Non-Small Cell Lung Cancer
Conditions
Brief summary
The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Safety and efficacy will also be measured.
Detailed description
Naïve patients ≥ 18 years of age with histological confirmation of locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M mutation. Evidence of measurable or evaluable metastatic disease is required. Primary objective: * To evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Secondary objectives: * To determine the safety and tolerability profile of osimertinib (AZD9291), measured using the number and severity of AEs entered into the Case Report Form (CRF); chemistry, blood count, vital signs, physical examination, weight, ECG and performance status (S). * To determine other efficacy parameters such as progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), duration of response (DOR), disease control rate (DCR), and tumor shrinkage (TS). * To correlate the parameters of clinical response efficacy documented with the EGFR mutational status. * To carry out a longitudinal analysis of EGFR mutations (including the T790M mutation) in plasma and serum. * To determine levels of BIM mRNA as well as mRNA levels of other biomarkers related to EGFR TKI response and determine whether they are predictors of treatment response. * To identify mechanisms of acquired resistance to osimertinib (AZD9291); mutations at the site of covalent binding to the drug (C797) or other mutations in tissue or blood. Type of study: Multicenter, international, single-arm, open-label, non-controlled phase IIa clinical study. Treatment: Patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily.
Interventions
DRUGOsimertinib
The patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily up to 78 weeks from the time of the first administered dose.
Sponsors
AstraZeneca
MedSIR
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient aged 18 years or older * Patients with histological confirmation of locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M mutation who are not candidates for local curative treatment. * Patients with a M1a stage according to the TNM version 7 including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease that is not a candidate for curative treatment (including patients who progress after chemoradiotherapy in stage III disease). * Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally. * ECOG (Eastern Cooperative Oncology Group) performance status less than or equal to 2. * Existence of measurable or evaluable disease (as per RECIST 1.1 criteria). Patients with asymptomatic and stable brain metastases are eligible for the study. * Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the primary tumor or metastatic tumor tissue, within the 60 days prior to study entry. * Life expectancy ≥12 weeks. * Adequate hematologic function: * Absolute neutrophil count (ANC) \> 1.5 x 109/L * platelet count \> 100.0 x109/L * hemoglobin \> 9.0 g/dL (\> 6.2 mmol/L). * Adequate coagulation: INR ≤ 1.5. * Adequate liver function * Adequate renal function. * Capacity to swallow, patient capable of completing treatment and accessible, ensuring proper follow-up. * Patients able to complete study and within geographical proximity allowing for adequate follow-up. * Resolution of all acute toxic effects of previous anti-cancer therapy (which can only be adjuvant or neoadjuvant) or surgical interventions not exceeding grade ≤ 1 according to the NCI CTCAE version 4.0 (except for alopecia or other side effects that the investigator does not consider to be a risk to patient safety). * All men or women of childbearing potential must use a contraception method during the study treatment and for at least 12 months after the last dose of the study drug. * Signed and dated informed consent form
Exclusion criteria
* Locally advanced lung cancer candidate for curative treatment through radical surgery and/or radio(chemo)therapy. * Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC with predominantly squamous cell cancer, or with any small-cell lung cancer component. * Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment that have not been confirmed centrally. * Patients who have received prior antineoplastic treatment for advanced disease. * Second active neoplasia * Patients with just one measurable or evaluable tumor lesion that has been resected or irradiated prior to their enrollment in the study. * Medical history of Interstitial Lung Disease (ILD) induced by drugs, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD. * Corrected QT Interval (QTc) \>470 msec, obtained from 3 ECGs at rest, using the QTc value determined according to the clinical screening ECG machine. * Any clinically significant abnormality in ECG rhythm, conduction or morphology at rest. * Any factor that increases the risk of QTc prolongation or risk of irregular heartbeat or sudden inexplicable death under the age of 40 in first-degree relatives or any concomitant medications that prolong the QT interval. * Uncontrolled, active or symptomatic metastases of CNS, carcinomatous meningitis or leptomeningeal disease indicated by known clinical symptoms, cerebral edema and/or progressive neoplasia. Patients with history of CNS metastasis or compression of the spinal cord are eligible if they have received local final treatment (e.g., radiotherapy, stereotactic surgery) and if they have remained clinically stable without using anticonvulsants and corticosteroids for a minimum of 4 weeks prior to the first day of study treatment. * Refractory nauseas and vomiting, chronic gastrointestinal disease, inability to swallow study drug or significant intestinal resection that restricts the adequate absorption of osimertinib (AZD9291). * Patients who have had a surgical procedure unrelated to the study within 7 days prior to the administration of the drug or a significant traumatic lesion during the 4 weeks prior to starting the administration of the study drug, patients who have not recovered from the side effects of any major surgery or patients who might need major surgery during the course of the study. * Pregnant or breastfeeding women. Women of childbearing potential, including women who had their last menstrual period within the last two years, must have a negative serum or urine pregnancy test in the 7 days prior to the start of the treatment. * Patients who are not willing to use an adequate contraception method until 12 months after the last dose of study treatment. * Patients with a serious concomitant systemic disorder (e.g., active infection, including HIV or heart disease) that is incompatible with the study (in the opinion of the investigator), history of bleeding diathesis or anticoagulant therapy (the use of low molecular weight heparin is permitted provided that it is used for prophylaxis). * Patients with a history of cancer that has been completely treated, with no evidence of malignant disease currently cannot be enrolled in the study if their chemotherapy was completed less than 6 months prior and/or have received a bone marrow transplant less than 2 years before the first day of study treatment. * Prior treatment with cytotoxic chemotherapy for advanced NSCLC; neoadjuvant/adjuvant chemotherapy is permitted if at least 6 months have elapsed between the end of chemotherapy and the first day of study treatment. * Patients who have received prior EGFR treatments for lung cancer. * Patients who have received treatment with an investigational drug within 3 weeks before the first day of study treatment. * Treatment with prohibited drugs within 14 days before the first day of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Through study completion. From baseline up to approximately 28 months. | Defined as the percentage of patients who achieved complete response \[CR\] and partial response \[PR\] to treatment in accordance to the revised RECIST guidelines (version 1.1) for target lesions: CR, disappearance of all target lesions; PR: at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DoR) | Through study completion. From baseline up to 41 months. | Time from the first documented response to documented disease progression or death, in accordance with RECIST 1.1 criteria. |
| Disease Control Rate | Through study completion. From baseline up to 41 months. | Percentage of patients with complete response, partial response or stable disease for a minimum of 24 weeks, assessed in accordance with the modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, during all study period from baseline up to 78 weeks from the time of the first administration dose |
| Tumor Shrinkage | Through study completion. From baseline up to 41 months. | Number of patients that presented tumor shrinkage |
| Overall Plasma EGFR Mutation Status at Baseline | Baseline | Percentage of patients with a positive sensitizing EGFR mutation in plasma at baseline |
| Overall Plasma Acquired Resistance to Osimertinib (AZD9291) | Through study completion. From baseline up to 41 months. | Percentage of patients who develop anti-drug mutations in plasma |
| Number of Participants With Grade 3 or 4 Adverse Events and SAEs | Through study completion. From baseline up to 41 months. | Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4. Adverse event(s) are those which, according to the protocol or in the opinion of the investigator, can cause serious or permanent damage or which rule out further treatment with the study drug. Grade 3 means severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 means life-threatening consequences; urgent intervention indicated. |
| Overall Survival (OS) | Through study completion. From baseline up to 41 months. | Time from the start of treatment to the time of death due to any cause. |
| Overall Plasma EGFR Mutation Status at Two Weeks After the First Study Dose | Two weeks after the first study dose | Measured by percentage of patients with a positive sensitizing EGFR mutation in plasma two weeks after the first study dose |
| Overall Plasma EGFR Mutation Status at Disease Progression | At the time of disease progression confirmed radiologically or clinically, up to 78 weeks | Measured by percentage of patients with a positive sensitizing EGFR mutation in plasma at disease progression |
| Plasma EGFR Thr790Met Mutation Status at Baseline | At baseline | Measured by percentage of patients with EGFR Thr790Met mutation in plasma at baseline |
| Plasma EGFR Thr790Met Mutation Status at Two Weeks After the First Study Dose | Two weeks after the first study dose | Measured by percentage of patients with EGFR Thr790Met mutation in plasma at two weeks after the first study dose |
| Plasma EGFR Thr790Met Mutation Status at Disease Progression | At the time of disease progression confirmed radiologically or clinically, up to 78 weeks | Measured by percentage of patients with EGFR Thr790Met mutation in plasma at disease progression |
| Progression-free Survival | Through study completion. From baseline up to 41 months. | Defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1. |
Countries
Spain
Participant flow
Pre-assignment details
Fifty-one patients were screened of whom 22 patients with advanced NSCLC harbouring pre-treatment sensitising EGFR and Thr790Met mutations were enrolled and started to receive first-line osimertinib.
Participants by arm
| Arm | Count |
|---|---|
| Osimertinib The patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily. Patients will receive study treatment until disease progression or occurrence of unacceptable side effects up to 78 weeks from the time of the first administered dose.
Osimertinib: The patients will be treated with 1 tablet of osimertinib (AZD9291) 80 mg per os (p.o.) daily up to 78 weeks from the time of the first administered dose. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Lack of Efficacy | 9 |
Baseline characteristics
| Characteristic | Osimertinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Central nervous system metastases No | 19 Participants |
| Central nervous system metastases Yes | 3 Participants |
| EGFR sensitizing mutation Ex19del | 6 Participants |
| EGFR sensitizing mutation Leu858Arg | 8 Participants |
| EGFR sensitizing mutation Thr790Met | 2 Participants |
| Race/Ethnicity, Customized Black | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 21 Participants |
| Region of Enrollment Spain | 22 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
| Smoking history Former | 9 Participants |
| Smoking history Never | 13 Participants |
| Tissue EGFR sensitizing mutation Ex19del | 10 Participants |
| Tissue EGFR sensitizing mutation Gly719X | 3 Participants |
| Tissue EGFR sensitizing mutation Leu858Arg | 9 Participants |
| Tissue EGFR sensitizing mutation Thr790Met | 22 Participants |
| Tumor stage IIIB | 2 Participants |
| Tumor stage IV | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 22 |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 10 / 22 |
Outcome results
Primary
Objective Response Rate (ORR)
Defined as the percentage of patients who achieved complete response \[CR\] and partial response \[PR\] to treatment in accordance to the revised RECIST guidelines (version 1.1) for target lesions: CR, disappearance of all target lesions; PR: at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Through study completion. From baseline up to approximately 28 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib | Objective Response Rate (ORR) | 77.3 percentage of patients |
Secondary
Disease Control Rate
Percentage of patients with complete response, partial response or stable disease for a minimum of 24 weeks, assessed in accordance with the modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, during all study period from baseline up to 78 weeks from the time of the first administration dose
Time frame: Through study completion. From baseline up to 41 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Disease Control Rate | 19 Participants |
Secondary
Duration of Response (DoR)
Time from the first documented response to documented disease progression or death, in accordance with RECIST 1.1 criteria.
Time frame: Through study completion. From baseline up to 41 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Duration of Response (DoR) | 20.0 months |
Secondary
Number of Participants With Grade 3 or 4 Adverse Events and SAEs
Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4. Adverse event(s) are those which, according to the protocol or in the opinion of the investigator, can cause serious or permanent damage or which rule out further treatment with the study drug. Grade 3 means severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 means life-threatening consequences; urgent intervention indicated.
Time frame: Through study completion. From baseline up to 41 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Number of Participants With Grade 3 or 4 Adverse Events and SAEs | 10 Participants |
Secondary
Overall Plasma Acquired Resistance to Osimertinib (AZD9291)
Percentage of patients who develop anti-drug mutations in plasma
Time frame: Through study completion. From baseline up to 41 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Overall Plasma Acquired Resistance to Osimertinib (AZD9291) | 7 Participants |
Secondary
Overall Plasma EGFR Mutation Status at Baseline
Percentage of patients with a positive sensitizing EGFR mutation in plasma at baseline
Time frame: Baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Overall Plasma EGFR Mutation Status at Baseline | 15 Participants |
Secondary
Overall Plasma EGFR Mutation Status at Disease Progression
Measured by percentage of patients with a positive sensitizing EGFR mutation in plasma at disease progression
Time frame: At the time of disease progression confirmed radiologically or clinically, up to 78 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Overall Plasma EGFR Mutation Status at Disease Progression | 8 Participants |
Secondary
Overall Plasma EGFR Mutation Status at Two Weeks After the First Study Dose
Measured by percentage of patients with a positive sensitizing EGFR mutation in plasma two weeks after the first study dose
Time frame: Two weeks after the first study dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Overall Plasma EGFR Mutation Status at Two Weeks After the First Study Dose | 5 Participants |
Secondary
Overall Survival (OS)
Time from the start of treatment to the time of death due to any cause.
Time frame: Through study completion. From baseline up to 41 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Overall Survival (OS) | 28.39 months |
Secondary
Plasma EGFR Thr790Met Mutation Status at Baseline
Measured by percentage of patients with EGFR Thr790Met mutation in plasma at baseline
Time frame: At baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Plasma EGFR Thr790Met Mutation Status at Baseline | 2 Participants |
Secondary
Plasma EGFR Thr790Met Mutation Status at Disease Progression
Measured by percentage of patients with EGFR Thr790Met mutation in plasma at disease progression
Time frame: At the time of disease progression confirmed radiologically or clinically, up to 78 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Plasma EGFR Thr790Met Mutation Status at Disease Progression | 2 Participants |
Secondary
Plasma EGFR Thr790Met Mutation Status at Two Weeks After the First Study Dose
Measured by percentage of patients with EGFR Thr790Met mutation in plasma at two weeks after the first study dose
Time frame: Two weeks after the first study dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Plasma EGFR Thr790Met Mutation Status at Two Weeks After the First Study Dose | 2 Participants |
Secondary
Progression-free Survival
Defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1.
Time frame: Through study completion. From baseline up to 41 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osimertinib | Progression-free Survival | 23.1 months |
Secondary
Tumor Shrinkage
Number of patients that presented tumor shrinkage
Time frame: Through study completion. From baseline up to 41 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osimertinib | Tumor Shrinkage | 17 Participants |