A Global Study to Assess the Effects of Osimertinib Following Chemoradiation in Patients With Stage III Unresectable Non-small Cell Lung Cancer (LAURA)

This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable EGFR mutation-positive NSCLC, including the most common EGFR sensitising mutations (Ex19Del and L858R), either alone or in combination with other EGFR mutations. Chemoradiation may have been given either given concurrently or sequentially. Patients whose disease has not progressed following chemoradiation will be randomised within 6 weeks of completion of chemoradiation to receive osimertinib or placebo in a 2:1 ratio, and treatment will be continued until disease progression, unacceptable toxicity or other discontinuation criteria are met. After progression, patients can be unblinded and may receive open-label osimertinib. After the final OS analysis, the study blind will be broken and patients still receiving open-label osimertinib will be supplied with open-label osimertinib by AstraZeneca for as long as their treating physician considers they are deriving clinical benefit.

Primary Outcome Measures

1. Progression-free Survival (PFS) by Blinded Independent Central Review (BICR)
   Time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on BICR assessment according to RECIST v1.1

Secondary Outcome Measures

1. Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation
   Number of PFS events (PFS is time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on BICR assessment according to RECIST v1.1)
2. Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA
   Number of PFS events (PFS is time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on blinded independent central review (BICR) assessment according to RECIST v1.1)
3. Central Nervous System (CNS) Progression-free Survival (PFS) by Blinded Independent Central Review (BICR)
   Time from randomisation until the date of CNS disease progression or death (by any cause in the absence of CNS progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on CNS BICR assessment according to RECIST v1.1
4. Overall Survival (Count)
   Number of patients with Overall Survival (OS), the time from the date of randomisation until date of death by any cause
5. Overall Survival (Duration)
   Time from the date of randomisation until death by any cause
6. Objective Response Rate by Blinded Independent Central Review (BICR)
   Percentage of evaluable patients with at least one BICR assessed visit response of complete response (CR) or partial response (PR). CR defined as disappearance of all target lesions (TL) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10mm. PR defined as \>= 30% decrease in the sum of diameters of target lesions (compared to baseline sum of diameters). Responses include both confirmed and unconfirmed BICR responses
7. Duration of Response, Unconfirmed by Blinded Independent Central Review (BICR)
   Date of PFS event - date of first unconfirmed response + 1 day (and expressed in months) for unconfirmed responses only
8. Disease Control Rate by Blinded Independent Central Review (BICR)
   Percentage of patients who have a best overall response of complete response (CR), partial response (PR) or stable disease (SD) as assessed by BICR
9. Tumour Shrinkage by Blinded Independent Central Review (BICR)
   Depth of response (or tumour shrinkage or change in tumour size) was assessed using BICR responses in target lesions. The best change in tumour size is the largest decrease from baseline or the smallest increase from baseline in the absence of a reduction
10. Proportion With Tumour Shrinkage by Blinded Independent Central Review (BICR)
    Proportion with depth of response (or tumour shrinkage or change in tumour size)
11. Time to Death or Distant Metastases by Blinded Independent Central Review (BICR)
    Time from the date of randomisation until the first date of distant metastases or date of death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is detected on a scan that is anywhere other than lung or regional lymph node according to RECIST v1.1 or proven by biopsy
12. Time to Study Treatment Discontinuation
    Time from randomisation to the earlier of the date of study treatment discontinuation (regardless of the reason for study treatment discontinuation) or death (i.e. date of study treatment discontinuation/death or censoring - date of randomisation + 1 day, expressed in months)
13. Time to First Subsequent Treatment
    Time from the date of randomisation to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death
14. Time to Second Subsequent Treatment
    Time from the date of randomisation to the earlier of the second subsequent anti-cancer therapy start date following study drug discontinuation or death
15. Second Progression-free Survival (PFS2)
    Time from randomisation to the earliest progression event following first objective disease progression, subsequent to the first subsequent therapy, or death.