Efficacy and Safety Evaluation of Autogene Cevumeran and Pembrolizumab Versus Pembrolizumab Monotherapy in Treatment-Naïve Advanced Melanoma Patients

The primary objective of this Phase II, open-label, multicenter, randomized study is to evaluate the **efficacy** of RO7198457 in combination with pembrolizumab compared to pembrolizumab alone in patients with previously untreated **advanced melanoma**. The primary endpoint is progression-free survival, which is clinically relevant as it measures the length of time during and after treatment that a patient lives with the disease without it worsening.

Secondary objectives include:

• Evaluating the efficacy of RO7198457 plus pembrolizumab compared with pembrolizumab alone based on Objective Response Rate (ORR), Overall Survival (OS), Duration of Response (DOR), and mean change from baseline in Health-Related Quality of Life (HRQoL) scores.
• Assessing the safety of RO7198457 plus pembrolizumab compared with pembrolizumab alone by examining the incidence and severity of adverse events, as well as changes from baseline in targeted vital signs and clinical laboratory test results.

The clinical trial involves a total of **70 participants** diagnosed with **advanced melanoma**, specifically targeting individuals with histologically confirmed metastatic or unresectable locally advanced melanoma. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific criteria, including an **ECOG Performance Status** of 0 or 1, a life expectancy of at least 12 weeks, and adequate hematologic and end-organ function. The trial population is characterized by individuals who are naive to prior systemic anti-cancer therapy for advanced melanoma, with certain exceptions as specified in the protocol. The study also considers vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the efficacy and safety of RO7198457 in combination with **pembrolizumab** versus pembrolizumab alone in patients with previously untreated advanced melanoma. The trial aims to assess the primary endpoint of progression-free survival, with secondary endpoints including objective response rate, overall survival, duration of response, and changes in health-related quality of life scores. The study will also monitor the incidence and severity of adverse events, as well as changes in vital signs and clinical laboratory test results.

Participants will be involved in the trial for a maximum treatment period of 24 months. The trial includes an initial screening visit to confirm eligibility based on criteria such as histologically confirmed metastatic or unresectable locally advanced melanoma, an ECOG performance status of 0 or 1, and adequate hematologic and end-organ function. Following the screening, participants will be randomized to receive either the combination therapy or pembrolizumab alone, administered via **IV infusion**. Regular follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The estimated duration of the trial is from March 2020 to December 2024, with the recruitment phase having commenced in March 2020. The trial is not classified as low intervention and is part of a confirmatory/registrational development program for the investigational product.

The clinical trial involves the administration of **RO7198457**, a gene therapy medicinal product, which is a **concentrate for dispersion for infusion**. The active substance in RO7198457 is **autogene cevumeran**, originating from nucleic acid. This investigational product is provided by Genentech, Inc. and is administered via **intravenous infusion**. The maximum daily dose is 1 microgram, with a total maximum dose of 1 microgram over a treatment period of up to 24 months. The administration schedule and participant compliance are monitored throughout the study to ensure adherence to the dosing regimen.

In addition to RO7198457, the trial includes the administration of **KEYTRUDA**, a commercially available medication with the active substance **pembrolizumab**, which is a protein-based therapeutic. KEYTRUDA is provided as a **concentrate for solution for infusion** and is manufactured by Merck Sharp & Dohme B.V. The product is administered via **intravenous infusion** with a maximum daily dose of 200 milligrams and a total maximum dose of 6.8 grams over a 24-month treatment period. The secondary packaging and labeling of KEYTRUDA have been modified for clinical trial use. Compliance with the dosing schedule is closely monitored to ensure the integrity of the trial data.

The study is designed to evaluate the efficacy and safety of RO7198457 in combination with pembrolizumab compared to pembrolizumab alone in patients with previously untreated advanced melanoma. The primary objective is to assess progression-free survival among participants. Both investigational and comparator treatments are administered under controlled conditions, with adherence to the protocol being a critical component of the trial's success.

The efficacy of the investigational treatment in this clinical trial will be assessed primarily through **Progression Free Survival** (PFS). This endpoint will evaluate the length of time during and after the treatment that a patient lives with the disease without it worsening. Secondary endpoints include the **Objective Response Rate** (ORR), **Overall Survival** (OS), and **Duration of Response** (DoR). Additionally, changes from baseline in Health-Related Quality of Life (HRQoL) scores will be measured using the two-item Global Health Status (GHS)/HRQoL subscale of the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) at specified timepoints. The incidence and severity of adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Changes from baseline in targeted vital signs and clinical laboratory test results will also be evaluated.