Phase 3 Randomized Open-label Trial of Datopotamab Deruxtecan Plus Pembrolizumab Versus Pembrolizumab in Advanced or Metastatic PD-L1 High NSCLC
- Trial ID
- 2023-507933-12-00
- Protocol
- DS1062-A-U304
- Sponsor
- Daiichi Sankyo Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone in subjects with non-squamous histology of advanced or metastatic non-small cell lung cancer (NSCLC). This comparison will be measured by progression-free survival (PFS) as assessed by blinded independent central review (BICR) and overall survival (OS). The clinical relevance of this objective lies in determining whether the combination therapy offers a significant improvement in survival outcomes for patients with this specific histological subtype of NSCLC, which could inform treatment decisions and improve patient prognosis.
Secondary objectives include:
- Comparing the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by PFS by BICR, across all randomized subjects.
- Further evaluating the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone.
- Evaluating the patient-reported outcomes (PROs) of Dato-DXd in combination with pembrolizumab and of pembrolizumab alone.
- Further evaluating the safety of Dato-DXd in combination with pembrolizumab.
- Assessing the immunogenicity of Dato-DXd in the investigational treatment arm.
- Comparing the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by OS, across all randomized subjects, including those with non-squamous and squamous histology.
Participants
The clinical trial involves a total of **514 participants** diagnosed with **Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)**, specifically those with non-squamous histology. The study population includes both male and female adults aged 18 years and older, with no upper age limit specified. Participants were selected based on their diagnosis and the absence of certain genomic alterations, such as EGFR, ALK, and ROS1, while those with KRAS mutations are eligible. The trial includes individuals with a life expectancy of at least three months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants must have measurable disease and adequate bone marrow function. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with study procedures and restrictions. The trial does not exclude vulnerable populations, indicating a broad inclusion of eligible subjects. Key inclusion criteria include high PD-L1 expression and a left ventricular ejection fraction of at least 50%. The sponsor has not provided additional information regarding specific lifestyle factors or health status beyond the inclusion criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **Datopotamab deruxtecan** in combination with **pembrolizumab** versus pembrolizumab alone in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations. The trial aims to assess progression-free survival (PFS) and overall survival (OS) as primary endpoints. The study is expected to run until April 2028, with recruitment having commenced in July 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 non-squamous NSCLC, high PD-L1 expression, and adequate bone marrow function. Following randomization, participants will receive intravenous infusions of the investigational products, with the treatment period lasting up to 24 months. Regular follow-up visits will be conducted to monitor safety, efficacy, and any adverse events. 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 approximately 24 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants must comply with scheduled visits, drug administration plans, and study procedures. The trial will ensure that all participants meet the inclusion criteria, such as being adults aged 18 years or older, having a life expectancy of at least three months, and not having known actionable genomic alterations. The study will be conducted in accordance with ethical guidelines and regulatory requirements.
Treatment
The clinical trial involves the administration of **Datopotamab deruxtecan**, an experimental medication provided as a **solution for infusion**. This pharmaceutical form is designed for **intravenous** administration. The dosing regimen for Datopotamab deruxtecan is set at a maximum daily dose of 6.0 mg/kg, with the total dose not exceeding 6.0 mg/kg. The treatment period is capped at 24 weeks. The active substance, Datopotamab deruxtecan, is a protein-based compound developed by Daiichi Sankyo, Inc. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
In addition to the experimental treatment, the trial includes the administration of **Pembrolizumab**, marketed as KEYTRUDA, which serves as both a comparator and a test treatment. Pembrolizumab is provided as a **concentrate for solution for infusion** and is also administered **intravenously**. The dosing for Pembrolizumab is standardized at a maximum daily dose of 200 mg, with the total dose not exceeding 200 mg. The treatment duration is similarly limited to 24 weeks. Pembrolizumab, a protein-based therapeutic agent, is manufactured by Merck Sharp & Dohme B.V. Participant compliance with the administration schedule is closely monitored to ensure the integrity of the trial data.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the combination of **Dato-DXd** and pembrolizumab versus pembrolizumab alone in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression. The primary efficacy 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 efficacy endpoints encompass a range of measures, including PFS2, overall response rate (ORR), duration of response (DoR), time to response (TTR), disease control rate (DCR), and time to deterioration (TTD). PFS2 is the time from randomization to the first documented disease progression on next-line therapy or death. ORR is the proportion of subjects achieving a best overall response (BOR) of confirmed complete response (CR) or partial response (PR). DoR measures the time from the first documentation of objective response to disease progression or death. TTR is the time from randomization to the first documentation of objective response. DCR is the proportion of subjects achieving a BOR of confirmed CR, PR, or stable disease (SD). TTD is 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 increase or death within 21 days of the increase.
Additional assessments include treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs), and various clinical parameters such as Eastern Cooperative Oncology Group performance status (ECOG PS), vital signs, laboratory parameters, electrocardiogram, echocardiogram/multigated acquisition scan findings, and ophthalmologic findings. The presence of anti-drug antibodies (ADA) will also be evaluated, with ADA prevalence and incidence being determined.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Sign and date the Tissue Screening and Main ICFs, prior to the start of any study-specific qualification procedures.
- Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time of informed consent. (Follow local regulatory requirements if the legal age of adult voluntary consent for study participation is >18 years old.
- Histologically documented non-squamous NSCLC that meets all of the following criteria (Note: Subjects with squamous histology were eligible prior to Protocol Version 5.0. After Protocol Version 5.0, subjects with squamous histology are not eligible. Subjects with mixed histology, including those with a squamous component, remain eligible for the study even after Protocol Version 5.0): a. Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition). Subjects with early-stage NSCLC who have relapsed should be restaged during screening to ensure their eligibility for the study. b. Documented negative test results for EGFR, ALK, and ROS1 AGAs based on analysis of tumor tissue. If test results for EGFR, ALK, and ROS1 are not available, subjects are required to undergo testing performed locally for these genomic alterations. c. No known AGAs in NTRK, BRAF, RET, MET, or other actionable driver kinases with locally approved therapies. (Testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to randomization). Subjects whose tumors harbor KRAS mutations are eligible for the study.
- Has provided a formalin-fixed tumor tissue sample. If a documented law or regulation prohibits (or does not approve) sample collection for exploratory biomarkers, then such sample will not be collected.
- Tumor has high PD-L1 expression (TPS ≥50%) as determined by PDL1 IHC 22C3 pharmDx assay by central testing (minimum of 6 slides).
- Has an adequate treatment washout period before Cycle 1 Day 1 as defined in protocol Section 5.1.
- Measurable disease based on local imaging assessment using RECIST Version 1.1 (see Section 10.4 of the protocol).
- Has left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before randomization.
- ECOG PS of 0 or 1 at screening.
- Has a life expectancy of at least 3 months.
- Adequate bone marrow function within 7 days before randomization as defined in protocol Section 5.1.
- If the subject is a female of childbearing potential, she must not be pregnant, breastfeeding or intend to become pregnant during the study; she must also have a negative serum pregnancy test at screening and must be willing to use highly effective birth control (as detailed in protocol Section 10.3.4) or avoid heterosexual intercourse upon randomization, during the Treatment Period, for 7 months following the last dose of Dato-DXd, and for 4 months following the last dose of pembrolizumab, whichever occurs later. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
- If male, the subject must be surgically sterile or must use a condom in addition to their partner using a highly effective birth control (Section 10.3.4 of the protocol) if their partner is of reproductive potential or avoid heterosexual intercourse upon enrollment, during the Treatment Period, and for 4 months following the last dose of Dato-DXd.
- Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the last dose of Dato-DXd. Preservation of sperm should be considered prior to enrollment in this study.
- Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the last dose of Dato-DXd, or for at least 4 months after the last dose of pembrolizumab, whichever occurs later. Preservation of ova should be considered prior to enrollment in this study.
- Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
Exclusion Criteria
- Has received prior systemic treatment for advanced or metastatic NSCLC.
- Has received prior treatment for NSCLC with any of the following, including in the adjuvant/neoadjuvant setting: a. Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I. b. TROP2-targeted therapy. c. Any anti-programmed death receptor-1 (PD-1), anti-PD-L1, or anti- PD-ligand 2 (L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137). d. Any other immune checkpoint inhibitors. 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/metastatic disease.
- Has spinal cord compression or active and untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases and who are asymptomatic may participate provided they are radiologically stable (ie, without evidence of progression) for at least 2 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 computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the brain at baseline (MRI preferred) is required for all subjects. For those subjects in whom CNS metastases are first discovered at the time of screening, are asymptomatic, and who do not require radiotherapy,the treating investigator should consider delay of study treatment to document stability of CNS metastases with repeat imaging 4 weeks from the time of detection of asymptomatic brain metastases (in which case, repeat of all screening activity may be required).
- Has received prior radiotherapy ≤4 weeks of start of study intervention or more than 30 Gy to the lung within 6 months of Cycle 1 Day 1 or has ongoing radiation-related toxicities requiring corticosteroids. A 2-week washout is permitted for palliative radiation to the non-thoracic region.
- History of another primary malignancy (beyond NSCLC) except for the following: - Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study treatment and of low potential risk for recurrence - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease - Subjects with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤T2cN0M0 without biochemical recurrence or progression and who in the opinion of the investigator are not deemed to require active intervention.
- Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
- Clinically severe pulmonary compromise, as judged by the investigator, resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli diagnosed within 3 months of Cycle 1 Day 1, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.), or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc), or prior complete pneumonectomy.
- Uncontrolled or significant cardiovascular disease, including: a. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >470 ms regardless of sex (based on the average of the 12-lead electrocardiogram determination at screening). b. Myocardial infarction within 6 months prior to randomization. c. Uncontrolled angina pectoris within 6 months prior to randomization. d. LVEF <50% by ECHO or MUGA scan within 28 days before randomization. e. New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening. Subjects with a history of Class 2 to 4 CHF prior to screening, must have returned to Class 1 CHF and have LVEF ≥50% (by either an ECHO or MUGA scan within 28 days before randomization) in order to be eligible. f. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) within 28 days before randomization.
- Has clinically significant corneal disease. For full list of principal exclusion criteria please see Clinical Study Protocol Section 5.2.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 18 Jul 2022 | 4 |
 Belgium | Not Recruiting | 18 Jul 2022 | 12 |
 France | Not Recruiting | 18 Jul 2022 | 39 |
 Germany | Not Recruiting | 18 Jul 2022 | 12 |
 Greece | Not Recruiting | 18 Jul 2022 | 15 |
 Hungary | Not Recruiting | 18 Jul 2022 | 15 |
 Italy | Not Recruiting | 18 Jul 2022 | 34 |
 The Netherlands | Not Recruiting | 18 Jul 2022 | — |
 Poland | Not Recruiting | 18 Jul 2022 | 17 |
 Portugal | Not Recruiting | 18 Jul 2022 | 13 |
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 |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 200 | 24 | PRD4323784 |
Datopotamab deruxtecan | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 6.0 | 24 | PRD9684738 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 200 | 24 | PRD4323105 |