either CR or PR, after the 21 evaluable patients were enrolled. [Thus], we moved to the second stage. Importantly, in the first 21 patients, [we detected] not 3, but 7 [responses, translating to a] 33.3% [objective] response rate. [This was a] highly positive phase 1 study, which is why we are now enrolling the phase 2 group of patients, an additional 29 evaluable patients, to reach [a total of] 50 [patients].
[At the 2023 ASCO Annual Meeting], I also presented [findings from] the [phase 2] TROPiCS-03 trial [NCT03964727] with sacituzumab govitecan in patients with endometrial cancer. That was an all-comers trial. We enrolled patients with endometrial cancer recurrence without prescreening.
[Conversely], in the [phase 2] investigator-initiated trial, in the first stage, we used immunohistochemistry [IHC] to evaluate the expression of TROP2. This was 1 of the eligibility criteria. [A total of] 92% of patients expressed TROP2, and 62% overexpressed the antigen. That is why, in the second stage of [this phase 2] trial, [which] we just opened, we are not requesting any more screening by IHC for TROP2. We found that the overwhelming majority [of patients] expressed the antigen, and sacituzumab govitecan has already been approved [by the FDA] for multiple indications in breast cancer, as well as in urothelial carcinoma, without the need for a companion diagnostic test.
Sacituzumab govitecan, in our experience, is a benign ADC, meaning that most of the toxicities are gastrointestinal toxicities and some bone marrow toxicities. Heavily pretreated patients have limited bone marrow reserves. Having said that, we have not seen any corneal toxicities or interstitial lung toxicities, [both of which] we see relatively frequently with other ADCs. We were pleased to see that no patients, at least in the group treated so far, developed these problems. Overall, we have been able to handle internal toxicity well. [No patient needed] to stop treatment or be removed from the trial because of toxicities. We were pleased about the overall minor toxicity of this agent.
The plan is to complete the phase 2 part of the trial [by enrolling] a total of 50 evaluable patients for response, [so we] have a clear understanding of the biologic activity of this agent in patients with endometrial cancer with measurable disease. Most of these patients harbor biologically aggressive histologic [disease subtypes], such as uterine serous carcinoma and carcinosarcoma.
[Sacituzumab govitecan] is a relatively new agent targeting the TROP2 antigen, which is highly differentially expressed in many human cancers. That is the great thing about this agent. The tolerability [of this agent] has been good. Medical oncologists and gynecologic oncologists should be aware of these new agents because there are many implications [for treating patients with] other cancers, [beyond] gynecological cancers, with sacituzumab govitecan.
Disclosures: Dr Santin reports consulting or advisory roles with Merck, R-Pharm, and Tesaro, as well as research funding from Boehringer Ingelheim (Inst), Genentech/Roche (Inst), Gilead Sciences (Inst), Immunomedics (Inst), Merck (Inst), Puma Biotechnology (Inst), R-Pharm (Inst), Tesaro (Inst), and Verastem (Inst).
Santin A, McNamara B, Siegel ER, et al. Preliminary results of a phase II trial with sacituzumab govitecan-hziy in patients with recurrent endometrial carcinoma overexpressing Trop-2. J Clin Oncol. 2023;41(suppl 16):5599. doi:10.1200/JCO.2023.41.16_suppl.5599