Morning versus afternoon pembrolizumab administration with carboplatin-pemetrexed in stage IV non-squamous NSCLC: randomized phase III trial
- Trial ID
- 2025-521891-78-00
- Protocol
- APHP241011
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to assess the efficacy of initiating pembrolizumab in the morning versus the afternoon in adults with stage IV non-squamous non-small cell lung cancer receiving first-line pembrolizumab plus carboplatin and pemetrexed, with 1-year survival rate as the main endpoint. Clinically, this evaluates whether the time of administration influences short-term survival benefit in metastatic disease. Secondary objectives include comparison of progression-free survival, overall survival, best tumor response rate, early tumor response rate, time to treatment discontinuation and cause of withdrawal, worst toxicity grades by category and by patient with time to onset, quality of life, quality of sleep, chronotype, optimal time of administration by mathematical modelling, and cost-utility.
Participants
The sponsor did not provide the total number of participants. The study population consisted of adult patients with stage IV non-squamous non-small cell lung cancer, including both female and male participants aged 18 years and older. Participants were selected from patients with histologically or cytologically confirmed metastatic disease, measurable disease, no prior systemic treatment for advanced or metastatic disease, adequate organ function, and an ECOG performance status of 0 or 1. Additional eligibility requirements included a life expectancy of at least 3 months, confirmation that EGFR- or ALK-directed therapy was not indicated, or the presence of a K-Ras mutation. Relevant lifestyle considerations were not provided.
Plans and Procedures
This is a randomized, multicenter, phase III clinical trial in adult patients with stage IV non-squamous non-small cell lung cancer. The study evaluates first-line treatment with pembrolizumab in combination with carboplatin and pemetrexed, with randomization based on the time of day of pembrolizumab administration, in the morning or in the afternoon. The main objective is to assess the effect of administration timing on 1-year survival rate. Trial participation begins with a screening visit to confirm eligibility criteria, including disease status, prior treatment history, performance status, organ function, and other protocol requirements. After enrollment and randomization, treatment and follow-up visits are performed according to the protocol to assess efficacy, safety, tumor response, quality of life, sleep, and chronotype. An end-of-study visit is performed at treatment completion or study discontinuation. Participant involvement is expected to last up to 1 year of assessment, within an overall trial period from June 2026 to January 2030. Early termination may occur because of disease progression, unacceptable toxicity, loss to follow-up, refusal, end of protocol, or death.
Treatment
The trial used pemetrexed as an intravenous formulation at a dose of 500 mg/m2, pembrolizumab as a solution for infusion at a dose of 250 mg by intravenous administration, and carboplatin as an intravenous formulation at a dose of 750 mg. All three products were administered as test treatments in the study. Pembrolizumab administration was scheduled in the morning, defined as 08:00 to 12:00, or in the afternoon, defined as 13:00 to 17:00, according to the randomized assignment. The study evaluated the effect of the time of pembrolizumab administration on 1-year survival rate. No non-experimental comparator treatment or placebo was specified in the source data. No additional information on dosing frequency, treatment cycle, or compliance monitoring was provided.
Efficacy
Efficacy will be assessed primarily by the 1-year milestone survival rate, defined as the survival probability at one year. Secondary efficacy assessments will include progression-free survival, defined as the time from randomisation to all-cause death or tumour progression, whichever occurs first, and overall survival, defined as the time from randomisation to all-cause death. Tumour activity will also be evaluated by best tumour response rate according to RECIST criteria over 1 year, using TAP/brain scan and/or PET scan and/or MRI. Early response rate according to RECIST criteria will be assessed at the first evaluation, usually at 6 weeks, using TAP/brain scan and/or PET scan and/or MRI. Time to treatment discontinuation will be measured from randomisation until treatment stop for any cause. The analysis will also include progression-free survival and overall survival as a function of the real time of pembrolizumab infusion start, treated as a continuous variable.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient with a histologically-confirmed or cytologically confirmed diagnosis of stage IV (M1a or M1b- AJCC 7th edition) non-squamous NSCLC.
- Patient with a confirmation that EGFR or ALK-directed therapy is not indicated (documentation of absence of tumor activating EGFR mutations AND absence of ALK gene rearrangements) OR presence of a K-Ras mutation.
- Patient with a measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment
- Patient who have not received prior systemic treatment for their advanced/metastatic NSCLC. Subjects who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
- Patient who have provided tumor tissue from locations not radiated prior to biopsy; formalin fixed specimens after the subject has been diagnosed with metastatic disease will be preferred for determination of PD-L1 status prior to randomisation. Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible.
- Patient ≥18 years of age on the day of signing informed consent.
- Patient with a life expectancy of at least 3 months.
- Patient with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
- Patient who have adequate organ function (CBC, liver and kidney)
- If female of childbearing potential, be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents as specified in the protocol.
- If male subject with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception.
- Patient who has voluntarily agreed to participate by giving written informed consent for the trial.
- Patient with an affiliation to French social security system
Exclusion Criteria
- Patient with predominantly squamous cell histology NSCLC.
- Patient who is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab.
- Before the first dose of trial treatment: a) Patient Has received prior systemic cytotoxic chemotherapy for metastatic disease b) Patient Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, cetuximab) c) Patient Had major surgery ( 30 Gy within 6 months of the first dose of trial treatment.
- Patient who received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment
- Patient who completed palliative radiotherapy within 7 days of the first dose of trial treatment.
- Patient who is expected to require any other form of antineoplastic therapy while on study.
- Patient who has received a live-virus vaccination within 30 days of planned treatment start.
- Patient who has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis.
- Patient who has a known history of prior malignancy except if the subject has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
- Patient who has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Patient who previously had a severe hypersensitivity reaction to treatment with another mAb.
- Patient who has a known sensitivity to any component of carboplatin or pemetrexed
- Patient with Contraindication to investigational medicinal products or to auxiliary medicinal products
- Patient who has active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
- Patient who is on chronic systemic steroids. Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
- Patient who is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤ 1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
- Patient who is unable or unwilling to take folic acid or vitamin B12 supplementation.
- Patient who had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms.
- Patient who has an active infection requiring therapy.
- Patient who has known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive).
- Patient who has known active Hepatitis B or C.
- Patient who has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
- Patient who has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
- Patient who has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management.
- Patient who is pregnant or breastfeeding, or expecting to conceive or father children with in the projected duration of the study
- Patients under AME
- Adults subject to a legal measure protection (guardianship, curatorship and safeguard of justice)
- Patients deprived of their liberty by a judicial or administrative decision
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 01 Jun 2026 | 254 |
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 |
|---|---|---|---|---|---|---|
PEMETREXED | Test | PHF00230MIG | INTRAVENOUS | 500 | 12 | SCP111841108 |
CARBOPLATIN | Test | PHF00230MIG | INTRAVENOUS | 750 | 12 | SCP10337134 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 250 | 12 | PRD12081132 |