A Phase 3, Randomized, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of Sacituzumab Tirumotecan (MK-2870) in Combination With Pembrolizumab With or Without Bevacizumab Compared With Standard of Care as Firstline Maintenance Treatment for Participants With Persistent, Recurrent, or Newly Diagnosed Metastatic Cervical Cancer With PD-L1 CPS Greater Than or Equal to 1 (TroFuse-036/GOG-3123/ENGOT-cx22)

This study evaluates maintenance treatment strategies in participants with persistent, recurrent, or newly diagnosed metastatic cervical cancer with PD-L1 Combined Positive Score (CPS) greater than or equal to 1. The study consists of two parts with distinct objectives addressing efficacy, safety, and patient-reported outcomes in this clinical setting.

The primary objectives are threefold. Part 1 (Safety Run-in) aims to evaluate the safety and tolerability of maintenance treatment with sacituzumab tirumotecan (sac-TMT) plus pembrolizumab with bevacizumab. Part 2 Maintenance has two primary objectives: first, to compare maintenance treatment with sacituzumab tirumotecan plus pembrolizumab, with or without bevacizumab, to standard of care (SoC) with respect to progression-free survival (PFS) per RECIST 1.1 as assessed by blinded independent central review (BICR); second, to compare maintenance treatment with sacituzumab tirumotecan plus pembrolizumab, with or without bevacizumab, to standard of care with respect to overall survival (OS). These primary endpoints are clinically relevant for establishing the therapeutic benefit of novel maintenance strategies in advanced cervical cancer, where treatment options remain limited and survival outcomes require improvement.

The secondary objectives for Part 2 Maintenance include:

• To evaluate maintenance treatment with sacituzumab tirumotecan plus pembrolizumab, with or without bevacizumab, versus standard of care with respect to PFS2 as assessed by the investigator.

• To evaluate safety and tolerability of maintenance treatment with sacituzumab tirumotecan plus pembrolizumab, with or without bevacizumab.

• To evaluate maintenance treatment with sacituzumab tirumotecan plus pembrolizumab, with or without bevacizumab, versus standard of care with respect to health-related quality of life (HRQoL) outcome.

This clinical trial enrolled a total of **713 participants** diagnosed with **persistent, recurrent, or newly diagnosed metastatic cervical cancer** with **PD-L1 combined positive score** greater than or equal to 1. The study population consisted exclusively of **female subjects**. Participants included **adults** and **elderly individuals**. All participants had histologically confirmed **squamous cell carcinoma**, **adenosquamous carcinoma**, or **adenocarcinoma of the cervix** that was not amenable to curative treatment through surgery or radiation. Eligible participants were required to have an **Eastern Cooperative Oncology Group performance status** of 0 or 1, indicating good functional capacity. Individuals infected with **human immunodeficiency virus** were permitted to participate if the infection was well controlled on **antiretroviral therapy**. Participants positive for **hepatitis B surface antigen** were required to have received **hepatitis B virus antiviral therapy** and demonstrate undetectable viral load. Those with a history of **hepatitis C virus infection** were required to have undetectable viral load at the time of enrollment.

This is a Phase III, randomized, open-label, multicenter clinical trial evaluating the efficacy and safety of sacituzumab tirumotecan (MK-2870) in combination with pembrolizumab with or without bevacizumab compared with standard of care as first-line maintenance treatment for participants with persistent, recurrent, or newly diagnosed metastatic cervical cancer with PD-L1 combined positive score greater than or equal to 1. The trial consists of two distinct parts: Part 1 is a safety run-in phase designed to evaluate the safety and tolerability of maintenance treatment with sacituzumab tirumotecan plus pembrolizumab with bevacizumab, while Part 2 focuses on maintenance treatment objectives comparing the investigational regimens to standard of care. The study employs an open-label design, meaning that participants and investigators are aware of the treatment assignments. The trial is expected to commence recruitment in November 2025 and is estimated to conclude in March 2033, representing an overall trial duration of approximately 7 years and 4 months.

Eligible participants must have a histologically confirmed diagnosis of squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix. The disease must be persistent, recurrent, or newly diagnosed metastatic cervical cancer that is not amenable to curative treatment through surgery or radiation. Participants must demonstrate an Eastern Cooperative Oncology Group performance status of 0 or 1, indicating good functional status. Tumor programmed cell death ligand 1 expression must show a combined positive score of 1 or greater. Participants with human immunodeficiency virus infection are eligible if they have well-controlled HIV on antiretroviral therapy. Those positive for hepatitis B surface antigen must have received hepatitis B virus antiviral therapy and demonstrate undetectable viral load. Participants with a history of hepatitis C virus infection must have undetectable viral load.

The investigational medicinal products include sacituzumab tirumotecan administered as a solution for injection via intravenous infusion at a maximum daily dose of 4 mg/kg for up to 84 days, and pembrolizumab administered as a concentrate for solution for infusion via intravenous infusion at a maximum daily dose of 400 mg for up to 84 days. Bevacizumab is administered as a concentrate for solution for infusion. Comparator treatments representing standard of care include cisplatin administered via intravenous infusion at a maximum daily dose of 50 mg/m² for up to 18 days, carboplatin administered via intravenous infusion at a maximum daily dose of 750 mg for up to 18 days, and paclitaxel administered via intravenous infusion at a maximum daily dose of 175 mg/m² for up to 18 days. Additional products include corticosteroids for local oral treatment.

The primary endpoints for Part 1 safety run-in include the number of participants who experience one or more adverse events and the number of participants who discontinue study treatment due to an adverse event. For Part 2 maintenance treatment, the primary endpoints are progression-free survival per Response Evaluation Criteria in Solid Tumors Version 1.1 as assessed by blinded independent central review, and overall survival. Secondary endpoints for Part 2 include progression-free survival 2 as assessed by the investigator, the number of participants who experience one or more adverse events, the number of participants who discontinue study treatment due to an adverse event, and changes from baseline in quality of life measures. Quality of life assessments include the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global health status and quality of life combined score, physical functioning combined score, and role functioning combined score, as well as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Cervical Cancer Module combined score.

Participant involvement in the trial extends for the duration of the maintenance treatment period, which may continue for up to 84 days depending on the assigned treatment arm. Following completion of maintenance treatment, participants will undergo follow-up assessments to monitor disease progression and survival outcomes. The screening visit will assess eligibility criteria including histological confirmation of diagnosis, disease status, performance status, and biomarker expression. Subsequent study visits during the treatment period will involve administration of study medications, safety assessments, tumor response evaluations, and quality of life questionnaires. An end-of-study visit will be conducted to perform final assessments. Participants may be withdrawn from the study early if they experience disease progression, unacceptable toxicity, withdrawal of consent, or if the investigator determines that continued participation is not in the participant's best interest. The trial will continue enrollment and follow-up until the estimated end date in 2033 to ensure adequate data collection for all efficacy and safety endpoints.

The experimental treatment regimen consists of sacituzumab tirumotecan (MK-2870), a humanised IgG1 monoclonal antibody against TROP2 conjugated to KL610023. This biological agent is supplied as a solution for injection and is administered via intravenous infusion. The maximum daily dose is 4 mg/kg, with a maximum total dose of 168 mg/kg over a treatment period of up to 84 days. Sacituzumab tirumotecan is classified as a test medicinal product in this clinical trial.

Pembrolizumab (MK-3475), marketed as KEYTRUDA 25 mg/mL concentrate for solution for infusion, is administered as part of the experimental treatment arm. This biological agent is a protein-based therapeutic supplied as a concentrate for solution for infusion. Pembrolizumab is administered via intravenous infusion at a maximum daily dose of 400 mg, with a maximum total dose of 5600 mg over a treatment period of up to 84 days. This medicinal product holds marketing authorisation in the European Union (EU/1/15/1024/002, EMEA/H/C/003820) and is manufactured by Merck Sharp & Dohme B.V.

Bevacizumab is utilised in the trial in multiple formulations. Avastin 25 mg/ml concentrate for solution for infusion is a biological agent containing bevacizumab as the active substance. This medicinal product is supplied as a concentrate for solution for infusion and holds marketing authorisation in Iceland (EU/1/04/300/001 and EU/1/04/300/002, EMEA/H/C/000582), manufactured by Roche Registration GmbH. MVASI 25 mg/mL concentrate for solution for infusion is a biosimilar formulation of bevacizumab, also supplied as a concentrate for solution for infusion, with European Union marketing authorisation (EU/1/17/1246/001 and EU/1/17/1246/002, EMEA/H/C/004728), manufactured by Amgen Technology (Ireland) UC. Both bevacizumab formulations are administered via routes specified as "other use" in the protocol, with a maximum treatment period of 1 day as per the dosing schedule parameters.

The standard-of-care comparator treatments include several chemotherapeutic agents. Cisplatin is a chemical agent administered via intravenous infusion at a maximum daily dose of 50 mg/m² and a maximum total dose of 300 mg/m² over a treatment period of up to 18 days. Carboplatin is another chemical comparator agent administered via intravenous infusion, with a maximum daily dose of 750 mg and a maximum total dose of 4500 mg over a treatment period of up to 18 days. Paclitaxel is administered via intravenous infusion at a maximum daily dose of 175 mg/m² and a maximum total dose of 1050 mg/m² over a treatment period of up to 18 days. These agents are classified as auxiliary medicinal products and represent established chemotherapy regimens for the treatment of cervical cancer.

An additional auxiliary medicinal product classified as a corticosteroid for local oral treatment (ATC code A01AC) is included in the trial protocol. This chemical agent has a maximum treatment period of 1 day. The specific dosing parameters are recorded as percent volume/volume, with maximum daily and total dose amounts documented as "00".

All biological agents in this trial are protein-based therapeutics, while the chemotherapeutic comparators are chemical compounds. The trial design incorporates both open-label administration and randomization to compare experimental combinations against standard-of-care therapy. Treatment compliance monitoring and dose modifications follow protocol-specified guidelines to ensure participant safety throughout the maximum treatment periods, which extend up to 84 days for the experimental biological agents and up to 18 days for the standard chemotherapy regimens.

Efficacy will be assessed through distinct objectives for the safety run-in phase (Part 1) and the maintenance treatment phase (Part 2). In Part 1, the primary focus is on evaluating the safety and tolerability of maintenance treatment with sacituzumab tirumotecan plus pembrolizumab with bevacizumab. The primary efficacy endpoints for Part 1 include the number of participants who experience one or more adverse events and the number of participants who discontinue study treatment due to an adverse event.

For Part 2 maintenance treatment, efficacy will be evaluated using progression-free survival per Response Evaluation Criteria in Solid Tumors Version 1.1 as assessed by blinded independent central review and overall survival as primary endpoints. Secondary efficacy endpoints include progression-free survival 2 as assessed by the investigator, the number of participants who experience one or more adverse events, and the number of participants who discontinue study treatment due to an adverse event. Patient-reported outcomes will be assessed through changes from baseline in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global health status and quality of life combined score, physical functioning combined score, and role functioning combined score, as well as changes from baseline in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Cervical Cancer Module combined score.