Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
NSCLC, Early-Stage NSCLC, Lung cancer, Double- Blind, PD-L1, MEDI4736, Durvalumab, Osimertinib, PFS, OS, Unresected lung cancer, Medically Inoperable, Operable with Patient refusal, SBRT, SABR, EGFR
Brief summary
This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study assessing the efficacy and safety of durvalumab with SoC SBRT versus placebo with SoC SBRT in patients with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC. An additional cohort will assess Osimertinib following SBRT in patients with early stage unresected T1 to T3N0M0 NSCLC harbouring an EGFR mutation.
Detailed description
Patients with Stage I/II lymph node negative NSCLC and confirmed to meet all eligibility criteria will be randomized 1:1 to receive either Durvalumab + SoC SBRT or placebo + SoC SBRT. The primary objective of main cohort is to assess the efficacy of Durvalumab with SoC SBRT compared to placebo with SoC SBRT in terms of PFS. Key secondary is to assess the efficacy of Durvalumab with SoC SBRT compared to placebo with SoC SBRT in terms of Overall Survival (OS). In addition, a study cohort with a sufficient number of patients harboring an EGFR-TKI sensitizing mutation, will receive Osimertinib treatment after completion of SoC SBRT as definitive treatment of Stage I/II lymph node-negative NSCLC. The primary objective of Osimertinib cohort is to assess efficacy of Osimertinib following SoC SBRT in terms of 4-year PFS. Key secondary objectives include safety, OS and efficacy of Osimertininb treatment with SBRT.
Interventions
DRUGDurvalumab
Durvalumab 1500 mg every 4 weeks \[q4w\] intravenously \[iv\] for up to 26 cycles or until progression or other discontinuation criteria are met.
OTHERPlacebo
Matching placebo for infusion every 4 weeks iv for up to 26 cycles or until progression or other discontinuation criteria are met.
DRUG(Osimertinib cohort, single-arm, open-label separate cohort)
Osimertinib 80 mg every day \[qd\] orally for up to 36 months or until progression or other discontinuation criteria are met. Osimertinib treatment should start from 7 to 14 days after completion of SBRT
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double- Blind
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Main Cohort Key Inclusion Criteria: 1. Age ≥18 years 2. Planned SoC SBRT as definitive treatment 3. World Health Organization (WHO)/ECOG PS of 0, 1 or 2 4. Life expectancy of at least 12 weeks 5. Body weight \>30 kg 6. Submission of tumor tissue sample if available 7. Adequate organ and marrow function required 8. Patients with central or peripheral lesions are eligible 9. Staging studies must be done during screening (PET-CT within 10 weeks) 10. Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions Main Cohort Key
Exclusion criteria
1. Mixed small cell and non-small cell cancer 2. History of allogeneic organ transplantation 3. History of another primary malignancy with exceptions 4. History of active primary immunodeficiency 5. Epidermal growth factor receptor local testing is strongly recommended prior to enrollment. Patients with a tumor harboring an EGFRm per local testing will be excluded from the main cohort 6. Prior exposure to immune-mediated therapy with exceptions Osimertinib Cohort Key Inclusion Criteria 1. Age ≥18 years 2. Planned SoC SBRT as definitive treatment 3. WHO/ECOG PS of 0, 1, or 2 4. Patients with central or peripheral lesions are eligible 5. Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions 6. Staging studies must be done during screening (PET-CT within 10 weeks) 7. Submission of tumor tissue sample if available 8. Confirmation by local laboratory that the tumor harbors one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R) 9. Adequate bone marrow reserve or organ function required 10. Female patients should be using highly effective contraceptive measures 11. Male patients should be asked to use barrier contraceptives (ie, condoms) during sex with all partners during the trial and avoid procreation Osimertinib Cohort Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 in subpopulation of patients with Stage I/II NSCLC | from randomization up to 6 years | Main Cohort |
| 4-year Progression-Free Survival (4y-PFS) by ICR according to RECIST 1.1 criteria | from treatment start up to 5 years | Osimertinib Cohort |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) assessed by BICR per RECIST 1.1 in all randomised patients with Stage I/II NSCLC | from randomization up to 6 years | Main Cohort |
| Overall Survival (OS) | from randomization up to 7 years | Main Cohort |
| Concentration of durvalumab in serum such as peak concentration and trough | 12 weeks after last dose | Main Cohort |
| Detection of ADA neutralising antibodies titers | up to 6 months after last dose | Main Cohort |
| Health-related quality of life in patients treated with durvalumab with SoC SBRT compared to placebo with SoC SBRT using the EORTC QLQ-C30 | from randomization up to 7 years | Main Cohort |
| Proportion of patients alive and progression free at 24 months from randomisation (PFS24) assessed by BICR according to RECIST 1.1 | at 24 months following randomization | Main Cohort |
| Time to progression (TTP) assessed by BICR according to RECIST 1.1 | from randomization up to 6 years | Main Cohort |
| Time to death or distant metastasis (TTDM) assessed by BICR according to RECIST 1.1 | from randomization up to 6 years | Main Cohort |
| Time from randomisation to second progression (PFS2) as defined by local standard clinical practice | from randomization up to 7 years | Main Cohort |
| Assessment of AEs by CTCAE v 5.0 as measures of the safety and tolerability of Durvalumab with SoC SBRT compared to placebo with SoC SBRT | up to 3 months after last dose | Main Cohort |
| Assessment of AEs by CTCAE v 5.0 as measures of the safety, tolerability and compliance of osimertinib with SoC SBRT therapy | Up to 35 days after last dose | Osimertinib Cohort |
| WHO performance status | from treatment start up to 5 years | Osimertinib Cohort |
| ECG QT interval | Up to 156 weeks of treatment or treatment discontinuation | Osimertinib Cohort |
| Overall Survival | from treatment start up to 5 years | Osimertinib Cohort |
| Time To Progression (TTP) | from treatment start up to 5 years | Osimertinib Cohort |
| Time to CNS progression | from treatment start up to 5 years | Osimertinib Cohort |
| PFS2 | from treatment start up to 5 years | Osimertinib Cohort |
| Site(s) of disease progression | from treatment start up to 5 years | Osimertinib Cohort |
| PFS by ICR using RECIST 1.1 | from treatment start up to 5 years | Osimertinib Cohort |
Countries
Australia, Belgium, Brazil, Canada, China, France, Germany, Greece, Israel, Italy, Japan, Netherlands, Poland, Puerto Rico, Russia, South Korea, Spain, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed