Efficacy and Safety of Almonertinib Combined With or Without Chemotherapy as an Adjuvant Treatment for Stage II-IIIA Non-small Cell Lung Carcinoma Following Complete Tumour Resection

Study Overview
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Brief Summary
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This is a multicenter, randomized, open label, phase III study.

Detailed Description
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This is a multicenter, randomized, open label, phase III study assessing the efficacy and safety of Almonertinib combined with or without chemotherapy as an adjuvant treatment in patients with epidermal growth factor receptor (EGFR) mutation positive stage II-IIIA non-squamous NSCLC following complete tumour resection: Eligible patients will be randomized to receive either Almonertinib alone (110mg, po, once daily) or Almonertinib (110mg, po, once daily) plus pemetrexed (500mg/m2, iv) and cisplatin (500mg/m2, iv) or pemetrexed (500mg/m2, iv) plus cisplatin (500mg/m2, iv) in a 3:2:1 ratio.

Official Title
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Efficacy and Safety of Almonertinib Combined With or Without Chemotherapy as an Adjuvant Treatment for EGFR Mutation Positive Stage II-IIIA Non-small Cell Lung Carcinoma Following Complete Tumour Resection: A Multicenter, Randomized Controlled, Open-label Clinical Study

Conditions
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Non-small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: Almonertinib
* Drug: Pemetrexed
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient who meets all of the following inclusion criteria will qualify for entry into the study: Male or female, aged at least 18 years. Histologically confirmed diagnosis of primary non small lung cancer (NSCLC) on predominantly non-squamous histology. Brain examination must be done prior to surgery as it is considered standard of care. Patients must be classified post-operatively as Stage II-IIIA on the basis of pathologic criteria. Confirmation by the central laboratory that the tumour 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 including T790M. Providing paraffin embedded section(10-15sheets),wax blocks or fresh frozen tissues. Complete surgical resection of the primary NSCLC is mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumour. World Health Organization Performance Status of 0 to 1. Women of childbearing age should take appropriate contraceptive measures from screening to 3 months after stopping the study treatment and should not breastfeed. Before starting the administration, the pregnancy test was negative. Male patients should be willing to use barrier contraception from screening to stopping study treatment for 3 months.(i.e., condoms). For inclusion in study, patient must provide a written informed consent. ≤10 weeks between surgery and randomization. Exclusion Criteria: Any patient who meets any of the following exclusion criteria will not qualify for entry into the study: Treatment with any of the following: Pre-operative or post-operative or planned radiation therapy for the current lung cancer Pre-operative (neo-adjuvant) platinum based or other chemotherapy Prior treatment with neoadjuvant or adjuvant EGFR-TKI at any time Any other anti-tumor treatment for lung cancer(Including proprietary Chinese patent medicine with anti-tumor effects and anti-tumor immunotherapy, etc.) Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug. Treatment with an investigational drug within five half-lives of the compound or any of its related material. Medications that are predominantly CYP3A4 strong inhibitors or inducers or sensitive substrates of CYP3A4 with a narrow therapeutic range within 7 days of the first dose of study drug.. Patients who have had only segmentectomies or wedge resections History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, or other solid tumours curatively treated with no evidence of disease for > 5 years following the end of treatment. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy. 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). Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of Almonertinib. Any of the following cardiac criteria: Mean resting corrected QT interval (QTc) > 470 ms obtained from 3 electrocardiograms (ECGs), using the screening clinic's ECG machine and Fridericia's formula for QT interval correction (QTcF). Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval > 250 ms). Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, 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. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. Inadequate bone marrow reserve or organ function. History of hypersensitivity to any active or inactive ingredient of Almonertinib, or to drugs with a similar chemical structure or class to Almonertinib. Patients who are allergic to pemetrexed or any other ingredients in the preparation, cisplatin or other platinum-containing compounds. Patients with contraindications of pemetrexed and cisplatin. Any severe and uncontrolled ocular disease that may, in the ophthalmologist's opinion, present a specific risk to the patient's safety. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements. Any disease or condition that, in the opinion of the Investigator, would compromise the safety of the patient or interfere with study assessments.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Almonertinib<br>Drug: Almonertinib 110 mg A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: The patient continues to receive treatment until the disease progresses or reaches termination criteria. The overall treatment last for 3 years. | Drug: Almonertinib<br>* Almonertinib 110mg PO once daily<br>|
| Experimental: Almonertinib/Pemetrexed/Cisplatin<br>Drug: Almonertinib 110 mg Drug: Pemetrexed 500 mg/m² IV on day 1 of each 21 day cycle. Number of cycles until disease progression or unacceptable toxicity develops. Drug: Cisplatin 75mg/m2 IV on day 1 of each 21 day cycle. Number of cycles until disease progression or unacceptable toxicity develops. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: The patient continues to receive treatment until the disease progresses or reaches termination criteria. The overall treatment last for 3 years. | Drug: Almonertinib<br>* Almonertinib 110mg PO once daily<br>Drug: Pemetrexed<br>* 500 milligrams per square meter (mg/m²) Pemetrexed<br>Drug: Cisplatin<br>* 75mg/m² Cisplatin taken intravenously (IV) once every 3 weeks concurrently<br>|
| Active Comparator: Pemetrexed/Cisplatin<br>Drug: Pemetrexed 500 mg/m² IV on day 1 of each 21 day cycle. Number of cycles until disease progression or unacceptable toxicity develops. Drug: Cisplatin 75mg/m2 IV on day 1 of each 21 day cycle. Number of cycles until disease progression or unacceptable toxicity develops. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: The patient continues to receive treatment until the disease progresses or reaches termination criteria. If disease progresses during the treatment period and conditions required for the cross-treatment are met according to the assessment process, the patient can start to receive the open cross-treatment of Almonertinib. The overall treatment last for 3 years. | Drug: Pemetrexed<br>* 500 milligrams per square meter (mg/m²) Pemetrexed<br>Drug: Cisplatin<br>* 75mg/m² Cisplatin taken intravenously (IV) once every 3 weeks concurrently<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) | Defined as the time from the date of randomization until the date of disease recurrence or death (by any cause in the absence of recurrence) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) | Defined as the proportion of patients alive and disease free at 2, 3 ,4and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Overall Survival (OS) | Defined as the time from the date of randomization until date of death due to any cause. | Start of study drug to Survival Endpoint through study completion, an average of 5 years, assessed up to 100 months | 
| Patient health-related quality of life and symptoms (HRQoL) by SF-36v2 Health Survey | Defined as a patient-reported survey of patient health. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section and the scores range from 0-100. A score of 0 is equivalent to maximum disability and a score of 100 is equivalent to no disability. | From date of randomization until treatment completion or discontinuation, assessed up to 100 months |