A Randomized Phase 3 Study of Datopotamab Deruxtecan (Dato-DXd) and Pembrolizumab, with or without Platinum Chemotherapy, in Subjects with No Prior Therapy for Advanced or Metastatic PD-L1 TPS<50% Non-squamous Non-small Cell Lung Cancer without Actionable Genomic Alterations (TROPION-Lung07)
- Trial ID
- 2022-500802-16-00
- Protocol
- DS1062-A-U303
- Sponsor
- Daiichi Sankyo Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of Datopotamab Deruxtecan (Dato-DXd) in combination with pembrolizumab, with or without platinum-based chemotherapy, against pembrolizumab plus pemetrexed and platinum-based chemotherapy. This comparison is measured by **Progression-Free Survival (PFS)** and **Overall Survival (OS)**, as assessed by blinded independent central review. These endpoints are clinically relevant as they provide insights into the potential of Dato-DXd to improve survival outcomes in patients with advanced or metastatic PD-L1 TPS <50% non-squamous non-small cell lung cancer without actionable genomic alterations.
Secondary objectives include: - Comparing the efficacy of Dato-DXd in combination with pembrolizumab, with or without platinum-based chemotherapy, versus pembrolizumab plus pemetrexed and platinum-based chemotherapy, as measured by objective response rate (ORR). - Further evaluating the efficacy of Dato-DXd in combination with pembrolizumab, with or without platinum-based chemotherapy, versus pembrolizumab plus platinum-pemetrexed chemotherapy, including PFS, ORR, Duration of Response (DoR), Time to Response (TTR), Disease Control Rate (DCR), and PFS2. - Evaluating the patient-reported outcomes (PROs) of Dato-DXd in combination with pembrolizumab, with or without platinum-based chemotherapy, versus pembrolizumab plus platinum-pemetrexed chemotherapy. - Further evaluating the safety of Dato-DXd in combination with pembrolizumab, with or without platinum-based chemotherapy, versus pembrolizumab plus platinum-pemetrexed chemotherapy. - Assessing the immunogenicity of Dato-DXd in combination with pembrolizumab, with or without platinum-based chemotherapy.
Participants
The clinical trial involves a total of **816 participants** diagnosed with **advanced or metastatic non-squamous non-small cell lung cancer** (NSCLC) characterized by a PD-L1 TPS of less than 50% and without actionable genomic alterations. The study population includes both male and female adults aged 18 years and older. Participants were selected based on their ability to comply with study requirements and their health status, specifically those who have not received systemic anticancer therapy for advanced or metastatic NSCLC. The trial includes individuals who have measurable disease as per RECIST v1.1 criteria. The study population is diverse, encompassing a vulnerable population, and is not restricted by gender. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to evaluate the efficacy of Dato-DXd in combination with pembrolizumab, with or without platinum-based chemotherapy, compared to pembrolizumab plus pemetrexed and platinum-based chemotherapy, focusing on progression-free survival and overall survival outcomes.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **Datopotamab Deruxtecan** in combination with **Pembrolizumab**, with or without platinum-based chemotherapy, in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with PD-L1 TPS <50% and without actionable genomic alterations. The trial aims to compare this combination against the standard treatment of **Pembrolizumab** plus **Pemetrexed** and platinum-based chemotherapy. The primary endpoints are **Progression-Free Survival (PFS)** and **Overall Survival (OS)**, assessed by blinded independent central review.
The trial is expected to last until November 2027, with recruitment starting in April 2023. Participants will be involved in the study for a maximum treatment period of 60 weeks, depending on the treatment arm. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be adults with measurable disease based on RECIST v1.1 criteria, and they must not have received prior systemic anticancer therapy for advanced or metastatic NSCLC.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study will also monitor secondary endpoints such as objective response rate, duration of response, and treatment-emergent adverse events. The trial is conducted under strict regulatory compliance to ensure the safety and well-being of all participants.
Treatment
**Pemetrexed** is administered as a **concentrate for solution for infusion**. The active substance, pemetrexed, is a chemical compound classified as a folate antimetabolite. The maximum daily dose is 500 mg/m², with a total maximum dose of 30,000 mg/m² over a treatment period of up to 60 days. The route of administration is via **intravenous infusion**.
**Datopotamab deruxtecan** is provided as a **solution for infusion**. This protein-based compound is administered intravenously, with a maximum daily dose of 6 mg/kg and a total maximum dose of 360 mg/kg over a 60-day treatment period. The product is developed by DAIICHI SANKYO, INC.
**Carboplatin** is available as a **concentrate for solution for infusion**. It is a chemical compound used as a platinum-based chemotherapeutic agent, acting by binding to DNA. The maximum daily dose is 750 mg, with a total maximum dose of 3,000 mg over a 12-day treatment period. Administration is conducted intravenously.
**Cisplatin** is also provided as a **concentrate for solution for infusion**. This chemical compound is another platinum-based chemotherapeutic drug, with a maximum daily dose of 75 mg/m² and a total maximum dose of 300 mg/m² over a 12-day treatment period. The route of administration is intravenous.
**Pembrolizumab**, marketed as KEYTRUDA, is a **solution for infusion**. It is a humanized monoclonal anti-programmed cell death-1 (PD-1) antibody. The maximum daily dose is 200 mg, with a total maximum dose of 4,800 mg over a 24-day treatment period. The administration is performed intravenously, and the product is developed by MERCK SHARP & DOHME BV.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. PFS is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first. OS is defined as the time from randomization to death due to any cause.
Secondary endpoints encompass a range of measures, including the Objective Response Rate (ORR), which is the proportion of subjects achieving a Best Overall Response (BOR) of confirmed complete response (CR) or confirmed partial response (PR). The Duration of Response (DoR) is defined as the time from the first documentation of objective response to the first radiographic disease progression or death. Time to Response (TTR) measures the time from randomization to the first documentation of objective response. Disease Control Rate (DCR) is the proportion of subjects achieving a BOR of confirmed CR, PR, or stable disease (SD). PFS2 is the time from randomization to the first documented disease progression on next-line therapy or death. The Time to Deterioration (TTD) is defined as the time from randomization to the first onset of a ≥10-point increase in symptoms such as cough, chest pain, or dyspnea, confirmed by a second adjacent ≥10-point increase or death within 21 days of such an increase.
Additional assessments include treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). These will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and graded by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The trial will also evaluate ADA prevalence and incidence, with titer and neutralizing antibodies determined when ADA is positive.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Sign and date the Main ICF, prior to the start of any study- specific qualification procedures. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
- Adults ≥18 at the time the Main ICF is signed. (Follow local regulatory requirements if the legal age of adult voluntary consent for study participation is >18 years old.)
- Has tumor with PD-L1 TPS <50% as determined by PD-L1 IHC 22C3 pharmDx assay by central testing (minimum of 6 slides). PD-L1 expression results available at the same central laboratory from screening for the purpose of entry into another Dato-DXd study may be used for tissue screening purposes in this study as long as the subject has not been randomized/enrolled in the other study.
- Has provided a formalin-fixed tumor tissue sample (minimum of 10 [preferably 15] × 4-micron sections or block equivalent) for the measurement of TROP2 protein expression and for the assessment of other exploratory biomarkers. This tissue requirement is in addition to the tissue required for PD-L1 testing for tissue screening purposes. If a documented law or regulation prohibits (or does not approve) sample collection, then such sample will not be collected, and the subject is still eligible for the study.
- Has not been treated with systemic anticancer therapy for advanced or metastatic nonsquamous NSCLC. Subjects who received adjuvant or neoadjuvant therapy other than those listed in the exclusion criteria are eligible if the adjuvant/ neoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced/metastatic disease and should not have progressed on or within the 6 months of completion.
- Has measurable disease based on local imaging assessment using RECIST v1.1; radiographic tumor assessment must be performed within 28 days before randomization. For more details regaridng the inclusion criteria please refer to protocol section 5.1
Exclusion Criteria
- Has received prior systemic treatment for advanced/metastatic NSCLC.
- Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant setting: a. Any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I b. TROP2-targeted therapy c. Any anti-PD-1, anti-PD-L1, or anti-programmed death-ligand (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137) d. Any other ICIs Subjects who received adjuvant or neoadjuvant therapy other than those listed above are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced or metastatic disease.
- Has received a live vaccine within 30 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. For any subject receiving an approved severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) vaccine, please follow the vaccine label and/or local guidance. The vaccine manufacturer and the date of administration should be recorded on the electronic case report form (Concomitant Medications page), as should any AEs relating to the vaccine (including hypersensitivity or allergies). Note: Any licensed SARS-CoV2 vaccine (including those authorized for emergency use) in a particular country is allowed in the study as long as the vaccine is an mRNA vaccine, adenoviral vaccine, or inactivated vaccine. Such vaccines will be treated just as any other concomitant therapy. Investigational vaccines (ie, those not licensed or authorized for emergency use) are not allowed.
- Has spinal cord compression or clinically active untreated CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging (Note: Repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 7 days before the first dose of study drug. Note: A contrasted computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the brain at baseline (MRI with contrast preferred) is required for all subjects. For those subjects in whom CNS metastases are first discovered at the time of screening, the treating investigator should consider delay of study treatment to document stability of CNS metastases with repeat imaging at least 4 weeks later (in which case, repeat of all screening activity may be required).
- Has uncontrolled or significant cardiovascular disease not controlled by maximal medical therapy, including: a. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval >470 msec regardless of sex (based on the 12-lead electrocardiogram [ECG] performed at screening). b. Myocardial infarction within 6 months prior to Cycle 1 Day 1. c. History of a serious cardiac arrhythmia requiring treatment d. Uncontrolled angina pectoris within 6 months prior to Cycle 1 Day 1. e. Left ventricular ejection fraction (LVEF) <50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before randomization. f. New York Heart Association (NYHA) Class II-IV congestive heart failure (CHF) at screening. Subjects with a history of Class II to IV CHF prior to screening, must have returned to Class I CHF and have LVEF ≥50% (by either an ECHO or MUGA scan within 28 days before randomization) in order to be eligible. g. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg within 28 days before randomization that is not resolved despite maximal medical therapy). For more deatails about the exclusion criteria, please refer to protocol section 5.2
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 03 Apr 2023 | 21 |
 Belgium | Not Recruiting | 03 Apr 2023 | 25 |
 Czechia | Not Recruiting | 03 Apr 2023 | 20 |
 France | Not Recruiting | 03 Apr 2023 | 75 |
 Germany | Not Recruiting | 03 Apr 2023 | 50 |
 Greece | Not Recruiting | 03 Apr 2023 | 50 |
 Hungary | Not Recruiting | 03 Apr 2023 | 25 |
 Italy | Not Recruiting | 03 Apr 2023 | 35 |
 The Netherlands | Not Recruiting | 03 Apr 2023 | — |
 Poland | Not Recruiting | 03 Apr 2023 | 35 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Datopotamab deruxtecan | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 6 | 60 | PRD9684738 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 200 | 24 | PRD4323784 |
PEMETREXED | Test | — | INTRAVENIOUS INFUSION | 500 | 60 | SUB09655MIG |
CARBOPLATIN | Test | — | INTRAVENOUS | 750 | 12 | SUB06614MIG |
CISPLATIN | Test | — | INTRAVENOUS | 75 | 12 | SUB07483MIG |