A Phase II-III Randomized Trial Evaluating Maintenance Pembrolizumab (± Pemetrexed) Until Progression Versus Observation (± Pemetrexed) After 6 Months of Platinum-based Doublet Chemotherapy Plus Pembrolizumab Induction Treatment in Patients With Stage IV Non-Small Cell Lung Cancer (NSCLC)
Overview
- Phase
- Phase 2
- Intervention
- Pemetrexed
- Conditions
- Metastatic NSCLC
- Sponsor
- Intergroupe Francophone de Cancerologie Thoracique
- Enrollment
- 1360
- Locations
- 43
- Primary Endpoint
- Phase II: 18-month overall survival (OS)
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several cancer types, including melanoma and NSCLC. As a matter of fact, first registration trials of immune-checkpoints inhibitors (ICI) in second-line settings (pembrolizumab as well as nivolumab or atezolizumab) had stated that ICI could be continued until disease progression or not tolerable toxicity, up to 5 years. This is only for the first-line registration studies that the arbitrary maximal duration of treatment of 2 years was set up by the Companies sponsoring such trials.
The aim is to study a de-escalation scheme of treatment from 2 years of immunotherapy to 6 months (27-weeks), in patients with controlled disease.
Detailed Description
This is a phase II-III randomized, open-labelled, multicentre study for NSCLC patients who are naive of treatment for advanced disease. Patients will be given first-line chemotherapy + pembrolizumab: platinum doublet for at least 3 cycles, either paclitaxel-carboplatin for patient with SCC or 3 cycles of pemetrexed-platinum salt followed by 2 cycles of pemetrexed and 6 cycles of pembrolizumab. Only patients with disease control, confirmed at 6 months (27-weeks) without drug-related toxicity imposing treatment discontinuation will be randomized 1:1 either to continuation of pembrolizumab (± pemetrexed for non-SCC) until disease progression or unacceptable toxicity or 2 years, or observation (± pemetrexed for non-SCC). Patients will be stratified by performance status (0 versus 1), histology (SCC versus non-SCC), PD-L1 (PD-L1 \< 1% versus 49%≥PD-L1 ≥ 1% versus PD-L1\>49%), sex and response at randomization (partial response versus stabilisation).
Investigators
Eligibility 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
- •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
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.
Arms & Interventions
Arm B : experimental arm
6 months treatment by chemotherapy + pembrolizumab followed by pemetrexed for patients with non-SCC or observation for patients with SCC
Intervention: Pemetrexed
Arm A : control Arm
6 months treatment by chemotherapy + pembrolizumab followed by pembrolizumab ± pemetrexed for patients with non-squamous cell carcinoma (SCC) until 2 years max
Intervention: Pembrolizumab before randomization
Arm A : control Arm
6 months treatment by chemotherapy + pembrolizumab followed by pembrolizumab ± pemetrexed for patients with non-squamous cell carcinoma (SCC) until 2 years max
Intervention: Chemotherapy
Arm A : control Arm
6 months treatment by chemotherapy + pembrolizumab followed by pembrolizumab ± pemetrexed for patients with non-squamous cell carcinoma (SCC) until 2 years max
Intervention: Pemetrexed
Arm A : control Arm
6 months treatment by chemotherapy + pembrolizumab followed by pembrolizumab ± pemetrexed for patients with non-squamous cell carcinoma (SCC) until 2 years max
Intervention: Pembrolizumab after randomization
Arm B : experimental arm
6 months treatment by chemotherapy + pembrolizumab followed by pemetrexed for patients with non-SCC or observation for patients with SCC
Intervention: Pembrolizumab before randomization
Arm B : experimental arm
6 months treatment by chemotherapy + pembrolizumab followed by pemetrexed for patients with non-SCC or observation for patients with SCC
Intervention: Chemotherapy
Outcomes
Primary Outcomes
Phase II: 18-month overall survival (OS)
Time Frame: 18 months after inclusion
Rate of patients not dead 18 months after inclusion
Phase III: overall survival
Time Frame: about 24 months after randomization
Time from date of inclusion to the date of death due to any cause
Secondary Outcomes
- Incidence, nature, and severity of adverse events(about 24 months after randomization)
- Time until definitive health related quality of life score deterioration(about 24 months after randomization)
- Change from baseline of EuroQol Quality of Life 5-Dimension 5-Level Scale(about 24 months after randomization)
- Progression-Free Survival (PFS)(about 24 months after randomization)
- OS according to histological subtype(about 24 months after randomization)
- PFS according to histological subtype(about 24 months after randomization)
- OS according to PDL1 tumor level(about 24 months after randomization)
- PFS according to PDL1 tumor level(about 24 months after randomization)