Phase III Randomized Study of Lurbinectedin and Atezolizumab Versus Atezolizumab in Maintenance Therapy for Extensive-Stage Small-Cell Lung Cancer

The primary objective of this study is to evaluate the **efficacy** of **lurbinectedin** in combination with **atezolizumab** compared with atezolizumab alone in patients with extensive-stage small-cell lung cancer (ES-SCLC). This evaluation is based on progression-free survival (PFS) and overall survival (OS) as assessed by an Independent Review Facility (IRF). The clinical relevance of this objective lies in determining whether the combination therapy can provide a significant improvement in survival outcomes for patients with ES-SCLC, a condition known for its aggressive nature and limited treatment options.

Secondary objectives include:

• Evaluating the efficacy of lurbinectedin in combination with atezolizumab compared with atezolizumab based on Investigator-assessed PFS, confirmed objective response rate (ORR), duration of response (DOR), PFS rates at 6 and 12 months, and OS rates at 12 and 24 months.
• Assessing the safety of lurbinectedin in combination with atezolizumab compared with atezolizumab based on the incidence and severity of adverse events.
• Evaluating the immunogenicity of atezolizumab with and without lurbinectedin based on the prevalence of anti-drug antibodies (ADA) to atezolizumab throughout treatment.
• Assessing the health-related quality of life of participants treated with lurbinectedin in combination with atezolizumab compared with atezolizumab.

The clinical trial involves a total of **326 participants** diagnosed with **Small-Cell Lung Cancer (SCLC)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of extensive-stage SCLC, adequate hematologic and end-organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Individuals with no prior systemic treatment for extensive-stage SCLC and those with ongoing response or stable disease after induction therapy were included. The trial also considers vulnerable populations. Participants' general health status is characterized by the resolution of toxicities from prior induction anti-cancer therapy to Grade 1 or better. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is a **Phase III**, randomized, open-label, multicenter study designed to evaluate the efficacy of **lurbinectedin** in combination with **atezolizumab** compared to atezolizumab alone as maintenance therapy in participants with extensive-stage small-cell lung cancer (ES-SCLC) following first-line induction therapy. The primary objective is to assess progression-free survival (PFS) and overall survival (OS) as determined by an Independent Review Facility (IRF). The trial is expected to conclude by March 2026, with recruitment having commenced in February 2022.

Participants will be randomly assigned to receive either the combination therapy or atezolizumab alone. The study involves multiple visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically or cytologically confirmed ES-SCLC, adequate hematologic and end-organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants must not have received prior systemic treatment for ES-SCLC and should have an ongoing response or stable disease after induction therapy.

Following the screening, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, assess adverse events, and evaluate the presence of anti-drug antibodies. The primary endpoints include IRF-assessed PFS and OS, while secondary endpoints encompass investigator-assessed PFS, objective response rate, duration of response, and incidence of adverse events. The study will also measure quality of life using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).

The expected duration of participant involvement is up to 92 days for those receiving lurbinectedin and up to 24 days for those on atezolizumab alone. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial is not classified as low intervention and is part of a confirmatory development program for the investigational products.

The clinical trial involves the administration of **Lurbinectedin**, an experimental medication, under the product name RO7508182. It is provided as a **solution for infusion** and is administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 3.2 mg/m² and a total maximum dose of 96 mg over a treatment period of 92 days. Lurbinectedin is a chemical compound known to inhibit transactivated transcription. The formulation is not pediatric, and the product is manufactured by Pharma Mar S.A.

Another experimental medication used in the trial is **Atezolizumab**, marketed under the name Tecentriq 1200 mg concentrate for solution for infusion. This medication is also administered as a **solution for infusion** via **intravenous infusion**. The maximum daily dose is 1200 mg, with a total maximum dose of 40.8 g over a treatment period of 24 days. Atezolizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, and is produced by Roche Registration GmbH. This formulation is also not intended for pediatric use.

In this study, Atezolizumab serves as both a standalone maintenance therapy and in combination with Lurbinectedin. The trial aims to compare the efficacy of the combination therapy against Atezolizumab alone in participants with extensive-stage small-cell lung cancer (ES-SCLC) following first-line induction therapy. The study does not include any placebo or comparator treatment beyond the standard-of-care therapy involving Atezolizumab.

The efficacy of the investigational treatment in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include **progression-free survival (PFS)** and overall survival (OS), both assessed by an Independent Review Facility (IRF). PFS is defined as the time from randomization to the first occurrence of documented disease progression or death from any cause, while OS is defined as the time from randomization to death from any cause.

Secondary endpoints encompass a range of measures, including investigator-assessed PFS, confirmed objective response rate (ORR), and duration of response (DOR), all determined according to RECIST v1.1 criteria. Additionally, PFS rates at 6 and 12 months, as well as OS rates at 12 and 24 months, will be evaluated. The incidence and severity of adverse events, including serious adverse events, will be monitored and classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. The prevalence and incidence of anti-drug antibodies (ADAs) to atezolizumab will also be assessed. Furthermore, time to confirmed deterioration (TTCD) in participant-reported physical functioning and global health status will be measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).