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

Primary Outcome Measures

• Progression-free survival (PFS) [ Time Frame: Approximately 13 months ]
  Defined as the 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 assessment according to RECIST 1.1

Secondary Outcome Measures

• PFS in patients with EGFR Ex19del or L858R mutation [ Time Frame: Approximately 13 months ]
  Defined as the 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 assessment according to RECIST 1.1

• PFS in patients with EGFR mutations Ex19del or L858R detectable in plasma-derived ctDNA [ Time Frame: Approximately 13 months ]
  Defined as the 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 assessment according to RECIST 1.1

• Time to CNS PFS [ Time Frame: MRI Brain Scan- Approximately 13 months ]
  Defined as earlier event of CNS progression or death based on blinded independent central review assessment according to RECIST 1.1

• Overall survival (OS) [ Time Frame: Approximately 45 months ]
  Defined as the time from randomization until death from any cause

• Objective response rate (ORR) [ Time Frame: Approximately 13 months ]
  Defined as the number (%) of patients with measurable disease with at least 1 visit response of CR (Complete response) or PR (Partial response) based on blinded independent central review assessment according to RECIST 1.1

• Duration of response (DoR) [ Time Frame: Approximately 13 months ]
  Defined as the time from the date of first documented response (i.e., subsequently confirmed) until the date of documented progression or death in the absence of disease progression based on blinded independent central review assessment according to RECIST 1.1

• Disease control rate (DCR) [ Time Frame: Approximately 13 months ]
  Defined as Disease control rate is defined as the percentage of subjects who have a best overall response of CR or PR or SD based on blinded independent central review assessment according to RECIST 1.1

• Tumor shrinkage [ Time Frame: Approximately 13 months ]
  Defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline based on blinded independent central review assessment according to RECIST 1.1

• Time to death or distant metastases (TTDM) [ Time Frame: Approximately 13 months ]
  Defined as the time from the date of randomization until the first date of distant metastasis or date of death in the absence of distant metastasis based on blinded independent central review assessment according to RECIST 1.1

• Time to treatment discontinuation [ Time Frame: Approximately 13 months ]
  Defined as the time from randomization to the earlier of the date of study treatment discontinuation (regardless of the reason for study treatment discontinuation) or death

• Second progression free survival on a subsequent treatment (PFS2) [ Time Frame: Assessed by investigator in accordance with clinical practice-approximately 21 months ]
  Time from randomisation to second progression (PFS2) is defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or date of death after starting subsequent anti-cancer treatment.

• Time to first subsequent therapy (TFST) [ Time Frame: Approximately 13 months ]
  Defined as the time from the date of randomization to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death

• Time to second subsequent therapy (TSST) [ Time Frame: Approximately 21 months ]
  Defined as the time from the date of randomization to the earlier of the date of second subsequent anti-cancer therapy start date following study drug discontinuation or death.

• Patients reported disease-related symptoms and HRQoL by EORTC QLQ-LC13 and EORTC QLQ-30 questionnaires [ Time Frame: Approximately 21 months ]
  Change in symptoms from baseline

• Incidence of Adverse Events (AEs) [ Time Frame: Approximately 14 months ]
  AEs graded by CTCAE version 5.0

• Plasma concentrations of osimertinib and AZD5104 [ Time Frame: Trough concentrations at Week 4,12 and 24 ]
  The pharmacokinetics exposure parameters derived from plasma concentrations of osimertinib and AZD5104

Eligibility

Inclusion Criteria

Male or female aged at least 18 years.

Patients with histologically documented NSCLC of predominantly non-squamous Pathology who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology).

The tumor harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations, assessed by cobas® EGFR Mutation Test v2 (Roche Diagnostics) in a CLIA certified (USA sites) or an accredited local laboratory (sites outside of the USA) or by central testing.

Patients must have received either concurrent chemoradiation or sequential chemoradiation including at least 2 cycles of platinum based chemotherapy and a total dose of radiation of 60 Gy ±10% (54 to 66 Gy).

Chemoradiation must be completed ≤6 weeks prior to randomization.

Patients must not have had disease progression during or following definitive platinum-based, chemoradiation therapy.

World Health Organization (WHO) performance status of 0 or 1.

Life expectancy >12 weeks at Day 1.

Female patients who are not abstinent (in line with the preferred and usual lifestyle choice) must be using adequate contraceptive measures, must not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-childbearing potential.