A Phase 3, Randomized, Placebo-Controlled Clinical Study to Evaluate the Safety and Efficacy of Stereotactic Body Radiotherapy (SBRT) with or without Pembrolizumab (MK-3475) in Participants with Unresected Stage I or II Non-Small Cell Lung Cancer (NSCLC) (KEYNOTE-867)
- Trial ID
- 2022-500413-11-00
- Protocol
- MK3475-867
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, placebo-controlled clinical study is to compare **Event-Free Survival (EFS)** in participants with unresected Stage I or II Non-Small Cell Lung Cancer (NSCLC) undergoing **Stereotactic Body Radiotherapy (SBRT)** with or without **pembrolizumab**. EFS is a critical endpoint in oncology trials as it measures the time until disease progression, recurrence, or death, providing insights into the treatment's efficacy in delaying disease events.
Secondary objectives include:
- To compare **Overall Survival (OS)**, which is a vital measure of treatment impact on longevity.
- To evaluate the time to death or distant metastases, offering insights into the treatment's ability to prevent cancer spread.
- To assess the safety and tolerability of SBRT combined with pembrolizumab, ensuring the treatment's risk-benefit profile is acceptable.
- To evaluate changes from baseline in global health status/quality of life (QoL), cough, chest pain, dyspnea, and physical functioning scale, which are important for understanding the treatment's impact on patient well-being and daily functioning.
Participants
The clinical trial involves a total of **343 participants** diagnosed with **unresected Stage I or II Non-Small Cell Lung Cancer (NSCLC)**. 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 confirmed diagnosis of NSCLC by histology or cytology, and staging confirmed by chest CT and PET scan. The trial includes individuals who are unable to undergo thoracic surgery due to existing medical conditions, as well as those who opt for stereotactic body radiotherapy (SBRT) as definitive therapy. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2, and demonstrate adequate organ function. Lifestyle considerations include the requirement for female participants to use highly effective contraception or maintain abstinence, and male participants to refrain from sperm donation and use contraception or maintain abstinence. The trial population also includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, placebo-controlled study designed to evaluate the safety and efficacy of **stereotactic body radiotherapy (SBRT)** with or without **pembrolizumab** in participants with unresected Stage I or II **non-small cell lung cancer (NSCLC)**. The trial employs a double-blind methodology to ensure unbiased results, with participants randomly assigned to receive either the active treatment or a placebo. The trial is expected to run from June 25, 2019, to July 1, 2026, encompassing a total duration of approximately seven years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as having previously untreated NSCLC confirmed as Stage I or II, and the inability to undergo thoracic surgery due to medical conditions. Following the screening, participants will be enrolled and randomized into treatment groups. The study includes regular follow-up visits to monitor the participants' health, assess the treatment's efficacy, and record any adverse events. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the primary endpoint of event-free survival (EFS) and secondary endpoints, including overall survival (OS) and quality of life measures.
The expected length of participant involvement is up to 12 months, corresponding to the maximum treatment period with pembrolizumab. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or any significant protocol deviations. The trial aims to provide comprehensive data on the safety and efficacy of pembrolizumab in combination with SBRT, contributing valuable insights into the treatment of unresected Stage I or II NSCLC.
Treatment
The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 3400 mg over the course of the treatment. The treatment period is set for a maximum of 12 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02. The pharmaceutical form is a solution for infusion, and the product is manufactured by Merck Sharp & Dohme BV. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.
The study also includes a **placebo** treatment, which is a normal saline solution designed to match the appearance and administration route of KEYTRUDA. The placebo is used to maintain the integrity of the double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the experimental drug, via intravenous infusion, to participants in the control group. This allows for a direct comparison of the safety and efficacy of pembrolizumab against the placebo in participants with unresected Stage I or II Non-Small Cell Lung Cancer (NSCLC).
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Event-Free Survival (EFS)**, which will be used to evaluate the effectiveness of the treatment in preventing disease progression or recurrence. Secondary endpoints include Overall Survival (OS), Time to Death or Distant Metastases (TDDM), and the number of participants who experience an adverse event (AE) or discontinue study treatment due to an AE. Additionally, changes from baseline in quality of life scores will be measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Lung Cancer Module 13 (EORTC QLQ-LC13). These scores will assess global health status, quality of life, cough, chest pain, dyspnea, and physical functioning.
The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial. The changes in quality of life scores will be evaluated from baseline to subsequent assessments, providing insights into the impact of the treatment on participants' well-being. The trial is designed to ensure rigorous assessment of the treatment's efficacy in participants with unresected Stage I or II Non-Small Cell Lung Cancer (NSCLC), with the aim of confirming the safety and efficacy of the investigational product, **Pembrolizumab** (MK-3475), in combination with Stereotactic Body Radiotherapy (SBRT).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has previously untreated non-small cell lung cancer (NSCLC) diagnosed by histology or cytology and confirmed as Stage I or II (T1 to limited T3, N0, M0) NSCLC (American Joint Committee on Cancer, AJCC) by chest computed tomography (CT) and positron emission tomography (PET) scan. Participants with pericardium invasion, >2 nodules or 2 nodules that cannot be treated in one field (>2 cm apart and/or total planned target volume [PTV] >163 cc) and diaphragm elevation suggestive of phrenic nerve invasion are excluded
- Cannot undergo thoracic surgery due to existing medical illness(es) as determined by the site’s multi-disciplinary tumor board. Medically operable participants who decide to treat with stereotactic body radiotherapy (SBRT) as definitive therapy rather than surgery are also eligible, if patient’s unwillingness to undergo surgical resection is clearly documented
- Has a Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- Is able to receive SBRT and does not have an ultra-centrally located tumor
- Has adequate organ function within 7 days prior to the start of study treatmet
- A female is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a) not a women of childbearing potential (WOCBP) OR b) A WOCBP and uses contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 120 days after the last dose of pembrolizumab/placebo and 180 days after the last radiotherapy dose
- Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of radiotherapy: refrain from donating sperm plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent or must agree to use contraception per study protocol, unless confirmed to be azoospermic
- Has a radiation therapy plan approved by the central radiation therapy quality assurance vendor
Exclusion Criteria
- Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4], tumor necrosis factor receptor superfamily member 4 [OX-40], tumor necrosis factor receptor superfamily member 9 [CD137])
- Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or breast
- Has received a live vaccine within 30 days prior to the first dose of study intervention
- Has received an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention administration
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
- Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. A prior NSCLC that occurred and was treated curatively at least 2 years prior to the date of the current diagnosis would be considered a separate primary lung cancer, and therefore an additional malignancy. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast c carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
- Has a known hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Has a known history of Hepatitis B or known active Hepatitis C virus infection
- Has an active autoimmune disease that has required systemic treatment in past 2 years, except replacement therapy
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) infection
- Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab/placebo and 180 days after the last radiotherapy dose
- Have not adequately recovered from major surgery or have ongoing surgical complications
- Has had an allogenic tissue/solid organ transplant
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 25 Jun 2019 | 12 |
 France | Not Recruiting | 25 Jun 2019 | 45 |
 Germany | Not Recruiting | 25 Jun 2019 | 15 |
 Hungary | Not Recruiting | 25 Jun 2019 | 90 |
 Italy | Not Recruiting | 25 Jun 2019 | 14 |
 The Netherlands | Not Recruiting | 25 Jun 2019 | — |
 Norway | Not Recruiting | 25 Jun 2019 | 20 |
 Poland | Not Recruiting | 25 Jun 2019 | 20 |
 Romania | Not Recruiting | 25 Jun 2019 | 5 |
 Spain | Not Recruiting | 25 Jun 2019 | 16 |
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 INFUSION | 200 | 12 | PRD4323105 |
Placebo to Keytruda-Normal Saline Solution | Placebo | N/A | — | — | — | N/A |