Durvalumab With Stereotactic Body Radiation Therapy (SBRT) vs Placebo With SBRT in Early Stage Unresected Non-small Cell Lung Cancer (NSCLC) Patients/ Osimertinib Following SBRT in Patients With Early Stage Unresected NSCLC Harboring an EGFR Mutation

Phase 3

Active, not recruiting

• Conditions: Carcinoma, Non-Small-Cell Lung
• Interventions: Other: Placebo; Drug: (Osimertinib cohort, single-arm, open-label separate cohort); Drug: Durvalumab

• Registration Number: NCT03833154
• Lead Sponsor: AstraZeneca

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.

Study Timeline

• Study First Submitted: 2019-01-25
• Study First Submitted QC: 2019-02-05
• Study First Posted: 2019-02-06
• Study Start: 2019-03-06
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-08
• Last Update Posted: 2025-04-09
• Primary Completion: 2027-04-16
• Study Completion: 2028-04-04

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 724

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 Exclusion Criteria

1. Mixed small cell and non-small cell cancer

2. Patients with known or increased risk factor for QTc prolongation

3. Treatment with any of the following:

   • Preoperative or adjuvant platinum-based or other chemotherapy for the disease under investigation
   • Prior treatment with neoadjuvant or adjuvant EGFR TKI
   • Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4

4. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib

5. Any of the following cardiac criteria

   • Mean resting corrected QT interval >470 msec, obtained from 3 ECGs
   • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
   • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained -sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval
   • Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SoC SBRT + Placebo Therapy (Main Cohort)	Placebo	SBRT Placebo (matching placebo for infusion) every 4 weeks iv for up to 26 cycles or until progression or other discontinuation criteria are met.
SoC SBRT + Osimertinib Therapy (Osimertinib cohort, single-arm, open-label separate cohort)	(Osimertinib cohort, single-arm, open-label separate cohort)	SBRT Osimertinib 80mg every day \[qd\] for oral administration up to 36 months or until progression. Osimertinib treatment should start within 7 to 14 days after completion of SBRT
SoC SBRT + Durvalumab Therapy (Main Cohort)	Durvalumab	SBRT Durvalumab (PD-L1 monoclonal antibody) 1500 mg every 4 weeks \[q4w\] intravenously \[iv\] for up to 26 cycles or until progression or other discontinuation criteria are met.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

Research Site; 🇬🇧 Manchester, United Kingdom