A Phase III, multisite, double-blinded randomized trial of BNT327 in combination with chemotherapy (etoposide/carboplatin) compared to atezolizumab in combination with chemotherapy (etoposide/carboplatin) in participants with first-line extensive-stage small-cell lung cancer

The primary objective is to assess the efficacy of BNT327 in combination with chemotherapy (etoposide plus carboplatin) followed by any subsequent therapy compared to atezolizumab in combination with chemotherapy (etoposide plus carboplatin) followed by any subsequent therapy in terms of a hazard ratio for overall survival (OS) in the intent-to-treat set (ITT Set). This comparison is clinically relevant for establishing whether BNT327 offers a survival benefit over the current standard immunotherapy approach in patients with first-line extensive-stage small-cell lung cancer.

The secondary objectives include:

• Evaluation of progression-free survival (PFS) of BNT327 in combination with chemotherapy (etoposide plus carboplatin) compared to atezolizumab in combination with chemotherapy (etoposide plus carboplatin) in the ITT Set as measured by PFS according to RECIST v1.1 assessed by investigator.

• Evaluation of the antitumor activity of BNT327 in combination with chemotherapy (etoposide plus carboplatin) compared to atezolizumab in combination with chemotherapy (etoposide plus carboplatin) in the ITT Set as measured by objective response rate (ORR) and duration of response (DOR).

• Evaluation of the progression-free survival (PFS) rate and overall survival (OS) rate at fixed timepoints in each treatment arm for the ITT Set.

• Evaluation of the safety and tolerability of BNT327 in combination with chemotherapy (etoposide plus carboplatin) in the Safety Analysis Set.

• Evaluation of patient reported outcomes (PRO) scores of quality-of-life using the EORTC QLQ-C30, QLQ-LC29, and FACT-GP5 for the ITT Set.

This clinical trial enrolled a total of **455 participants** diagnosed with first-line **extensive-stage small-cell lung cancer (ES-SCLC)**. The study population included both **male and female** participants aged **18 years and older**, encompassing **adults** and **elderly** individuals. Participants were required to have histologically or cytologically confirmed ES-SCLC with no prior systemic therapy for this condition. Key selection criteria included an **ECOG performance status** of 0 or 1, a minimum body weight of at least 40 kg, and at least one measurable lesion based on **RECIST v1.1**. Adequate hematologic, coagulation, and organ function, including liver and kidney function, were required. Participants of child-bearing potential were required to have negative pregnancy tests and agree to highly effective contraception methods throughout the trial period and for specified durations after the last dose of treatment. Male participants who were sexually active with partners born female were also required to use contraception and avoid donating or cryopreserving germ cells during the trial. The trial included a **vulnerable population**. All participants provided written informed consent in accordance with **ICH GCP** and local legislation prior to any trial-specific procedures.

This is a **Phase III**, multisite, **double-blind**, **randomized controlled trial** evaluating the efficacy and safety of **BNT327** in combination with **chemotherapy** compared to **atezolizumab** in combination with chemotherapy in participants with first-line **extensive-stage small-cell lung cancer**. The trial employs a randomized design where participants are allocated to receive either the investigational treatment (BNT327 plus etoposide and carboplatin) or the comparator treatment (atezolizumab plus etoposide and carboplatin). All investigational medicinal products are administered via **intravenous infusion**. The primary objective is to assess the efficacy of BNT327 in combination with chemotherapy followed by any subsequent therapy compared to atezolizumab in combination with chemotherapy followed by any subsequent therapy in terms of a **hazard ratio** for **overall survival** in the intent-to-treat set.

The trial is designed to enroll participants who are 18 years of age or older with histologically or cytologically confirmed extensive-stage small-cell lung cancer who have not received prior systemic therapy for this condition. Eligible participants must have at least one measurable lesion based on **RECIST v1.1** criteria, an **ECOG performance status** of 0 or 1, and adequate hematologic and organ function. Participants of child-bearing potential must have a negative serum **beta-human chorionic gonadotropin** test at screening within 7 days of the first dose of investigational medicinal product. Both male and female participants must agree to practice highly effective contraception during the trial and for a specified period after the last dose of trial treatment.

The maximum treatment period for BNT327 and atezolizumab is 48 weeks, while the maximum treatment period for the chemotherapy agents (carboplatin, cisplatin, and etoposide) is 12 weeks. The maximum daily dose of BNT327 is 1500 mg with a maximum total dose of 51000 mg. For atezolizumab, the maximum daily dose is 1200 mg with a maximum total dose of 40800 mg. The chemotherapy agents have the following maximum dosing parameters: carboplatin 750 mg daily (3000 mg total), cisplatin 80 mg/m² daily (240 mg/m² total), and etoposide 100 mg/m² daily (1200 mg/m² total).

The trial includes a screening visit where informed consent is obtained and eligibility criteria are assessed. During the treatment period, participants receive the assigned investigational medicinal products according to the trial protocol. Follow-up visits are conducted to assess tumor response, progression-free survival, and overall survival, as well as to monitor for **treatment-emergent adverse events**. Tumor assessments are performed based on investigator's assessment using RECIST v1.1 criteria. The end-of-study visit marks the completion of participant involvement in the trial. The estimated recruitment start date is December 2025, and the estimated trial end date is November 2028.

Early termination from the study may occur due to various conditions including but not limited to disease progression, unacceptable toxicity, withdrawal of consent, or investigator's decision. Participants may experience dose delays, infusion interruptions, or discontinuation of study treatment due to adverse events. The trial protocol includes provisions for monitoring and managing adverse events to ensure participant safety throughout the study duration.

The primary endpoint is overall survival, defined as the time from randomization to death from any cause. Secondary endpoints include **progression-free survival** (time from randomization to first objective tumor progression or death), **objective response rate** (proportion of participants achieving complete or partial response), **duration of response** (time from onset of objective response to progression or death), progression-free survival rates at 6, 12, and 18 months, overall survival rates at 6, 12, 18, and 24 months, and the occurrence of treatment-emergent adverse events including Grade ≥3, serious, and fatal events. Additional secondary endpoints assess quality of life using the **EORTC QLQ-C30** Global Health status/Quality-of-Life score, physical functioning, and lung cancer-specific symptoms measured by the **EORTC QLQ-LC29** questionnaire, including coughing, shortness of breath, and hemoptysis items, as well as the **Functional Assessment of Cancer Therapy** overall bother item.

The experimental medication BNT327 is administered as a powder for concentrate for solution for infusion. The active substance is BNT327, a protein-based compound. The maximum daily dose is 1500 mg, with a maximum total dose of 51000 mg administered over a maximum treatment period of 48 weeks. The route of administration is intravenous infusion. The product has been packaged and labeled specifically for clinical trial use.

The comparator treatment atezolizumab is provided as Tecentriq 1200 mg concentrate for solution for infusion. The pharmaceutical form is solution for infusion, containing atezolizumab as the active substance, which is a protein-based compound. The maximum daily dose is 1200 mg, with a maximum total dose of 40800 mg administered over a maximum treatment period of 48 weeks. Administration is performed via intravenous infusion. The product has been packaged and labeled for the clinical trial.

The chemotherapy agent carboplatin is used as part of the combination therapy regimen. The maximum daily dose is 750 mg, with a maximum total dose of 3000 mg over a maximum treatment period of 12 weeks. The route of administration is intravenous infusion. The product has been packaged and labeled for clinical trial purposes.

The chemotherapy agent cisplatin is administered as an alternative platinum-based compound. The maximum daily dose is 80 mg/m², with a maximum total dose of 240 mg/m² over a maximum treatment period of 12 weeks. Administration is performed via intravenous infusion. The product has been packaged and labeled for the clinical trial.

The chemotherapy agent etoposide is used in combination with platinum-based therapy. The maximum daily dose is 100 mg/m², with a maximum total dose of 1200 mg/m² administered over a maximum treatment period of 12 weeks. The route of administration is intravenous infusion. The product has been packaged and labeled for clinical trial use.

The primary efficacy endpoint is overall survival, defined as the time from randomization to death from any cause. Secondary efficacy endpoints include progression-free survival, defined as the time from randomization to first objective tumor progression or death from any cause, whichever occurs first. Objective response rate is assessed as the proportion of participants achieving a confirmed complete response or partial response as best overall response. Duration of response is measured as the time from onset of objective response to first occurrence of objective tumor progression or death from any cause, whichever occurs first. Progression-free survival rates are evaluated at 6, 12, and 18 months based on investigator's assessment. Overall survival rates are assessed at 6, 12, 18, and 24 months. Additional endpoints include change from baseline in EORTC QLQ-C30 Global Health status and Quality-of-Life score, change from baseline in EORTC QLQ-C30 physical functioning, and changes from baseline in specific scales of the EORTC QLQ-LC29 questionnaire, including coughing scale, shortness of breath scale, and the coughed up blood item. Change from baseline in the Functional Assessment of Cancer Therapy overall bother item is also measured.