Phase 3 Randomized Study of Tucatinib, Trastuzumab, and mFOLFOX6 vs. mFOLFOX6 with Cetuximab or Bevacizumab in HER2+ Metastatic Colorectal Cancer

The primary objective of this study is to compare **progression-free survival (PFS)** per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1) according to blinded independent central review (BICR) assessment between treatment arms. This is clinically relevant as it evaluates the efficacy of the treatment regimens in delaying disease progression in patients with unresectable or metastatic HER2+ colorectal cancer.

Secondary objectives include:

• To compare overall survival (OS) between treatment arms.
• To compare confirmed objective response rate (cORR) per RECIST v1.1 according to BICR assessment between treatment arms.
• To assess PFS per RECIST v1.1 according to investigator (INV) assessment.
• To evaluate cORR per RECIST v1.1 according to INV assessment.
• To evaluate duration of response (DOR) per RECIST v1.1 according to BICR assessment.
• To evaluate DOR according to INV assessment.
• To evaluate time from randomization to disease progression on next-line treatment or death from any cause (PFS2).
• To assess the overall safety profiles by the treatment arms.
• To evaluate the pharmacokinetics (PK) of tucatinib.
• To assess the change from baseline in selected items of the global health status/quality of life (QoL), physical functioning, and appetite loss by treatment arms using the European Organization for Research and Treatment of Cancer Quality of Life 30-item core questionnaire (EORTC QLQ-C30).
• To assess the time to meaningful change in global health status/QoL, physical functioning, and appetite loss by treatment arms using the EORTC QLQ-C30.

The clinical trial involves a total of **245 participants** diagnosed with **unresectable or metastatic HER2+ colorectal cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having histologically or cytologically documented adenocarcinoma of the colon or rectum that is locally advanced, unresectable, or metastatic. Additionally, participants must have HER2+ disease and RAS wild-type status, as determined by specific testing protocols. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The study also considers lifestyle factors, such as the absence of symptomatic brain metastases, although previously treated asymptomatic brain metastases are permissible. The trial population includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **tucatinib** in combination with **trastuzumab** and mFOLFOX6 compared to mFOLFOX6 with or without either **cetuximab** or **bevacizumab** in patients with HER2+ metastatic colorectal cancer. The primary objective is to compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1) as assessed by blinded independent central review (BICR) between the treatment arms. The trial is expected to run until October 31, 2028, with recruitment having commenced on November 21, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically documented adenocarcinoma of the colon or rectum, HER2+ status, and measurable disease per RECIST v1.1. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 20 cycles of treatment, with each cycle lasting approximately 3 weeks. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. The trial will also assess secondary endpoints such as overall survival (OS), confirmed objective response rate (cORR), and duration of response (DOR), among others.

The clinical trial involves the administration of **Tucatinib**, marketed as TUKYSA, in two different dosages: 150 mg and 50 mg film-coated tablets. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 600 mg, with a total treatment period of up to 20 weeks. The tablets are stored in HDPE bottles for clinical use, with specific storage conditions of 2-8°C and a shelf-life of 36 months. The active substance, tucatinib, is of chemical origin and is provided by SEAGEN B.V.

**Cetuximab**, marketed as Erbitux, is used as a comparator treatment in the trial. It is provided as a 5 mg/mL solution for infusion, administered intravenously. The maximum dose is 400 mg/m², with a treatment period of up to 15 weeks. Cetuximab is a protein-based substance, supplied by MERCK EUROPE B.V.

**Trastuzumab**, marketed as Herceptin, is another comparator treatment. It is available as a 150 mg powder for concentrate for solution for infusion, administered intravenously. The maximum dose is 8 mg/kg, with a treatment period of up to 20 weeks. Trastuzumab is a protein-based substance, provided by ROCHE REGISTRATION GMBH.

**Bevacizumab**, marketed as Avastin, is also used as a comparator treatment. It is provided as a 25 mg/mL concentrate for solution for infusion, administered intravenously. The maximum dose is 5 mg/kg, with a treatment period of up to 15 weeks. Bevacizumab is a protein-based substance, supplied by ROCHE REGISTRATION GMBH.

Participant compliance with the dosing schedule is monitored throughout the trial. The trial aims to compare progression-free survival between treatment arms, with a focus on HER2+ metastatic colorectal cancer. The study is conducted under strict regulatory conditions, ensuring the safety and efficacy of the treatments administered.

Efficacy in this clinical trial will be assessed primarily through **progression-free survival (PFS)**, as defined by the time from randomization to the assessment of disease progression or death from any cause, whichever occurs first. This will be evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and assessed by a blinded independent central review (BICR). Secondary endpoints include overall survival (OS), defined as the time from randomization to death from any cause, and confirmed objective response rate (cORR), which is the proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1, as assessed by BICR.

Additional secondary endpoints involve PFS as assessed by investigators, duration of response (DOR), and time to second progression or death (PFS2). Pharmacokinetic assessments will be conducted using individual plasma concentrations of tucatinib. Patient-reported outcomes (PROs) will be measured for changes from baseline in global health status/quality of life and physical functioning using the EORTC QLQ-C30 scale. The time to meaningful change is defined as the time from baseline to the first onset of a ≥10-point change from baseline in these scales.