A Study of Osimertinib With or Without Chemotherapy Versus Chemotherapy Alone as Neoadjuvant Therapy for Patients With EGFRm Positive Resectable Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a Phase III, randomised, controlled, 3-arm, multi-centre study of neoadjuvant osimertinib as monotherapy or in combination with chemotherapy, versus SoC chemotherapy alone, for the treatment of patients with resectable EGFRm Non-Small Cell Lung Cancer

Official Title
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A Phase III, Randomised, Controlled, Multi-center, 3-Arm Study of Neoadjuvant Osimertinib as Monotherapy or in Combination With Chemotherapy Versus Standard of Care Chemotherapy Alone for the Treatment of Patients With Epidermal Growth Factor Receptor Mutation Positive, Resectable Non-small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Placebo
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, at least 18 years of age. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative Histologically or cytologically documented non-squamous NSCLC with completely resectable (Stage II - IIIB N2) disease (according to Version 8 of the IASLC Cancer Staging Manual [IASLC Staging Manual in Thoracic Oncology 2016]). Complete surgical resection of the primary NSCLC must be deemed achievable, as assessed by a MDT evaluation (which should include a thoracic surgeon, specialised in oncologic procedures). Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 at enrolment, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (eg., T790M, G719X, Exon20 insertions, S7681 and L861Q). Exclusion Criteria: Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. History of another primary malignancy (including any known or suspected synchronous primary lung cancer), except for the following: Malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of investigational product (IP) and of low potential risk for recurrence; Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease; Adequately treated carcinoma in situ without evidence of disease; Any synchronous Stage IA primary lung cancer that is ≤2 cm and planned to be resected during surgery for the Stage II to IIIB N2 lung tumour. Patients who have pre-operative radiotherapy treatment as part of their care plan Mixed small cell and NSCLC histology Stages I, IIIB N3, IIIC, IVA, and IVB NSCLC T4 tumours infiltrating the great vessels, the carina, the trachea, the oesophagus, the heart, and/or the vertebral body; and/or any bulky N2 disease. Patients who are candidates to undergo only segmentectomies or wedge resections Prior treatment with any systemic anti-cancer therapy for NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug Prior treatment with EGFR-TKI therapy Current use of (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4 (at least 3 weeks prior)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm 1: Placebo with platinum-based chemotherapy<br>Placebo plus investigator's choice of platinum-based standard of care chemotherapy (pemetrexed/carboplatin or pemetrexed/cisplatin) | Drug: Cisplatin<br>* Cisplatin (75mg/m2) to be administered with pemetrexed on Day 1 of every 3-week cycle for 3 cycles.<br>Drug: Carboplatin<br>* Carboplatin (AUC5) to be administered with pemetrexed on Day 1 of every 3-week cycle for 3 cycles<br>Drug: Placebo<br>* Oral<br>Drug: Pemetrexed<br>* Pemetrexed (500 mg/m2) to be administered with cisplatin or carboplatin on Day 1 of every 3-week cycle for 3 cycles<br>|
| Experimental: Arm 2: Osimertinib with platinum-based chemotherapy<br>Osimertinib 80 mg QD (Dose may be reduced to 40 mg QD at the discretion of the investigator) plus investigator's choice of platinum-based standard of care chemotherapy (pemetrexed/carboplatin or pemetrexed/cisplatin) | Drug: Osimertinib<br>* Oral<br>* Other names: AZD9291; TAGRISSO;Drug: Cisplatin<br>* Cisplatin (75mg/m2) to be administered with pemetrexed on Day 1 of every 3-week cycle for 3 cycles.<br>Drug: Carboplatin<br>* Carboplatin (AUC5) to be administered with pemetrexed on Day 1 of every 3-week cycle for 3 cycles<br>Drug: Pemetrexed<br>* Pemetrexed (500 mg/m2) to be administered with cisplatin or carboplatin on Day 1 of every 3-week cycle for 3 cycles<br>|
| Experimental: Arm 3: Osimertinib monotherapy<br>Osimertinib 80 mg QD (Dose may be reduced to 40 mg QD at the discretion of the investigator) | Drug: Osimertinib<br>* Oral<br>* Other names: AZD9291; TAGRISSO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Pathological Response (MPR) | Defined as ≤10% residual cancer cells in the main tumour, as assessed per central pathology laboratory post-surgery | From date of randomization to an average of 12 weeks after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) | Defined as absence of any viable cancer cells in the dissected tumour samples, including the main tumour, lymph nodes, and margins as assessed per central pathology laboratory post-surgery | From date of randomization to an average of 12 weeks after the first dose | 
| Event-free survival (EFS) | An event is defined as documented disease progression that precludes surgery or prevents completion of definitive surgery; recurrence or a new lesion, local or distant (a new primary malignancy, confirmed by pathology if clinically feasible, is not considered to be an EFS event); death due to any cause | From date of randomization up to approximately 5.5 years after the last patient is randomized | 
| Overall Survival (OS) | OS will be defined as the time from the date of randomisation until death due to any cause | From date of randomization up to approximately 5.5 years after the last patient is randomized | 
| Disease free survival (DFS) | DFS is defined as the time from the date of surgery until the first date of disease recurrence (local or distant) or date of death due to any cause, whichever occurs first. | From date of randomization up to approximately 5.5 years after the last patient is randomized | 
| Downstaging | Measured using pathologic mediastinal lymph node evaluation | From date of randomization to an average of 12 weeks after the first dose | 
| Difference between treatment arms in change from baseline in EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items) | Assess disease-related symptoms, functioning, and global health status/quality-of-life in patients | From date of randomization up to approximately 5.5 years after the last patient is randomized | 
| Concordance of EGFRm status between tumour tissue DNA and patient-matched plasma-derived ctDNA |  | Baseline | 
| Corcordance of EGFR mutation status between the local and central cobas EGFR mutation test results from baseline tumour samples |  | Baseline | 
| PK plasma concentrations of osimertinib |  | From the pre-dose of Cycle 2 to post-dose of Cycle 3 (each cycle is 21 days) | 
| Difference between treatment arms in change from baseline in EORTC QLQ-LC13 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items) | Assess lung cancer-associated symptoms and side effects from conventional chemotherapy and radiotherapy | From date of randomization up to approximately 5.5 years after the last patient is randomized | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Resectable; NSCLC; Osimertinib; EGFRm Positive; Neoadjuvant; Adjuvant