PEmbRolizumab verSus chEmotherapy and pEmbrolizumab in Non-small-cell Lung Cancers (NSCLC) With PDL1 ≥ 50 %

Study Overview
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Brief Summary
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PERSEE is a French national phase 3 academic study comparing the chemotherapy-pembrolizumab combination to pembrolizumab alone as a first-line treatment for advanced NSCLC molecularly defined by a PDL1 expression ≥ 50% of tumour cells and no EGFR mutations or ALK rearrangement. The main hypothesis is the superiority of the chemo-immunotherapy combination over mono-immunotherapy in terms of progression-free survival evaluated by an independent review committee. One of the anticipated benefits of using the chemotherapy-pembrolizumab combination starting from the first line setting for NSCLC patients with PD L1 ≥ 50% is a reduced risk of early progression, which is known to occur with pembrolizumab monotherapy, and therefore, a better PFS.

Detailed Description
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PERSEE is a french academic, prospective, randomized, controlled and open-label phase 3 study. This trial compares the combination of chemotherapy and pembrolizumab with pembrolizumab alone as first-line treatment for advanced NSCLC molecularly characterized by a PDL1 expression level ≥ 50% and no EGFR mutations or ALK rearrangement. This is a strategy trial whose primary objective is to evaluate the superiority of the chemotherapy-pembrolizumab combination over pembrolizumab using PFS as the primary endpoint as evaluated by an independent review committee. PERSEE trial is planned to include 292 patients treated at approximately 30 GFPC-affiliated or GFPC-associated centres. After the screening period, patients will be randomized on a 1:1 basis to the Chemotherapy Immunotherapy Arm or the Immunotherapy Arm. Randomization will be stratified according to tumor histology (squamous versus non squamous) and according to the presence or absence of brain metastases. Patients enrolled in this study will receive either of the following treatment regimens: Chemotherapy-Immunotherapy Arm: Four induction cycles once every 3 weeks associating, on the first day of each cycle: Cisplatin 75 mg/m² or carboplatin area under the curve (AUC) 5 mg/mL/min, pemetrexed 500 mg/m² and pembrolizumab 200 mg for non-squamous NSCLC. Carboplatin AUC 6 mg/mL/min, paclitaxel 200 mg/m² and pembrolizumab 200 mg for squamous NSCLC. After the 4 induction cycles, a maintenance therapy will be possible for patients who are responding or stable, as follows: Non squamous NSCLC: pembrolizumab and pemetrexed combination or either drug as monotherapy (if toxicity has been identified for one of them). Squamous NSCLC: pembrolizumab monotherapy. For pembrolizumab: treatment may be continued for a maximum of 35 cycles or until disease progression, death, unacceptable toxicity, or following the Investigator's or the patient's decision to stop. For pemetrexed, treatment may be continued until disease progression, death, unacceptable toxicity, or following the Investigator's or the patient's decision to stop. Immunotherapy Arm: Pembrolizumab 200 mg once every 3 weeks for a maximum of 35 cycles or until disease progression, death, unacceptable toxicity, or the Investigator's or the patient's decision to stop. Evaluations will be performed every 6 weeks (±7 days) during the first 4 cycles in both treatment arms, then every 9 weeks (±7 days) for the first 12 months since D1 of cycle 1 and every 12 weeks (±7 days) thereafter. Evaluations will include: tumor assessment according to RECIST v1.1, survival status, concomitant medications and AE recording. QoL/PRO questionnaires will be performed at each cycle for the first 5 cycles in both treatment arms, then every 9 weeks (±7 days) for the first 12 months since D1 of cycle 1 and every 12 weeks (±7 days) thereafter. The length of the inclusion period is 36 months (3 years). The total study duration per patient will be a maximum of two years for the last patients included, and a maximum of five years for the first patients included (i.e. End-of-study Time Point for surviving patients) The total study duration includes the following: Screening Period: up to 28 days. Treatment Period: up to 60 months. Post-study Follow up Period: until death or lost to follow-up.

Official Title
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Randomized, Open-label, Controlled Phase III Trial Comparing Pembrolizumab-platinum Based Chemotherapy Combination With Pembrolizumab Monotherapy in First Line Treatment of Non-small-cell Lung Cancers (NSCLC) With PDL1 Expression ≥50%

Conditions
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Non-small-cell Lung Cancer

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Pembrolizumab and Chemotherapy drugs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older at diagnosis. Histologically or cytologically confirmed NSCLC. Stage IV NSCLC. Unresectable and non-eligible to radiotherapy stage III NSCLC are permitted. For non-squamous NSCLCs and non-smoking squamous NSCLCs, no known activating mutations of EGFR and no ALK or ROS-1 rearrangements. PD-L1 expression on ≥ 50 % of tumor cells, which will be determined locally. No prior systemic treatment for lung cancer. Patients who received adjuvant therapy are eligible if the adjuvant therapy was completed at least 12 months prior to the development of metastatic disease. Palliative radiotherapy completed within one day before randomization (stereotaxic or not) is authorized. At least 1 target lesion in a non-irradiated area, measurable according to RECIST v1.1. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1. Life expectancy >12 weeks. Patients with brain metastases at inclusion are accepted, provided that these metastases are asymptomatic, or symptomatic but treated (surgery or radiotherapy without or with corticosteroids ≤10 mg/day), and that they are stable on the day of inclusion. No history of other malignant tumor during the previous 5 years, except for adequately treated carcinomas (in situ cervical carcinoma, basal cell carcinoma, squamous cell skin carcinoma) and low grade localized prostate cancer (Gleason <6). Adequate organ function, as demonstrated by laboratory results within 7 days prior to the first administration of study treatment: Normal hepatic function: bilirubin ≤1.5 x upper limit of normal (ULN), alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) ≤2.5 x ULN or ≤5 x ULN in case of liver metastases Normal renal function: calculated creatinine clearance (CrCl, using local formula) of at least 60 mL/min for cisplatin or 45 ml/mn for carboplatin Normal hematological function: absolute neutrophil count ≥1.5 giga/L and/or platelets ≥100 giga/L, hemoglobin ≥8 g/dL Normal coagulation function: International Normalized Ratio (INR) or prothrombin time ≤1.5 x ULN and activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless the patient is receiving anticoagulant therapy. For patients of childbearing potential: use of an adequate method of contraception during the course of the study through 180 days after the last dose of study treatment (women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first administration of study treatment). Note: Abstinence is acceptable if this is the usual lifestyle and the patient's preferred contraception. For male subjects, male condom or abstinence are acceptable. Signed informed consent to participate in the study Affiliation with or benefit from French social security. Exclusion criteria : NSCLC with expression of PD-L1 <50%. NSCLC with known activating mutation of EGFR or ALK or ROS-1 translocation. Neuroendocrine tumor. In cases of mixed tumors, if small cell elements are present, the patient is ineligible. Any previous treatment with immunotherapy regardless of the line of treatment. Before the first dose of study treatment: Has received prior systemic treatment for metastatic disease (chemotherapy or targeted therapy). Had major surgery <3 weeks prior to first dose. Received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study treatment. Uncontrolled and untreated superior cava syndrome. Untreated and unstable symptomatic brain metastases. Leptomeningeal disease. Serious concurrent conditions during the previous 6 months (severe or unstable angina pectoris, coronary or peripheral artery bypass graft of <6 months, class 3 or 4 congestive heart failure, ischemic stroke, grade ≥2 peripheral neuropathy, psychiatric or neurological disorders that may interfere with the patient's understanding of the study or with his/her informed consent. Severe or non controlled systemic diseases deemed incompatible with the protocol. Severe infections within 4 weeks prior to inclusion, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Other previous or concomitant cancers, with the exception of basal cell carcinoma, squamous cell skin carcinoma, in situ cervical carcinoma treated, and low grade localized prostate cancer (Gleason score <6) if appropriately treated, unless the initial tumor has been diagnosed and definitively treated >5 years prior to the study, with no signs of relapse. Psychological, family, social, or geographical factors that may interfere with the monitoring of the patient as defined by the protocol. Any protected person (legal person protected by legal protection [guardianship, tutorship], person deprived of liberty, pregnant woman, breastfeeding woman, and minor). Patients who participated in other concomitant studies unless observational and received study therapy or used an investigational device within 4 weeks prior to start of study treatment. Known or suspected active autoimmune disease requiring an immunosuppressive therapy during the previous 6 months (corticosteroids or other immunosuppressive treatment). Any hormone replacement therapy (i.e. thyroxine [T4], insulin, or replacement systemic corticosteroids for adrenal or pituitary insufficiency, etc.) is not considered an immunosuppressive treatment and is authorized. Patients with hyperthyroidism or hypothyroidism who are stable under hormone replacement therapy may also be included. Chronic use of immunosuppressive drugs and/or corticosteroids (>10 mg of prednisone daily). However, during the 14 days prior to randomization the use of the following is authorized: Corticosteroids as pre treatment for the administration of chemotherapy and/or for allergies or type IV hypersensitivity responses Daily prednisone (≤10 mg) as replacement therapy Inhaled or topical steroids. Live-virus vaccination within 30 days of planned start of study treatment (seasonal flu vaccines that do not contain live virus are permitted). Previous allogenic tissue or organ transplant. History of human immunodeficiency virus (HIV) infection (positive HIV1/2 antibody test results). Active hepatitis B or C. Previous history of interstitial lung disease (ILD) or non infectious pneumonia (other than chronic obstructive pulmonary disease [COPD]), requiring oral or systemic steroids, current pneumonia, or anticipated ILD. Known allergies or adverse reactions to the study drugs or hypersensitivity reaction to treatment with another monoclonal antibody (mAb).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A national, multicenter, phase III, prospective, open label, 1:1 randomized, interventional study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pembrolizumab<br>Pembrolizumab | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg once every 3 weeks for a maximum of 35 cycles or until disease progression, death, unacceptable toxicity, or the Investigator's or the patient's decision to stop.<br>|
| Active Comparator: Chemotherapy-Pembrolizumab<br>Chemotherapy and Pembrolizumab | Drug: Pembrolizumab and Chemotherapy drugs<br>* An induction therapy followed by a maintenance therapy. 4 induction cycles every 3 weeks associating, on the first day of each cycle: Cisplatin 75mg/m² or carboplatin AUC 5mg/mL/min, pemetrexed 500mg/m² and pembrolizumab 200mg for non squamous NSCLC. Carboplatin AUC 6mg/mL/min, paclitaxel 200mg/m² and pembrolizumab 200mg for squamous NSCLC. After the 4 induction cycles, a maintenance therapy will be possible for patients who are responding or stable: Non squamous NSCLC: pembrolizumab and pemetrexed combination or either drug as monotherapy. Squamous NSCLC: pembrolizumab monotherapy. For pembrolizumab: treatment may be continued for a maximum of 35 cycles or until disease progression, death, unacceptable toxicity, or following the Investigator's or the patient's decision to stop. For pemetrexed, treatment may be continued until disease progression, death, unacceptable toxicity, or following the Investigator's or the patient's decision to stop.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) according to RECIST 1.1 assessed by blinded inependant centra review (BICR) | Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, according to RECIST 1.1 assessed by blinded inependant centra review (BICR) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival according to RECIST 1.1 evaluated by investigators | Time from date of randomization until the date of first documented progression or death from any cause, whichever came first, according to RECIST v1.1 and evaluated by investigators | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | 
| Progression-free survival according to iRECIST assessed by blinded inependant centra review (BICR) | Time from date of randomization until the date of first documented progression or death from any cause, whichever came first, according to iRECIST assessed by blinded inependant centra review (BICR) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first assessed up to 60 months | 
| Objective Response Rate (ORR) | Proportion of patients who achieved a complete response (CR) or partial response (PR) according to RECIST v1.1 from the date of first treatment administration until disease progression or the introduction of a new treatment. | From date of first treatment administration until the date of first documented progression or death or the introduction of a new treatment, whichever came first, assessed up to 60 months | 
| Overall survival (OS) | Time from date of randomization until the date of death from any cause. | From date of randomization until the date of death from any cause assessed up to 60 months | 
| Duration of treatment (DOT) | Time from the first treatment administration until the date of last treatment administration. | From date of the first treatment administration until the date of last treatment administration, up to 60 months | 
| Duration of objective response (DOR) | Time from the first documented objective response (CR or PR) until the date of disease progression or death, whichever came first. | From date of the first documented objective response (CR or PR) until the date of first documented progression or death from any cause, whichever came first, assessed up to 60 months | 
| Adverse events (AE) | Proportion (%) of patients with any adverse event (AE) and number of events per treatment arm for all AEs, all serious AEs (SAEs) and all AEs of grade ≥3 according to the National Cancer Institute (NCI) Common terminology criteria for adverse events (CTCAE) v5.0 criteria. | Up to 30 days after the last dose of study treatment for non-serious AEs. Up to 100 days or 30 days if initiating new treatment, after the last dose, for SAE. | 
| Adverse events of special interest (AESI) | Proportion (%) of patients with any adverse event of special interest (AESI), defined as immune-related AE (IrAE), according to the National Cancer Institute (NCI) Common terminology criteria for adverse events (CTCAE) v5.0 criteria. . | Up to 100 days or 30 days if initiating new treatment, after the last dose. | 
| PFS in three subgroups of patients according to PD-L1 expression (50-74%, 75-100%, and 90-100%), presence or absence of brain metastasis and histology (squamous versus non squamous). | Time from date of randomization until the date of first documented progression or death from any cause, whichever came first, according to RECIST v1.1 | From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 60 months | 
| OS in three subgroups of patients according to PD-L1 expression (50-74%, 75-100%, and 90-100%), presence or absence of brain metastasis and histology (squamous versus non squamous). | Time from randomization until the date of death from any cause. | From date of randomization until the date of death from any cause assessed up to 60 months | 
| ORR in three subgroups of patients according to PD-L1 expression (50-74%, 75-100%, and 90-100%), presence or absence of brain metastasis and histology (squamous versus non squamous). | Proportion of patients who achieved a complete response (CR) or partial response (PR) according to RECIST v1.1 | From date of first treatment administration until the date of first documented progression or death or the introduction of a new treatment, whichever came first, assessed up to 60 months | 
| DOR in three subgroups of patients according to PD-L1 expression (50-74%, 75-100%, and 90-100%), presence or absence of brain metastasis and histology (squamous versus non squamous). | Time from the first documented objective response (CR or PR) until the date of disease progression or death, whichever came first. | From date of the first documented objective response (CR or PR) until the date of first documented progression or death from any cause, whichever came first, assessed up to 60 months | 
| DOT in three subgroups of patients according to PD-L1 expression (50-74%, 75-100%, and 90-100%), presence or absence of brain metastasis and histology (squamous versus non squamous). | Time from the first treatment administration until the date of last treatment administration. | From date of the first treatment administration until the date of last treatment administration, assessed up to 60 months | 
| AE in three subgroups of patients according to PD-L1 expression (50-74%, 75-100%, and 90-100%), presence or absence of brain metastasis and histology (squamous versus non squamous). | Proportion (%) of patients with any adverse event (AE) and number of events per treatment arm for all AEs, all serious AEs (SAEs) and all AEs of grade ≥3 according to the National Cancer Institute (NCI) Common terminology criteria for adverse events (CTCAE) v5.0 criteria. | Up to 30 days after the last dose of study treatment for non-serious AEs. Up to 100 days or 30 days if initiating new treatment, after the last dose, for SAE. | 
| AESI in three subgroups of patients according to PD-L1 expression (50-74%, 75-100%, and 90-100%), presence or absence of brain metastasis and histology (squamous versus non squamous). | Proportion (%) of patients with any adverse event (AE) and number of events per treatment arm for all AEs, all serious AEs (SAEs) and all AEs of grade ≥3 according to the National Cancer Institute (NCI) Common terminology criteria for adverse events (CTCAE) v5.0 criteria. | Up to 100 days or 30 days if initiating new treatment, after the last dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small-cell lung cancer, PDL1≥50%, advanced stage, Pembrolizumab, Chemotherapy-pembrolizumab combination