Phase 3 Randomized Trial of Pembrolizumab Versus Placebo in Stage IB-IIIA NSCLC Post-Resection and Adjuvant Therapy
- Trial ID
- 2023-509137-39-00
- Protocol
- MK-3475-091
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to prospectively investigate whether adjuvant treatment with **pembrolizumab** after completion of radical surgery (lobectomy/pneumonectomy) with or without standard adjuvant chemotherapy for stage IB (T ≥ 4 cm) -II-IIIA non-small cell lung cancer (NSCLC) patients improves **Disease-Free Survival (DFS)**, as assessed locally by the investigator, compared to placebo in the PD-L1 strong positive subgroup or overall population. This is clinically relevant as it aims to determine the efficacy of pembrolizumab in extending DFS, which is a critical endpoint in cancer treatment, indicating the time patients remain free from disease recurrence.
Secondary objectives include: - To prospectively compare DFS as assessed by the investigator in the PD-L1 positive population (TPS ≥1%). - To prospectively determine and compare **Overall Survival (OS)** in the PD-L1 strong positive and overall population. - To prospectively determine and compare OS in the PD-L1 positive population. - To prospectively determine and evaluate the **Lung Cancer Specific Survival (LCSS)** in the whole population irrespective of PD-L1 status. - To prospectively assess the safety of pembrolizumab after radical surgery followed by standard adjuvant chemotherapy. - No evidence of disease (NED) at clinical examination and baseline radiological assessment as documented by contrast-enhanced chest/upper abdomen CT scan, brain CT/MRI, and clinical examination within 12 weeks prior to the randomization date.
Participants
The clinical trial involves a total of **309 participants** diagnosed with **Stage IB (T ≥ 4 cm), II, and IIIA non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have undergone complete surgical resection. Participants were selected based on specific inclusion criteria, such as the absence of chronic use of immunosuppressive agents, no history of interstitial lung disease, and an ECOG performance status of 0-1. The trial also considers lifestyle factors, requiring participants to have no active autoimmune diseases requiring systemic treatment in the past two years and no active infections requiring therapy. The study population is characterized by a diverse range of health statuses, with an emphasis on ensuring adequate organ function and the absence of severe comorbidities that could impede participation. Both genders are included, and the trial does not exclude vulnerable populations. Participants are required to adhere to specific contraceptive measures if of childbearing potential, and those with a history of other malignancies must have been in remission for at least five years. The trial aims to evaluate the efficacy of adjuvant treatment with pembrolizumab in improving disease-free survival compared to placebo.
Plans and Procedures
The clinical trial is designed as a **randomized**, phase 3 study to evaluate the efficacy of the **anti-PD-1 monoclonal antibody pembrolizumab** compared to placebo in patients with early-stage non-small cell lung cancer (NSCLC) following surgical resection and standard adjuvant therapy. The primary objective is to assess whether adjuvant treatment with pembrolizumab improves **disease-free survival (DFS)** in both the PD-L1 strong positive subgroup and the overall population. The trial is expected to conclude by February 2027, with recruitment having commenced in November 2015.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed stage IB (T ≥ 4 cm), II, or IIIA NSCLC, and the availability of tumor samples for PD-L1 expression assessment. Following the screening, eligible participants will proceed to randomization, where they will be assigned to receive either pembrolizumab or placebo. The treatment period will last up to 52 weeks, with pembrolizumab administered intravenously at a maximum daily dose of 200 mg.
Throughout the trial, participants will attend regular follow-up visits to monitor their health status, assess treatment efficacy, and record any adverse events. The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted. The expected length of participant involvement is approximately 52 weeks, although certain conditions, such as the development of severe adverse events or withdrawal of consent, may lead to early termination from the study.
Secondary endpoints include overall survival (OS) in the overall population and the PD-L1 positive subgroups, as well as toxicity assessments according to CTCAE version 4.03. The trial is not classified as low intervention, and it aims to confirm the safety and efficacy of pembrolizumab in the specified patient population. Participants are required to adhere to specific inclusion criteria, such as no chronic use of immunosuppressive agents, adequate organ function, and no active autoimmune disease requiring systemic treatment. The trial excludes individuals with a history of interstitial lung disease, active infections requiring therapy, or prior treatment with immune-modulating agents.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. Pembrolizumab is an **anti-PD-1 monoclonal antibody** and is provided in a concentration of 25 mg/mL. The pharmaceutical form is a solution for infusion, and it is administered via the **intravenous route**. The maximum daily and total dose is 200 mg, with a treatment period extending up to 52 weeks. Pembrolizumab is of biological/biotechnological origin and is not classified as an Advanced Therapy Investigational Medicinal Product (ATIMP). The product is manufactured by Merck Sharp & Dohme B.V. and is identified by the sponsor product code MK-3475. The trial aims to evaluate the efficacy of pembrolizumab in improving Disease-Free Survival (DFS) in patients with early-stage non-small cell lung cancer (NSCLC) after surgical resection and standard adjuvant therapy.
The study also includes the use of **sodium chloride** as a non-experimental treatment, serving as a placebo comparator. Sodium chloride is utilized in the trial to provide a control for evaluating the effects of pembrolizumab. The pharmaceutical form, active substance name, and other specific details regarding sodium chloride are not provided in the trial data. The role of sodium chloride in the trial is to act as a placebo, ensuring the study's design allows for a comparison between the active treatment and a non-active control.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of **Disease-Free Survival (DFS)**. The primary endpoints include DFS in the PD-L1 strong positive subgroup and DFS in the overall population. Secondary endpoints will further assess DFS in the PD-L1 positive population, Overall Survival (OS) in the overall population, OS in the PD-L1 strong positive subgroup, OS in the PD-L1 positive population, Lung Cancer-Specific Survival (LCSS) in the overall population, and toxicity according to CTCAE version 4.03.
The trial will involve the administration of pembrolizumab, an anti-PD-1 monoclonal antibody, compared to a placebo in patients with early-stage non-small cell lung cancer (NSCLC) following resection and completion of standard adjuvant therapy. The efficacy parameters will be measured and analyzed at specified intervals throughout the trial duration, with the estimated end date set for February 2, 2027. The assessments will be conducted locally by investigators, ensuring a comprehensive evaluation of the treatment's impact on disease progression and patient survival.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Registration - step 1 (ORTA step 1) ♦ Before patient registration, written informed consent for tumor testing must be given according to ICH/GCP and national/local regulations. For patients that accept to participate in the translational research, we recommend the informed consent for translational research be signed before registration step 1;
- ♦ Participants who receive adjuvant chemotherapy must begin adjuvant chemotherapy within 12 weeks of the surgery date. Patients receiving adjuvant chemotherapy must be randomized and dosed with pembrolizumab/placebo at least 3 weeks but no more than 12 weeks from the last dose of chemotherapy (Day 1 of last cycle).
- ♦ ECOG Performance status 0-1;
- ♦ Pathological diagnosis of NSCLC confirmed at surgery, any histology is eligible;
- ♦ Adequate organ function performed within 10 days of treatment initiation;
- ♦ No prior or planned neoadjuvant or adjuvant radiotherapy and/or neoadjuvant chemotherapy for the current malignancy is allowed;
- ♦ No prior treatment with an anti-PD-1, anti-PD-L1/2, anti-CD137, CTLA-4 modulators or any other immune-modulating agents ; patients receiving live vaccine within 30 days prior to the first infusion of study treatment are not eligible;
- ♦No current participation in a interventional clinical trial or treatment with an investigational agent or use of an investigational device within 4 weeks of the first infusion of study treatment;
- ♦ No known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive). No known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay;
- ♦ No chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 3 days prior to the first infusion of trial treatment:
- ♦ Confirmed UICC v7 stage IB with T ≥ 4 cm, II-IIIA NSCLC after complete surgical resection (lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy) as documented in the pathology report; (Note: TNM stage according to the 7th edition of the TNM classification for lung cancer)
- ♦ Availability of tumor sample obtained at surgical resection for PD-L1 Immunohistochemistry (IHC) expression assessment. Patients must submit the tumor sample during screening for PDL1 IHC expression testing at a central pathology laboratory. Patients will be eligible to participate regardless of the level of PD-L1 status, however tissue must be considered satisfactory for characterization of PD-L1 status. Patients whose samples are inadequate for PD-L1 determination will not be randomized;
- ♦ Resection margins proved microscopically free (R0); Resection margins are evaluated at the bronchial, venous and arterial stumps, peribronchial soft tissue, any peripheral margin near the tumor or of additionally resected tissue;
- ♦ A systematic complete mediastinal lymph node dissection or a lobe-specific mediastinal lymph node dissection is recommended. At a minimum, the pathology and/or operative report must include the examination of at least two different mediastinal lymph node (N2) levels, one of which is the subcarinal (level 7) and the second of which is lobespecific;
- ♦ In the uncommon clinical situation where the surgeon thoroughly examines a particular mediastinal lymph node level and does not find any lymph nodes, that mediasintal lymph node level may be counted among the minimum two required levels. However, the surgeon must clearly document in the operative report or in a separate written statement that the lymph node level was explored and no lymph nodes were present. Normal appearing lymph nodes, if present, must be biopsied or/removed; No extracapsular extension of tumor in resected mediastinal (N2) lymph nodes. Extracapsular tumor extension is permitted in resected N1 lymph nodes;
- ♦ The highest mediastinal node removed can be positive for malignancy;
- ♦ Carcinoma in situ can be present at bronchial margin;
- ♦ Patients with two synchronous primary non-small cell lung cancers are excluded from the study;
- ♦ Corticosteroid use on study for management of ECIs (pembrolizumab Event of Clinical Interest), as premedication for the administration of chemotherapies, and/or a premedication for IV contrast allergies/reactions is allowed;
- ♦ Corticosteroid use on study for management of ECIs (pembrolizumab Event of Clinical Interest), as premedication for the administration of chemotherapies, and/or a premedication for IV contrast allergies/reactions is allowed;
- ♦ Daily prednisone at doses of 5-7.5 mg is allowed as an example of replacement therapy. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy;
- ♦ Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are preferred; if submitting unstained slides, the slides must be freshly cut and submitted to the central testing laboratory;
- ♦ At least 18 years;
- Central confirmation of PD-L1 status - step 2 This central confirmation through EORTC is required for enrolling the patient in step 3.
- Randomization - step 3 (ORTA step 2) ♦ Before patient randomization, written informed consent (‘Main Study’) for participation in the study must be given according to ICH/GCP, and national/local regulations;
- ♦ No evidence of disease (NED) at clinical examination and baseline radiological assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination within 12 weeks prior to the randomization date;
- ♦ Adjuvant chemotherapy is not mandatory but considered for patients with stage IB (T ≥ 4 cm) and strongly recommended for stage II and IIIA, and will be administered according to national and local guidelines. Patients who received more than 4 cycles of adjuvant therapy are not eligible;
- ♦ Patients not receiving adjuvant chemotherapy must be randomized and dosed with pembrolizumab/placebo within 12 weeks of their surgery date.
- ♦ No history of interstitial lung disease (ILD) OR a history of (noninfectious) pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis;
- ♦ No active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Any replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement are also allowed;
- ♦ No history of a hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible; Note: prior radiotherapy for another malignancy (breast cancer/lymphoma/germ cell tumors, etc.) is not an exclusion criterion, the same applies for prior anti-cancer systemic chemotherapy.
- ♦ No previous allogeneic tissue/solid organ transplant;
- ♦ No active infection requiring therapy;
- ♦ No surgery or chemotherapy related toxicity (non-hematological, toxicity resolved to grade 1 , with the exception of alopecia, fatigue, neuropathy and lack of appetite /nausea);
- ♦ Female patients with childbearing potential must have a negative urine or serum pregnancy test at screening (within 72 hours of first infusion of study medication). If the urine test cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as (by other than medical reasons);
- ♦ ≥45 years of age and has not had menses for greater than 1 year;
- Amenorrheic for > 2 years without a hysterectomy and oophorectomy and an FSH value in the postmenopausal range upon pretrial (screening) evaluation;
- ♦ Whose status is post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the subject must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last infusion of study treatment. Information must be captured appropriately within the site's source documents;
- ♦ If of childbearing potential, female patients must be willing to use two adequate barrier methods throughout the study, starting with the screening visit up to 120 days after last infusion of chemotherapeutic and investigational agents as specified in the protocol; Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- ♦ Male patients with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods throughout the trial starting with the screening visit through 120 days after the last infusion of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner;
- ♦ Female patients who are breast feeding must discontinue nursing prior to the first infusion of study treatment and until 120 days after the last study treatment;
- ♦ Absence of severe comorbidities that in the opinion of the Investigator might hamper the participation to the study and/or the treatment administration;
Exclusion Criteria
- Not available. According to study design, all exclusion criteria are included within inclusion criteria.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 10 Nov 2015 | 9 |
 Belgium | Not Recruiting | 10 Nov 2015 | 18 |
 Czechia | Not Recruiting | 10 Nov 2015 | 35 |
 Denmark | Not Recruiting | 10 Nov 2015 | 10 |
 Estonia | Not Recruiting | 10 Nov 2015 | 28 |
 France | Not Recruiting | 10 Nov 2015 | 31 |
 Germany | Not Recruiting | 10 Nov 2015 | 56 |
 Greece | Not Recruiting | 10 Nov 2015 | 19 |
 Hungary | Not Recruiting | 10 Nov 2015 | 9 |
 Ireland | Not Recruiting | 10 Nov 2015 | 17 |
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 USE | 200 | 52 | PRD4323105 |
Sodium chloride | Placebo | N/A | — | — | — | N/A |