Advanced Non Small Cell Lung Cancer (NSCLC)
Conditions
Keywords
Non-small cell lung carcinoma (NSCLC), treatment of lung cancer after first metastasis, lung cancer, lung adenocarcinoma, Squamous cell lung carcinoma, Large-cell lung carcinoma, Non small cell lung carcinoma, Non small cell lung cancer, Non-small cell lung cancer, NSCLC, Large cell lung carcinoma, Large cell lung cancer, HSP90, AUY922, Pemetrexed, Docetaxel, EGFR TKI, EGFR mutations
Brief summary
The purpose of this study was to determine if AUY922 had superior efficacy when compared to chemotherapy agents docetaxel or pemetrexed in patients whose tumor had EGFR mutations. The primary purpose of this study was to compare the efficacy of AUY922, when administered i.v. on a once-weekly schedule at 70 mg/m2, versus docetaxel or pemetrexed in adult patients with advanced NSCLC, whose tumors harbored EGFR activating mutations, and had developed resistance to EGFR TKI.
Interventions
DRUGAUY922
AUY922 was to be given by i.v. once weekly at 70 mg/m2 until disease progression, death or any other reason for discontinuation from study treatment.
DRUGDocetaxel
Docetaxel was to be given i.v. once every 3 weeks at 75 mg/m2 until progression or unacceptable toxicity
DRUGPemetrexed
Pemetrexed was to be given once every 3 weeks at 500 mg/m2 until progression or unacceptable toxicity
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with histologically or cytologically documented, locally advanced (stage IIIB who are not amenable to combined modality treatment) or recurrent or metastatic (Stage IV) non-small cell lung cancer. 2. Patients must have EGFR gene mutation in their tumors. This can be source - documented by one of the following: • Provide a pathology report that indicates the patient's tumor had EGFR activating mutation in the past. Or: • Perform testing (local or central) in an archival tumor or a fresh baseline biopsy tumor tissue to show the presence of EGFR activating mutation. 3. Patients must have documented clinical benefit (CR, PR, or patients with SD for 6 months or greater) on prior EGFR TKI (e.g. erlotinib or gefitinib) followed by documented progression according to RECIST. 4. Patients must have received prior platinum containing treatment. 5. WHO performance status of 0-1
Exclusion criteria
1. Patients who have received more than two prior lines of antineoplastic therapy for advanced disease. Chemotherapy administered as neoadjuvant or adjuvant treatment more than six months prior to study enrollment is not considered a prior line of therapy for purposes of this study. 2. Evidence of spinal cord compression or current evidence of CNS metastases. Screening CT/MRI of the brain is mandatory. Note: Patients who have been treated for CNS metastases by radiation or gamma knife surgery, who been stable for at least 2 months and have discontinued high dose corticosteroids will be eligible for protocol participation 3. Prior treatment with an HSP90 inhibitor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 16 months | Compared PFS between the treatment of AUY922 to comparators Pemetrexed or Docetaxel. Progression-free survival (PFS) based on local investigator assessment per RECIST 1.1 was the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient had not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | from randomization until death up to death | OS is defined as the time from the date of randomization to date of death due to any cause. If a death has not been observed by the date of analysis cutoff, then OS was to be censored at the last known date patient was alive. |
| Disease Control Rate (DCR) | baseline, until disease progression up to 24 months | Duration of DCR will be compared between treatment arms. The duration of DCR will be based on local investigator assessment per RECIST 1.1 |
| Time to Response (TRR) | baseline, until disease progression up to 24 months | TTR was to compare between treatment arms. The TTR was to be based on local investigator assessment per RECIST 1.1 |
| Overall Response Rate (ORR) | 16 months | ORR was to be compared between treatment arms. The ORR was to be based on local investigator assessment per Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST 1.1). Per this criteria for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.This outcome measure was originally planned to be analyzed up to 24 months. The DMC recommendation at the IA was to stop the study for futility. As a result, collection of all the efficacy assessments was stopped at that time. |
| Rate of Adverse Events (AEs) | baseline, until disease progression up to 24 months | To evaluate safety and tolerability of AUY922 compared to chemotherapy agents pemetrexed or docetaxel. |
| Change in Laboratory Paramenters | baseline, until disease progression up to 24 months | Changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), Dose interruptions, reductions and dose intensity. |
| Time to Progression (TTP) | baseline, until disease progression up to 24 months | TTP will be compared between treatment arms. The TTP will be based on local investigator assessment per RECIST 1.1 |
| Duration of Response (DOR) | baseline, until disease progression up to 24 months | The DOR will be compared between treatment arms. The DOR will be based on local investigator assessment per RECIST 1.1 |
Countries
France, Hong Kong, Italy, Japan, Netherlands, Norway, Poland, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Patients were randomized in a ratio of 1:1 to receive either AUY922 or pemetrexed/docetaxel. A total of 59 participants were randomized in the study: 31 to the AUY922 arm and 28 to the chemotherapy arm. 2 patients from the AUY922 arm & 5 from the chemotherapy arm were not treated. Only 52 received at least 1 dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| AUY922 Arm Participants were assigned to one of two treatment arms in a ratio of 1:1. This was the investigational drug arm.
AUY922 was to be administered weekly. | 31 |
| Chemotherapy Arm Participants were assigned to one of two treatment arms in a ratio of 1:1. This was the control arm drug arm.
Pemetrexed or docetaxel was to be was to be given once every three weeks. | 28 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Progressive disease | 22 | 16 |
| Overall Study | Study terminated by sponsor | 2 | 1 |
| Overall Study | Subject/Guardian decision | 1 | 1 |
| Overall Study | Untreated | 2 | 5 |
Baseline characteristics
| Characteristic | AUY922 Arm | Chemotherapy Arm | Total |
|---|---|---|---|
| Age, Continuous | 61.8 Years STANDARD_DEVIATION 10.1 | 62.1 Years STANDARD_DEVIATION 10.34 | 61.9 Years STANDARD_DEVIATION 10.13 |
| Sex: Female, Male Female | 27 Participants | 21 Participants | 48 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 29 | 21 / 23 | 49 / 52 |
| serious Total, serious adverse events | 10 / 29 | 6 / 23 | 16 / 52 |
Outcome results
Primary
Progression Free Survival (PFS)
Compared PFS between the treatment of AUY922 to comparators Pemetrexed or Docetaxel. Progression-free survival (PFS) based on local investigator assessment per RECIST 1.1 was the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient had not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: 16 months
Population: Efficacy analysis set (EAS) compromised of a subset of patients in the FAS who received 2 lines of prior antineoplastic therapy consisting of a platinum-based treatment \& an EGFR TKI treatment. The DMC recommendation at Interim analysis was to stop the study for futility. As a result, collection of all efficacy assessments was stopped.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AUY922 Arm | Progression Free Survival (PFS) | 1.5 Months |
| Chemotherapy Arm | Progression Free Survival (PFS) | 2.3 Months |
90% CI: [0.35, 1.63]
Secondary
Change in Laboratory Paramenters
Changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), Dose interruptions, reductions and dose intensity.
Time frame: baseline, until disease progression up to 24 months
Population: The data monitoring committee (DMC's) recommendation based on the Interim Analysis (IA) results was to terminate the study early due to futility; collection of efficacy data for assessment was stopped at that time.
Secondary
Disease Control Rate (DCR)
Duration of DCR will be compared between treatment arms. The duration of DCR will be based on local investigator assessment per RECIST 1.1
Time frame: baseline, until disease progression up to 24 months
Population: The data monitoring committee (DMC's) recommendation based on the Interim Analysis (IA) results was to terminate the study early due to futility; collection of efficacy data for assessment was stopped at that time.
Secondary
Duration of Response (DOR)
The DOR will be compared between treatment arms. The DOR will be based on local investigator assessment per RECIST 1.1
Time frame: baseline, until disease progression up to 24 months
Population: The data monitoring committee (DMC's) recommendation based on the Interim Analysis (IA) results was to terminate the study early due to futility; collection of efficacy data for assessment was stopped at that time.
Secondary
Overall Response Rate (ORR)
ORR was to be compared between treatment arms. The ORR was to be based on local investigator assessment per Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST 1.1). Per this criteria for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.This outcome measure was originally planned to be analyzed up to 24 months. The DMC recommendation at the IA was to stop the study for futility. As a result, collection of all the efficacy assessments was stopped at that time.
Time frame: 16 months
Population: The data monitoring committee's (DMC's) recommendation based on the Interim Analysis (IA) results was to terminate the study early due to futility; collection of efficacy data for assessment was stopped at that time.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUY922 Arm | Overall Response Rate (ORR) | Complete Response (CR) | 0 Participants |
| AUY922 Arm | Overall Response Rate (ORR) | Partial Response (PR) | 3 Participants |
| AUY922 Arm | Overall Response Rate (ORR) | ORR (CR + PR) | 3 Participants |
| Chemotherapy Arm | Overall Response Rate (ORR) | Complete Response (CR) | 0 Participants |
| Chemotherapy Arm | Overall Response Rate (ORR) | Partial Response (PR) | 2 Participants |
| Chemotherapy Arm | Overall Response Rate (ORR) | ORR (CR + PR) | 2 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from the date of randomization to date of death due to any cause. If a death has not been observed by the date of analysis cutoff, then OS was to be censored at the last known date patient was alive.
Time frame: from randomization until death up to death
Population: The data monitoring committee (DMC's) recommendation based on the Interim Analysis (IA) results was to terminate the study early due to futility; collection of efficacy data for assessment was stopped at that time.
Secondary
Rate of Adverse Events (AEs)
To evaluate safety and tolerability of AUY922 compared to chemotherapy agents pemetrexed or docetaxel.
Time frame: baseline, until disease progression up to 24 months
Population: The data monitoring committee (DMC's) recommendation based on the Interim Analysis (IA) results was to terminate the study early due to futility; collection of efficacy data for assessment was stopped at that time.
Secondary
Time to Progression (TTP)
TTP will be compared between treatment arms. The TTP will be based on local investigator assessment per RECIST 1.1
Time frame: baseline, until disease progression up to 24 months
Population: The data monitoring committee (DMC's) recommendation based on the Interim Analysis (IA) results was to terminate the study early due to futility; collection of efficacy data for assessment was stopped at that time.
Secondary
Time to Response (TRR)
TTR was to compare between treatment arms. The TTR was to be based on local investigator assessment per RECIST 1.1
Time frame: baseline, until disease progression up to 24 months
Population: The data monitoring committee (DMC's) recommendation based on the Interim Analysis (IA) results was to terminate the study early due to futility; collection of efficacy data for assessment was stopped at that time.