A Phase III, Double-blind, Randomised, Placebo-Controlled, International Study to Assess the Efficacy and Safety of Adjuvant Osimertinib Versus Placebo in Participants With EGFR Mutation-positive Stage IA2-IA3 Non-small Cell Lung Cancer, Following Complete Tumour Resection

Official Summary

This is a global study to assess the effects of osimertinib in participants with EGFRm stage IA2-IA3 non-small cell lung cancer following complete tumour resection.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: TRIPLE
• Enrollment: 390 participants

Study Arms

• Osimertinib (EXPERIMENTAL)
  Osimertinib 80mg, orally, once daily (Dose may be reduced to 40 mg once daily if required at the discretion of the investigator)
• Placebo (PLACEBO_COMPARATOR)
  Matching placebo for osimertinib, orally, once daily

Interventions

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

Primary Outcomes

• Disease-Free Survival (DFS) in high-risk stratum (From date of randomisation up to approximately 10 years)

Secondary Outcomes

• Disease-Free Survival (DFS) in overall population (From date of randomisation up to approximately 10 years)
• Overall Survival (OS) in high-risk stratum and the overall population (From date of randomization up to approximately 10 years)
• PK plasma concentrations of osimertinib and of metabolite AZ5104 in overall population (From date of randomisation up to approximately 10 years)
• Impact of osimertinib versus placebo on physical functioning (From date of randomisation up to approximately 10 years)
• Central Nervous System (CNS) Disease-Free Survival (DFS) in both the high-risk stratum and the overall population (From date of randomisation up to approximately 10 years)

Eligibility Criteria

Inclusion Criteria

1. Male or female, at least ≥ 18 years.
2. NSCLC, of non-squamous histology.
3. Stage IA2 or IA3 disease, based on TNM8 classification.
4. Complete surgical resection (R0) of the primary NSCLC by lobectomy, bilobectomy, segmentectomy or sleeve resection.
5. Complete recovery from surgery at the time of randomisation. Study intervention cannot commence within 4 weeks following surgery. No more than 12 weeks may have elapsed between surgery and randomisation for participants.
6. World Health Organization performance status of 0 or 1.
7. Provision of tumour sample for central pathology assessment of pathologic risk factors and to assess EGFR mutation status prior to randomisation.
8. A tumour which harbours one of the 2 EGFR mutations (Ex19del, L858R) by cobas® EGFR Mutation Test v2 (Roche Diagnostics) or FoundationOne® test.
9. Minimum life expectancy of \> 6 months.
10. Females must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential. Male subjects must be willing to use barrier contraception.

Exclusion Criteria

1. Mixed small cell and non-small cell cancer history.
2. Participants with incomplete (R1/R2) resection, or who have undergone pneumonectomy or only wedge resection.
3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including HCV and HIV or active uncontrolled HBV infection.
4. History of another primary malignancy, including any known or suspected synchronous primary lung cancer except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence.
5. Any of the following cardiac criteria:

   * Mean resting QTcF interval \> 470 ms, obtained from triplicate ECGs performed at screening.
   * Any abnormalities in rhythm, conduction, or morphology of resting ECG,
   * Any factors that increase the risk of QTcF prolongation or risk of arrhythmic events.
6. History of interstitial lung disease.
7. Inadequate bone marrow reserve or organ function.
8. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study intervention.
9. Prior treatment with any anticancer therapy for NSCLC (including chemotherapy, radiotherapy, immunotherapy, and EGFR-TKIs).
10. Major surgery or significant traumatic injury within 4 weeks of the first dose of study intervention.
11. Participants currently receiving medications or herbal supplements known to be strong inducers of CYP3A4.

Trial Locations

• Research Site, Anchorage, Alaska, United States
• Research Site, Los Angeles, California, United States
• Research Site, Orange, California, United States
• Research Site, Grand Junction, Colorado, United States
• Research Site, Newark, Delaware, United States
• Research Site, Atlanta, Georgia, United States
• Research Site, Chicago, Illinois, United States
• Research Site, Frederick, Maryland, United States
• Research Site, Morristown, New Jersey, United States
• Research Site, Flushing, New York, United States
• ...and 10 more locations

Study Officials

• Jonathan Goldman, MD — PRINCIPAL_INVESTIGATOR
  University of California, Los Angeles
• Yasuhiro Tsutani, MD, PhD — PRINCIPAL_INVESTIGATOR
  Kindai University Facility of Medicine
• Jie He, MD, PhD — PRINCIPAL_INVESTIGATOR
  The Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS)

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