A Randomized Phase 3 Trial Comparing Continuation Nivolumab-Ipilimumab Doublet Immunotherapy Until Progression Versus Observation in Treatment-naive Patients With PDL1-positive Stage IV Non-Small Cell Lung Cancer (NSCLC) After Nivolumab-Ipilimumab Induction Treatment
Overview
- Phase
- Phase 3
- Intervention
- Ipilimumab
- Conditions
- Non-Small Cell Lung Cancer Metastatic
- Sponsor
- Intergroupe Francophone de Cancerologie Thoracique
- Enrollment
- 265
- Locations
- 47
- Primary Endpoint
- Progression Free Survival (PFS1)
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
Non Small Cell lung cancer (NSCLC) remains the first cause of death by cancer in the World. For the patients presenting a NSCLC stage IV, the median of survival is about 15 months today. The chemotherapy with platinum is the standard treatment for these patients but immunotherapy showed these efficacy in 1st line for patients PD-L1 positive. On the other hand, the duration of treatment by immunotherapy is not clear. Indeed, prolonged responses and long survivals have been described in patients having interrupted the treatment. In the melanoma, a treatment of 6 months of ipilimumab demonstrated its efficacy. The objective of the study is to demonstrate that a treatment of 6 months followed by an observation (stop and go) is not less effective than a treatment given until progression or toxicity. This strategy would allow to decrease the accumulated toxicities, to improve the quality of life of the patients and to decrease the costs.
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.
- •Histologically-proven NSCLC (squamous or non-squamous)
- •Stage IV (M1, including M1a pleural involvement) disease (8th classification TNM, UICC 2015)
- •ECOG PS \< 1
- •Weight loss\< 10% in previous 3 months
- •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 mixt histology including a SCLC component
- •Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861X mutations in exon 21, G719A/S mutation in exon 18) or HER exon 20 insertion (either tissue or plasma cfDNA mutation).
- •Known ALK or ROS1 gene rearrangement as assessed by immunohistochemistry, FISH or NGS sequencing
- •Previous or active cancer within the previous 5 years (except for treated carcinoma in situ of the cervix or basal cell skin cancer). Patients with a prostate adenocarcinoma history within the previous 5 years could be included in case of localized prostate cancer, with good prognostic factors according to d'Amico classification (≤ T2a and Score de Gleason ≤ 6 and PSA (ng/ml) ≤ 10), provided they were treated in a curative way (surgery or radiotherapy, without any chemotherapy)
- •Superior vena cava (SVC) syndrome persisting after SVC stenting
- •Thoracic radiotherapy needed at initiation of tumor treatment, except bone palliative radiotherapy on a painful or compressive metastasis, respecting 4 weeks delay between the end of radiotherapy and the beginning of induction immunotherapy treatment
- •Symptomatic untreated brain metastasis (without previous whole brain radiotherapy or stereotactic ablative brain radiotherapy or without surgical resection). At least 4 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, with no evolution on brain MRI or CT-scan within the previous month 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 rheumatoid polyarthritis, Lupus, Wegener disease. Patients with type I diabetes, or hypothyroidism, or immune cutaneous disease (vitiligo, psoriasis, alopecia) not needing any immunosuppressive systemic treatment, are allowed to be included.
Arms & Interventions
Arm A : standard treatment
6 months of treatment by nivolumab + ipilimumab then nivolumab + ipilimumab then in case of progression platinum-based doublet recommended
Intervention: Ipilimumab
Arm A : standard treatment
6 months of treatment by nivolumab + ipilimumab then nivolumab + ipilimumab then in case of progression platinum-based doublet recommended
Intervention: Nivolumab
Arm B : experimental arm
6 months of treatment by nivolumab + ipilimumab then observation the in case of progression nivolumab + ipilimumab then in case of progression platinum-based doublet recommended
Intervention: Ipilimumab
Arm B : experimental arm
6 months of treatment by nivolumab + ipilimumab then observation the in case of progression nivolumab + ipilimumab then in case of progression platinum-based doublet recommended
Intervention: Nivolumab
Outcomes
Primary Outcomes
Progression Free Survival (PFS1)
Time Frame: 24 months after randomization of the last subject
Time between the date of randomization and the first date of documented progression, as determined by BICR (Blinded Independent Central Review), or death due to any cause, whichever occurs first.
Secondary Outcomes
- Overall survival (OS)(6, 12 and 18 months after randomization)
- Quality of life (QoL)(24 months after randomization of the last subject)
- Biological correlative exploratory studies (PD-L1)(6 months)
- Biological correlative exploratory studies (PD-L1 H score)(6 months)
- Biological correlative exploratory studies (CD3/CD8)(6 months)
- Biological correlative exploratory studies (chemokines)(6 months)
- Biological correlative exploratory studies (cytokines)(6 months)
- Progression Free Survival (PFS2)(24 months after randomization of the last subject)
- Biological correlative exploratory studies (neutrophil)(6 months)