Non-Small Cell Lung Cancer
Conditions
Keywords
Resectable; NSCLC; Osimertinib; EGFRm Positive; Neoadjuvant; Adjuvant
Brief summary
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
Interventions
DRUGOsimertinib
Oral
DRUGCisplatin
Cisplatin (75mg/m2) to be administered with pemetrexed on Day 1 of every 3-week cycle for 3 cycles.
DRUGCarboplatin
Carboplatin (AUC5) to be administered with pemetrexed on Day 1 of every 3-week cycle for 3 cycles
DRUGPlacebo
Oral
DRUGPemetrexed
Pemetrexed (500 mg/m2) to be administered with cisplatin or carboplatin on Day 1 of every 3-week cycle for 3 cycles
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The two arms with SoC chemotherapy (placebo plus chemotherapy versus osimertinib plus chemotherapy) will be double-blinded and placebo-controlled. Osimertinib monotherapy arm will be open label, sponsor-blind.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response (MPR) - IASLC Method | From date of randomization to an average of 12 weeks after the first dose | Defined as ≤10% viable cancer cells in the surgical specimen, as assessed per central pathology laboratory post-surgery (IASLC method). Patients will only be considered to have an MPR if they also have an R0 margin result. |
| Major Pathological Response (MPR) - Chemotherapy Method | From date of randomization to an average of 12 weeks after the first dose | Defined as ≤10% viable cancer cells in the surgical specimen, as assessed per central pathology laboratory post-surgery (chemotherapy method). Patients will only be considered to have an MPR if they also have an R0 margin result. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) - IASLC Method | From date of randomization to an average of 12 weeks after the first dose | 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 using IASLC method. Patients will only be considered to have pCR if they also have an R0 margin result based on site assessment. |
| Pathological Complete Response (pCR) - Chemotherapy Method | From date of randomization to an average of 12 weeks after the first dose | 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 using chemotherapy method. Patients will only be considered to have pCR if they also have an R0 margin result based on site assessment. |
| Downstaging | From date of randomization to an average of 12 weeks after the first dose. | Measured using pathologic mediastinal lymph node evaluation. Pathological downstaging is defined as baseline N2 patients becoming N1/N0 or N1 to N0 at the time of surgery. Only patients with pathological staging at both baseline and surgery are included in this analysis. |
| Concordance of EGFRm Status Between Tumor Tissue DNA and Patient-matched Plasma-derived ctDNA (Mutation Ex19Del or L858R) | Screening/Baseline | Comparing the baseline central cobas® EGFR Mutation Test V2 between tumor tissue DNA and matched plasma ctDNA results (excluding invalid results). Since this endpoint uses pre-randomization data, treatment arms were combined for the analysis. |
| Concordance of EGFR Mutation Status Between the Local and Central Test Results From Baseline Tumor Samples (Mutation Ex19Del or L858R) | Screening/Baseline | Comparing the local EGFR mutation test result used for patient selection with the retrospective baseline central cobas® EGFR Mutation Test V2 results (excluding invalid results). Since this endpoint uses pre-randomization data, treatment arms were combined for the analysis. |
| Change From Baseline in EORTC QLQ-C30 Primary Subscale Scores (Neoadjuvant Period) | Assessed at baseline, Cycle 2 Day1, Cycle 3 Day1, and Pre-surgical assessment (on D64, -1 to +21 days ). | Average change from baseline across all visits are reported. The analysis was performed using a MMRM analysis on the change from baseline in the score at each visit, including subject (random effect), treatment, visit (fixed effect \& repeated measure) and treatment by visit interaction as explanatory variables, with the baseline score as a covariate along with the baseline score by assessment interaction. EORTC QLQ-C30 has 30 questions and questions are combined to produce symptom scales, individual symptom items, functional scales, and global health status (GHS)/quality of life (QoL). Each of the scale/items range from 0-100 after a linear transformation. Positive change from baseline scores on the GHS/QoL and functioning scales indicate improvement on health status/function, and negative change scores on symptom scales/items represent less symptom severity/improvement on symptom status. |
| Change From Baseline in EORTC QLQ-LC13 Primary Subscale Scores (Neoadjuvant Period) | Assessed at baseline, Cycle 2 Day1, Cycle 3 Day1, and Pre-surgical assessment (on D64, -1 to +21 days). | Average change from baseline across all visits are reported. The analysis was performed using a MMRM analysis on the change from baseline in the score at each visit, including subject (as a random effect), treatment, visit (as fixed effect and repeated measure) and treatment by visit interaction as explanatory variables, with the baseline score as a covariate along with the baseline score by assessment interaction. EORTC QLQ-LC13 has 13 questions and scores range from 0-100 after a linear transformation. Questions assess cough, hemoptysis, dyspnea, site specific pain, sore mouth, dysphagia, peripheral neuropathy, and alopecia and pain medication. While the QLQ-LC13 includes more scales, only the Coughing, Pain in chest, and Dyspnea subscale scores were analyzed for this endpoint. Negative change from baseline scores indicates less symptom severity, and thus improvement on health status. |
| PK Plasma Concentrations of Osimertinib | From the pre-dose of Cycle 2 to post-dose of Cycle 3 (each cycle is 21 days) | Summary of plasma concentrations (nM) of Osimertinib |
| PK Plasma Concentrations of AZ5104 | From the pre-dose of Cycle 2 to post-dose of Cycle 3 (each cycle is 21 days) | Summary of plasma concentrations (nM) of AZ5104 |
Countries
Austria, Brazil, Bulgaria, Canada, Chile, China, France, Germany, India, Israel, Italy, Japan, Mexico, Peru, Poland, Russia, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States, Vietnam
Contacts
PRINCIPAL_INVESTIGATORJamie Chaft, MD
Memorial Sloan Kettering, USA
PRINCIPAL_INVESTIGATORkeiju Aokage, MD
National Cancer Center Hospital East, Japan
PRINCIPAL_INVESTIGATORWalter Weder, MD
Thoraxchirurgie Bethanien, Switzerland
Participant flow
Recruitment details
This Phase III, randomized, controlled, 3-arm, multi-center study was conducted in patients with resectable EGFRm NSCLC. A total of 1044 participants were screened between 16DEC2020 and 08DEC2023. 358 were randomized in a 1:1:1 ratio to 3 study arms. 2 participants were randomized to Osi + Chemo arm but did not receive any treatment (2 withdrawn).
Pre-assignment details
All participants completed a pre-screening and screening period during which EGFR mutation type, disease stage, and inclusion/exclusion criteria were assessed, clinical laboratories, and radiological assessment were administered. Prior to randomization, the Investigator decided which chemotherapy regimen (carboplatin/pemetrexed or cisplatin/pemetrexed) a patient will receive in the event of randomization to a chemotherapy containing treatment arm.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 64.1 years STANDARD_DEVIATION 9.71 |
| Age, Customized >=50 and <65 years | 140 Participants |
| Age, Customized <50 years | 11 Participants |
| Age, Customized >=65 and <75 years | 138 Participants |
| Age, Customized >=75 years | 13 Participants |
| Race/Ethnicity, Customized Asian | 90 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 6 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 114 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 85 Participants |
| Sex: Female, Male Female | 72 Participants |
| Sex: Female, Male Male | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 121 | 7 / 117 | 7 / 120 |
| other Total, other adverse events | 106 / 119 | 88 / 117 | 101 / 120 |
| serious Total, serious adverse events | 24 / 119 | 13 / 117 | 24 / 120 |
Outcome results
None listed