A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study of Osimertinib as Maintenance Therapy in Patients With Locally Advanced, Unresectable EGFR Mutation-positive Non-Small Cell Lung Cancer (Stage III) Whose Disease Has Not Progressed Following Definitive Platinum-based Chemoradiation Therapy (LAURA).

Official Summary

A global study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable Epidermal Growth Factor Receptor Mutation Positive non-small cell lung cancer

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 130 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 216 participants

Study Arms

• Osimertinib (EXPERIMENTAL)
  Osimertinib (80mg or 40mg orally, once daily), in accordance with the randomization schedule.
• Placebo Osimertinib (PLACEBO_COMPARATOR)
  Matching placebo for Osimertinib (80mg or 40mg orally, once daily), in accordance with the randomization schedule

Interventions

• DRUG: Osimertinib 80mg/40mg — The initial dose of Osimertinib 80mg once daily can be reduced to 40mg once daily. Treatment can continue until disease progression, unacceptable toxicity or other discontinuation criteria are met.
• DRUG: Placebo Osimertinib 80mg/40mg — The initial dose of Placebo Osimertinib 80mg once daily can be reduced to 40mg once daily. Treatment can continue until disease progression, unacceptable toxicity or other discontinuation criteria are met

Primary Outcomes

• Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) (Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months)

Secondary Outcomes

• Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Ex19del or L858R Mutation (Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months)
• Number of Participants With Progression-free Survival (PFS) Events in Patients With EGFR Mutations Ex19del or L858R Detectable in Plasma-derived ctDNA (Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months)
• Central Nervous System (CNS) Progression-free Survival (PFS) by Blinded Independent Central Review (BICR) (Every 8 weeks for first 48 weeks, then every 12 weeks until BICR-confirmed radiological disease progression. Assessed up to date of DCO (05Jan24) to a maximum of approximately 63 months)
• Overall Survival (Count) (Date of randomisation to date of death by any cause. Assessed up to a maximum of approximately 63 months)
• Overall Survival (Duration) (Date of randomisation to date of death by any cause. Assessed up to a maximum of approximately 63 months)

Eligibility Criteria

Inclusion Criteria

1. Male or female aged at least 18 years.
2. 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).
3. 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) or FoundationOne® test in a CLIA certified (USA sites) or an accredited local laboratory (sites outside of the USA) or by central testing (cobas® v2 only).
4. 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).
5. Chemoradiation must be completed ≤6 weeks prior to randomization.
6. Patients must not have had disease progression during or following definitive platinum-based, chemoradiation therapy.
7. World Health Organization (WHO) performance status of 0 or 1.
8. Life expectancy \>12 weeks at Day 1.
9. 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.

Exclusion Criteria

1. Mixed small cell and non-small cell lung cancer histology
2. History of interstitial lung disease (ILD) prior to chemoradiation
3. Symptomatic pneumonitis following chemoradiation
4. Any unresolved toxicity Common Terminology Criteria for Adverse Events (CTCAE) \> Grade 2 from the prior chemoradiation therapy
5. Any of the following cardiac criteria:

   * Mean resting corrected QT interval (QTc) \>470 msec, obtained from 3 ECGs
   * Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG
   * Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes
6. Inadequate bone marrow reserve or organ function
7. History of other malignancies, except: adequately treated non-melanoma skin cancer or lentigo maligna , curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence of disease for \> 5 years following the end of treatment and which, in the opinion of the treating physician, do not have a substantial risk of recurrence of the prior malignancy.
8. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
9. 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
10. Prior treatment with any prior chemotherapy, radiation therapy, immunotherapy or investigational agents for NSCLC outside of that received in the definitive setting for Stage III disease (chemotherapy and radiotherapy in SCRT and CCRT regimens is allowed for treatment of Stage III disease).
11. Prior treatment with EGFR-TKI therapy
12. Major surgery as defined by the investigator within 4 weeks of the first dose of study drug.
13. Patients currently receiving (unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3 weeks prior to receiving the first dose of study drug).
14. Contraindication to MRI, including but not limited to, claustrophobia, pace makers, metal implants, intracranial surgical clips and metal foreign bodies

Trial Locations

• Research Site, Duarte, California, United States
• Research Site, Atlanta, Georgia, United States
• Research Site, Florham Park, New Jersey, United States
• Research Site, Salt Lake City, Utah, United States
• Research Site, Madison, Wisconsin, United States
• Research Site, Ciudad Autónoma de Bs. As., Argentina
• Research Site, Ciudad Autónoma de Bs. As., Argentina
• Research Site, Mar del Plata, Argentina
• Research Site, Rosario, Argentina
• Research Site, San Salvador de Jujuy, Argentina
• ...and 10 more locations

Study Officials

• Suresh S Ramalingam, MD — PRINCIPAL_INVESTIGATOR
  Emory University School of Medicine, Atlanta, U.S.
• Shun Lu, MD — PRINCIPAL_INVESTIGATOR
  Shanghai Chest Hospital, Shanghai, China

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