Randomized Phase II-III Trial of Maintenance Pembrolizumab ± Pemetrexed Versus Observation ± Pemetrexed in Stage IV Non-Small Cell Lung Cancer Post-Induction Therapy
- Trial ID
- 2024-515945-40-00
- Protocol
- IFCT-2103
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of pembrolizumab or observation, with or without pemetrexed, following a 6-month induction treatment in patients with stage IV Non-Small Cell Lung Cancer (NSCLC). This evaluation is clinically relevant as it aims to determine the potential benefits of continued pembrolizumab therapy in maintaining disease control after initial treatment, which could inform treatment strategies for NSCLC.
Secondary objectives include:
- Evaluating the **tolerance** of pembrolizumab or observation, with or without pemetrexed, after the induction treatment.
- Assessing the **quality of life** of patients receiving pembrolizumab or observation, with or without pemetrexed, post-induction treatment.
- Evaluating the efficacy of pembrolizumab or observation, with or without pemetrexed, according to the histological subtype (squamous cell carcinoma vs. non-squamous) and according to PD-L1 tumor level.
Participants
The clinical trial focuses on evaluating the efficacy of pembrolizumab or observation in patients with **non-small cell lung cancer**. The study population includes both male and female participants, aged between 18 and 74 years, with a confirmed diagnosis of metastatic non-small cell lung cancer (Stage IV). Participants are required to have an Eastern Cooperative Oncology Group Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes individuals who have not received prior systemic anticancer therapy for advanced or metastatic disease. Participants must have measurable tumor disease as per RECIST 1.1 criteria and a life expectancy of more than three months. The trial population was selected based on specific inclusion criteria, including adequate biological functions and tumor tissue availability for molecular analysis. Lifestyle considerations such as weight loss of less than 10% within three months of study entry are noted. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **pembrolizumab** or observation, with or without **pemetrexed**, following a 6-month induction treatment in patients with stage IV **non-small cell lung cancer** (NSCLC). This is a phase II-III randomized, double-blind, controlled trial. The trial aims to assess the overall survival (OS) and progression-free survival (PFS) among participants, with primary endpoints including 18-month OS from inclusion and OS from the randomization date. Secondary endpoints focus on the time until definitive health-related quality of life score deterioration and PFS at 6 months, stratified by histological subtype and PD-L1 tumor expression levels.
The trial is expected to last until December 31, 2034, with recruitment having commenced on May 4, 2022. Participants will be involved in the study for a maximum treatment period of 104 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 adverse events, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have histologically confirmed metastatic NSCLC, an ECOG performance status of 0 or 1, and measurable tumor disease, among other conditions. Exclusion criteria are not specified in the provided data.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial involves the administration of **pembrolizumab** and other chemotherapeutic agents such as **carboplatin**, **paclitaxel**, and **cisplatin**, delivered via infusion or intravenous injection. The study is not categorized as low intervention and is conducted under commercial confidentiality. The trial's main objective is to determine the efficacy of maintenance therapy with **pembrolizumab** in prolonging survival and maintaining quality of life in patients with advanced NSCLC.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Pemetrexed** is utilized as a **solution for infusion** with a maximum daily dose of 500 mg/m² and a total dose of 17,500 mg/m² over a maximum treatment period of 24 weeks. The route of administration is via **infusion**, and the substance is chemically synthesized.
**Carboplatin** is administered as a **solution for infusion** with a maximum daily dose of 900 mg and a total dose of 3,600 mg over a 12-week period. The administration is conducted through **infusion**, and the substance is derived from chemical synthesis.
**Paclitaxel** is provided as a **solution for infusion** with a maximum daily dose of 175 mg/m² and a total dose of 700 mg/m² over a 12-week period. The administration route is **infusion**, and the substance is chemically synthesized.
**Cisplatin** is administered as a **solution for infusion** with a maximum daily dose of 75 mg/m² and a total dose of 300 mg/m² over a 12-week period. The administration is via **infusion**, and the substance is chemically synthesized.
**Pembrolizumab**, marketed as **Keytruda 25 mg/mL concentrate for solution for infusion**, is used as a **biological** treatment. It is administered with a maximum daily dose of 200 mg and a total dose of 200 mg over a 104-week period. The route of administration is **infusion**. Pembrolizumab is also used as a comparator treatment with a maximum total dose of 1,800 mg over a 6-week period, administered via **intravenous injection**.
Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules. The trial evaluates the efficacy of pembrolizumab or observation, with or without pemetrexed, following a 6-month induction treatment in patients with stage IV Non-Small Cell Lung Cancer (NSCLC).
Efficacy
The efficacy of the clinical trial will be assessed through a series of predefined **endpoints**. The primary endpoints include the 18-month overall survival (OS) from inclusion in both arms and the overall survival from the randomization date. Secondary endpoints will evaluate the time until definitive Health Related Quality of Life (HRQol) score deterioration, progression-free survival (PFS) from randomization at 6 months in both arms, overall survival according to the histological subtype (squamous cell carcinoma vs. non-squamous), overall survival according to PD-L1 tumor level of expression in each arm, and progression-free survival from randomization at 6 months according to PD-L1 tumor level of expression in each arm.
The trial will involve the administration of **pembrolizumab** or observation (squamous) ± **pemetrexed** (non-squamous carcinoma) following a 6-month induction treatment. The efficacy parameters will be measured and collected at specific timepoints, with the primary focus on survival rates and quality of life metrics. The analysis will be conducted using validated scales and methodologies appropriate for assessing overall survival and progression-free survival in patients with stage IV Non-Small Cell Lung Cancer (NSCLC).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed Written Informed Consent: • Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. • Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
- Patients with histologically confirmed metastatic NSCLC (Stage IV accordingly to 8th classification TNM, UICC 2015). A cytologically-proven NSCLC is allowed if a cytoblock has been prepared.
- PD-L1 tumor content as assessed locally by the investigator center.
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
- Weight loss< 10% within 3 months of study entry.
- No prior systemic anticancer therapy (including EGFR or ALK inhibitors) given as primary therapy for advanced or metastatic disease.
- Age≥ 18 years, <75 years
- Life expectancy > 3 months
- Measurable tumor disease by CT or MRI per RECIST 1.1 criteria
- The Investigator must confirm prior to enrolment that the patient has adequate tumor tissue available. Tumor biopsy should be exploitable for molecular analysis. If archival tissue is either insufficient or unavailable, the patient may still be eligible upon discussion with IFCT. Note: Tumor tissue collected after the patient was diagnosed with metastatic disease is preferred. Tumor tissue sample must not be from locations previously radiated. Tumor sample must be 1 block or at least 7 unstained slides of analyzable tissue.
- Adequate biological functions: Creatinine Clearance ≥ 45 mL/min (Cockroft or MDRD or CKD-epi); neutrophils≥ 1500/mm3 ; platelets ≥100 000/mm3 ; Hemoglobin≥ 9g/dL ; AST and ALT< 3x ULN, total bilirubin < 2xULN (patients with hepatic metastases or Gilbert’s syndrome must have AST and ALT ≤ 5 x ULN and a baseline total bilirubin ≤ 2xULN).
- Women of childbearing potential (WOCBP) and sexually active should use an efficacious contraception method within the 28 days preceding the first dose and during the 6 months following the last dose of treatment. Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) prior to the start of study drug.
- For Male subjects who are sexually active with WOCBP, an efficacious contraception method should be used during the treatment and during the 6 months following the last dose.
- Patient has national health insurance coverage.
Exclusion Criteria
- Small cell lung cancer or tumors with mixed histology including a SCLC component. Note : Sarcomatoid histology is allowed. Neuro-endocrine large cell lung cancer with molecular features of small-cell lung cancer (i.e; Rb loss associated with TP53 mutation) will not be eligible. Other neuro-endocrine large cell subtypes, i.e. with adenocarcinoma features (STK11 or K-Ras mutations) will be eligible. In case of doubt, please contact the sponsor.
- Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861X mutations in exon 21, G719A/S mutation in exon 18, exon 20 insertion) or HER2 exon 20 insertion (either tissue or plasma cfDNA mutation).
- Known ALK, ROS1, Ret, NTRK, NRG1 gene rearrangement as assessed by immunohistochemistry, FISH or NGS (ADN or ARN) sequencing by local genetics and/or pathology laboratory.
- Previous or active cancer within the previous 3 years (except for treated carcinoma in situ of the cervix, or basal cell skin cancer treated or not). Patients with a prostate adenocarcinoma history within the previous 3 years could be included in case of localized prostate cancer, with good prognostic factors according to d'Amico classification (≤T2a, score de Gleason ≤ 6 and PSA ≤ 10 (ng/ml)) provided they were treated in a curative way (surgery or radiotherapy, without any chemotherapy).
- Superior vena cava syndrome persisting despite VCS stenting.
- Radiotherapy needed at initiation of tumour treatment, except bone palliative radiotherapy on a painful or compressive metastasis, respecting 1-week delay between the end of radiotherapy and the beginning of treatment
- Symptomatic untreated brain metastasis (without previous whole brain radiotherapy or stereotactic ablative brain radiotherapy or without surgical resection). At least 2 weeks delay between the end of radiotherapy and the beginning of induction immunotherapy treatment should be respected. Asymptomatic brain metastasis, not needing corticosteroids greater than 10 mg prednisone equivalent daily or mannitol infusions, are allowed.
- History of previous primary immunodeficiency, organ transplantation needing an immunosuppressive treatment, any immunosuppressive drug within 28 days before randomization date, or history of severe toxicity (grade 3/4) by immune mechanism linked to another immunotherapy treatment.
- Systemic treatment with corticosteroids with greater dose than 10 mg prednisone equivalent daily, within 14 days before initiation of the immunotherapy induction. Inhaled, nasal or topic corticosteroids are allowed.
- History of active autoimmune disease including but not limited to rheumatoid polyarthritis, myasthenia, autoimmune hepatitis, systemic Lupus, Wegener's granulomatosis, vascular thrombosis associated with antiphospholipid syndrome, Sjogren’s syndrome with interstitial pulmonary disease, recent Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with type I diabetes, or hypothyroidy, or immune cutaneous disease (vitiligo, psoriasis, alopecia) or benign rheumatoid polyarthritis not needing any immunosuppressive systemic treatment, or benign sicca syndrome (Sjogren) without interstitial pulmonary disease, or history of past Guillain-Barre syndrome, totally reversible with no sequalae, no systemic immunosuppressive treatment during the last 20 years, are allowed to be included.
- Active inflammatory intestinal disease (Crohn disease, Hemorrhagic recto-colitis, coeliac disease) or any serious chronic intestinal disease with uncontrolled diarrhea.
- Active uncontrolled infection including tuberculosis, known acute viral hepatitis B and C according to serological tests. Patients with serological sequalae of cured viral hepatitis are allowed to be included. Past primary pulmonary tuberculosis in youth does not consist of a contra-indication. Past tuberculosis disease history does not consist of a contra-indication provided the patient was treated during at least 6 months by anti-tuberculosis antibiotic treatment.
- Known HIV infection
- Living attenuated vaccine received within the 30 previous days
- Previous treatment with anti-PD-1, anti-PD-L1, Anti-CTLA4 or any ICI antibody
- Previous treatment with chemotherapy for lung cancer. However, if a patient has a lung adenocarcinoma, previous cisplatin treatment for another cancer type with squamous histology (Head and Neck, bladder) may be allowed provided the sponsor accepts, and provided blood tests are normal (see above).
- General serious condition such as congestive uncontrolled cardiac failure, uncontrolled cardiac arrythmia, uncontrolled ischemic cardiac disease (unstable angina or history of myocardial infarction within the previous 6 months), history or stroke within the 6 previous months. Patients with a significant cardiac history, even if controlled, should have a LVEF > 50%.
- Pre-existing moderate or severe lung interstitial disease as assessed by the diagnosis CT-scan.
- Inability to comply with study and/or follow-up procedures for family, social, geographic or psychological reasons.
- Pregnant, lactating, or breastfeeding women.
- Patients deprived of liberty by judicial or administrative decision
- Patient who is subject to legal protection or who is unable to express his will
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 04 May 2022 | 1360 |
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 |
|---|---|---|---|---|---|---|
PACLITAXEL | Comparator | — | INTRAVENOUS INJECTION | 175 | 12 | SUB09583MIG |
CISPLATIN | Test | — | INFUSION | 75 | 12 | SUB07483MIG |
CARBOPLATIN | Comparator | — | INTRAVENOUS INJECTION | 900 | 12 | SUB06614MIG |
CISPLATIN | Comparator | — | INTRAVENOUS INJECTION | 75 | 12 | SUB07483MIG |
CARBOPLATIN | Test | — | INFUSION | 900 | 12 | SUB06614MIG |
PACLITAXEL | Test | — | INFUSION | 175 | 12 | SUB09583MIG |
PEMBROLIZUMAB | Comparator | — | INTRAVENOUS INJECTION | 200 | 6 | SUB167136 |
PEMETREXED | Test | — | INFUSION | 500 | 24 | SUB09655MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 200 | 104 | PRD4323105 |
PEMETREXED | Comparator | — | INTRAVENOUS INJECTION | 500 | 24 | SUB09655MIG |