Clinical trial NCT04547504: PEmbRolizumab verSus chEmotherapy and pEmbrolizumab in Non-small-cell Lung Cancers (NSCLC) With PDL1 ≥ 50 %
Official title: 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%
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Non-small-cell Lung Cancer
Keywords: Non-small-cell lung cancer
PDL1≥50%
advanced stage
Pembrolizumab
Chemotherapy-pembrolizumab combination
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
Collaborators: name: Groupe Francais De Pneumo-Cancerologie
First posted: 2020-09-14
Enrollment: 349
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A national, multicenter, phase III, prospective, open label, 1:1 randomized, interventional study
Primary purpose: TREATMENT

Brief summary: 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: 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:

1. 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.
2. 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.

Eligibility criteria: Inclusion Criteria:

1. Age 18 years or older at diagnosis.
2. Histologically or cytologically confirmed NSCLC.
3. Stage IV NSCLC. Unresectable and non-eligible to radiotherapy stage III NSCLC are permitted.
4. For non-squamous NSCLCs and non-smoking squamous NSCLCs, no known activating mutations of EGFR and no ALK or ROS-1 rearrangements.
5. PD-L1 expression on ≥ 50 % of tumor cells, which will be determined locally.
6. 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.
7. Palliative radiotherapy completed within one day before randomization (stereotaxic or not) is authorized.
8. At least 1 target lesion in a non-irradiated area, measurable according to RECIST v1.1.
9. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.
10. Life expectancy \>12 weeks.
11. 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.
12. 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).
13. Adequate organ function, as demonstrated by laboratory results within 7 days prior to the first administration of study treatment:

    1. 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
    2. Normal renal function: calculated creatinine clearance (CrCl, using local formula) of at least 60 mL/min for cisplatin or 45 ml/mn for carboplatin
    3. Normal hematological function: absolute neutrophil count ≥1.5 giga/L and/or platelets ≥100 giga/L, hemoglobin ≥8 g/dL
    4. 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.
14. 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.
15. Signed informed consent to participate in the study
16. Affiliation with or benefit from French social security.

Exclusion criteria :

1. NSCLC with expression of PD-L1 \<50%.
2. NSCLC with known activating mutation of EGFR or ALK or ROS-1 translocation.
3. Neuroendocrine tumor. In cases of mixed tumors, if small cell elements are present, the patient is ineligible.
4. Any previous treatment with immunotherapy regardless of the line of treatment.
5. Before the first dose of study treatment:

   1. Has received prior systemic treatment for metastatic disease (chemotherapy or targeted therapy).
   2. Had major surgery \<3 weeks prior to first dose.
   3. Received radiation therapy to the lung that is \>30 Gy within 6 months of the first dose of study treatment.
6. Uncontrolled and untreated superior cava syndrome.
7. Untreated and unstable symptomatic brain metastases.
8. Leptomeningeal disease.
9. 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.
10. Severe or non controlled systemic diseases deemed incompatible with the protocol.
11. Severe infections within 4 weeks prior to inclusion, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
12. 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.
13. Psychological, family, social, or geographical factors that may interfere with the monitoring of the patient as defined by the protocol.
14. Any protected person (legal person protected by legal protection \[guardianship, tutorship\], person deprived of liberty, pregnant woman, breastfeeding woman, and minor).
15. 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.
16. 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.
17. 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:

    1. Corticosteroids as pre treatment for the administration of chemotherapy and/or for allergies or type IV hypersensitivity responses
    2. Daily prednisone (≤10 mg) as replacement therapy
    3. Inhaled or topical steroids.
18. Live-virus vaccination within 30 days of planned start of study treatment (seasonal flu vaccines that do not contain live virus are permitted).
19. Previous allogenic tissue or organ transplant.
20. History of human immunodeficiency virus (HIV) infection (positive HIV1/2 antibody test results).
21. Active hepatitis B or C.
22. 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.
23. Known allergies or adverse reactions to the study drugs or hypersensitivity reaction to treatment with another monoclonal antibody (mAb).

Primary outcomes:
measure: Progression-free survival (PFS) according to RECIST 1.1 assessed by blinded inependant centra review (BICR)
timeFrame: 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 outcomes:
measure: Progression-free survival according to RECIST 1.1 evaluated by investigators
timeFrame: 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
measure: Progression-free survival according to iRECIST assessed by blinded inependant centra review (BICR)
timeFrame: 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
measure: Objective Response Rate (ORR)
timeFrame: 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
measure: Overall survival (OS)
timeFrame: From date of randomization until the date of death from any cause assessed up to 60 months
measure: Duration of treatment (DOT)
timeFrame: From date of the first treatment administration until the date of last treatment administration, up to 60 months
measure: Duration of objective response (DOR)
timeFrame: 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
measure: Adverse events (AE)
timeFrame: 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.
measure: Adverse events of special interest (AESI)
timeFrame: Up to 100 days or 30 days if initiating new treatment, after the last dose.
measure: 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).
timeFrame: From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 60 months
measure: 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).
timeFrame: From date of randomization until the date of death from any cause assessed up to 60 months
measure: 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).
timeFrame: 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
measure: 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).
timeFrame: 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
measure: 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).
timeFrame: From date of the first treatment administration until the date of last treatment administration, assessed up to 60 months
measure: 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).
timeFrame: 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.
measure: 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).
timeFrame: Up to 100 days or 30 days if initiating new treatment, after the last dose.
Other outcomes:
measure: Early progression rate
timeFrame: Up to 6 weeks from the first day of treatment
measure: Following of the quality of life with European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Cancer patients.
timeFrame: Up to 60 months
measure: Following of the quality of life with European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Lung Cancer patients.
timeFrame: Up to 60 months
measure: Following of the quality of life with European Quality of life 5 dimensions and 3 Levels
timeFrame: Up to 60 months
measure: Exploratory analyses to identify novel biomarkers
timeFrame: From date of randomization until the date of first documented progression, assessed up to 60 months
measure: Progression-free survival 2 (PFS2) according to RECIST 1.1
timeFrame: time from randomization to tumor progression on second-line therapy, or death from any cause.
Locations:
city: Aix-en-Provence
country: France
facility: CH du Pays d'Aix
city: Amiens
country: France
facility: CHU AMIENS - Hôpital Sud
city: Angers
country: France
facility: Chu Angers
city: Brest
country: France
facility: CHRU de Brest
city: Caen
country: France
facility: Centre de lutte contre le cancer - Centre François Baclesse
city: Chambéry
country: France
facility: Centre Hospitalier Métropole Savoie
city: Créteil
country: France
facility: CH Intercommunal de Créteil
city: Limoges
country: France
facility: Chu Dupuytren
city: Lorient
country: France
facility: CH de Lorient - Hôpital du Scorff
city: Lyon
country: France
facility: Centre Léon Berard
city: Marseille
country: France
facility: Institut Paoli-Calmette
city: Marseille
country: France
facility: Hôpital Européen Marseille
city: Marseille
country: France
facility: CHU MARSEILLE_ Hopital Nord
city: Meaux
country: France
facility: CH MEAUX
city: Paris
country: France
facility: APHP - Hôpital Cochin
city: Pessac
country: France
facility: CHU Bordeaux - Hôpital du Haut Levêque
city: Pringy
country: France
facility: CH d'Annecy-genevois
city: Quimper
country: France
facility: Centre Hospitalier de Cornouaille
city: Rennes
country: France
facility: CHU RENNES - Hôpital Pontchailloux
city: Roche Sur Yon
country: France
facility: CH La Roche Sur Yon - CHD Les Oudairies
city: Rouen
country: France
facility: CHU ROUEN - Hôpital Charles Nicolle
city: Saint-Aubin-lès-Elbeuf
country: France
facility: Saint Aubin Les Elbeuf
city: Saint-Denis
country: France
facility: CH La Réunion - Site Félix Guyon
city: Saint-Pierre
country: France
facility: CHU La Réunion - Groupe Hospitalier Sud
city: Saint-Priest-en-Jarez
country: France
facility: SAINT-PRIEST EN JAREZ - Institut de Cancérologie de la Loire
city: Strasbourg
country: France
facility: Institut de Cancérologie Strasbourg Europe
city: Toulon
country: France
facility: Hôpital d'Instruction des Armées Toulon - Saint Anne
city: Villefranche-sur-Saône
country: France
facility: Ch Villefranche Sur Saone
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Institut de Cancérologie, CHU Brest, Hôpital Morvan
name: Renaud DESCOURT, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Oncology, Centre Léon Bérard, Lyon
name: Chantal DECROISETTE, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Service de pneumologie, CH intercommunal de Créteil
name: Christos CHOUAID, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Descourt R, Chouaid C, Perol M, Besse B, Greillier L, Bylicki O, Ricordel C, Guisier F, Gervais R, Schott R, Auliac JB, Robinet G, Decroisette C. First-line pembrolizumab with or without platinum doublet chemotherapy in non-small-cell lung cancer patients with PD-L1 expression >/=50. Future Oncol. 2021 Aug;17(23):3007-3016. doi: 10.2217/fon-2020-1202. Epub 2021 Jun 22.