Non-small Cell Lung Cancer (NSCLC)
Conditions
Keywords
erlotinib, EGFR mutation, naquotinib, Non-small cell lung cancer (NSCLC), ASP8273, gefitinib
Brief summary
The purpose of the study was to evaluate the progression free survival (PFS), based on independent radiologic review (IRR), of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations. This study also assessed Overall survival (OS); Overall response rate (ORR) as assessed by IRR; PFS as assessed by the investigator; Disease control rate (DCR) as assessed by IRR; Duration of Response (DOR) by IRR; Safety of ASP8273; and Quality of Life (QOL) and patient-reported outcome (PRO) parameters.
Interventions
DRUGnaquotinib mesilate
Participants received ASP8273 300 mg orally once daily on an empty stomach (no food for at least 2 hours before and 1 hour after taking drug) at approximately the same time every day.
DRUGErlotinib
Participants received erlotinib 150 mg orally once daily on an empty stomach (no food for at least 2 hours before and 1 hour after taking drug) at approximately the same time every day. At the beginning of the trial, prior to site initiation and shipment of study drug supplies, each investigator selected either erlotinib or gefitinib to be utilized for all participants randomized to the comparator arm at their site.
DRUGGefitinib
Participants received gefitinib 250 mg was taken orally once daily with water, with or without food, at approximately the same time every day. At the beginning of the trial, prior to site initiation and shipment of study drug supplies, each investigator selected either erlotinib or gefitinib to be utilized for all participants randomized to the comparator arm at their site.
Sponsors
Astellas Pharma Global Development, Inc.
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
* Subject agrees not to participate in another interventional study while on treatment. * Female subject must either: * Be of nonchildbearing potential: postmenopausal (defined as at least 1 year without any menses) prior to Screening, or documented surgically sterile * Or, if of childbearing potential: Agree not to try to become pregnant during the study and for 28 days after the final study drug administration; And have a negative serum pregnancy test at Screening; And, if heterosexually active, agree to consistently use 2 forms of highly effective birth control (at least 1 of which must be a highly effective method and one must be a barrier method) starting at Screening and throughout the study period and for 28 days after the final study drug administration. * Female subject must not be breastfeeding at Screening or during the study period, and for 28 days after the final study drug administration. * Female subject must not donate ova starting at Screening and throughout the study period, and for 28 days after the final study drug administration. * Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at Screening and continue throughout the study period and for 90 days after the final study drug administration. * Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after the final study drug administration. * Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. * Subject has histologically confirmed locally advanced, metastatic or unresectable Stage IIIB/IV adenocarcinoma NSCLC (newly diagnosed or recurrent). Subjects with mixed histology are eligible if adenocarcinoma is the predominant histology. * Subject has predicted life expectancy ≥ 12 weeks in the opinion of the investigator. * Subject must meet all of the following criteria on the laboratory tests that will be analyzed centrally within 7 days prior to the first dose of study drug. In case of multiple laboratory data within this period, the most recent data should be used. * Neutrophil count \> 1,000/mm3 * Platelet count ≥ 7.5 x 104 /mm3 * Hemoglobin \> 8.0 g/dL * Serum creatinine ˂ 2.0 x upper limit of normal (ULN) or an estimated glomerular filtration rate (eGFR) of \> 50 mL/min as calculated by the Cockcroft Gault Method * Total bilirubin ˂1.5 x ULN (except for subjects with documented Gilbert's syndrome) * AST and ALT ˂ 3.0 x ULN or ≤ 5 x ULN if subject has documented liver metastases * Serum sodium level is ≥ 130 mmol/L * Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or without T790M mutation, by local or central testing on examination of a NSCLC FFPE specimen (archival or fresh biopsy). Subjects harboring both exon 19 deletion and exon 21 L858R mutations are not eligible. A tissue sample from the same block used to determine eligibility by local testing should be available to send to the central lab for confirmatory testing. Subjects randomized based on local results indicating presence of EGFR mutation may remain on study if central results are discordant. * Subject must have at least 1 measureable lesion based on RECIST V1.1. Previously irradiated lesions will not be considered as measurable lesions.
Exclusion criteria
* Subject has received intervening anticancer treatment or previous treatment with chemotherapy for metastatic disease other than palliative local radiation to painful bone metastases completed at least 1 week prior to the first dose of study drug. The administration of neoadjuvant or adjuvant chemotherapy is allowed as long as it has finalized ≥ 6 months before the first dose of study drug. * Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib, dacomitinib, ASP8273, etc). * Subject has received investigational therapy within 28 days or 5 half-lives prior to the first dose of study drug. * Subject has received radiotherapy within 1 week prior to the first dose of study drug. If the subject received radiotherapy \> 1 week prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response. * Subject has symptomatic central nervous system (CNS) metastasis. Subject with previously treated brain or CNS metastases are eligible provided that the subject has recovered from any acute effects of radiotherapy, does not have brain metastasis related symptoms, is not requiring systemic steroids for at least 2 weeks prior to study drug administration, and any whole brain radiation therapy was completed at least 4 weeks prior to study drug administration, or any stereotactic radiosurgery (SRS) was completed at least 2 weeks prior to study drug administration. Steroid inhaler use or ointment treatment for other concomitant medical disease is permitted. * Subject has received blood transfusions or hematopoietic factor therapy within 14 days prior to the first dose of study drug. * Subject has had a major surgical procedure (other than a biopsy) within 14 days prior to the first dose of study drug, or one is planned during the course of the study. * Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection. * Subject has known history of serious hypersensitivity reaction to a known ingredient of ASP8273, erlotinib or gefitinib. * Subject has evidence of an active infection requiring systemic therapy within 14 days prior to the planned first dose of study drug. * Subject has severe or uncontrolled systemic diseases including uncontrolled hypertension (blood pressure \> 150/100 mmHg) or active bleeding diatheses. * Subject has history of drug-induced interstitial lung disease (ILD) or any evidence of active ILD. * Subject has ongoing cardiac arrhythmia that is Grade ≥ 2 or uncontrolled atrial fibrillation of any grade. * Subject currently has Class 3 or 4 New York Heart Association congestive heart failure. * Subject has history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months prior to the planned first dose of study drug. * Subject has history of gastrointestinal ulcer or gastrointestinal bleeding within 3 months prior to the planned first dose of study drug. * Subject has concurrent corneal disorder or any ophthalmologic condition which, in the investigator's opinion, makes the subject unsuitable for study participation (i.e., advanced cataracts, glaucoma). * Subject has difficulty taking oral medication or any digestive tract dysfunction or inflammatory bowel disease that would interfere with the intestinal absorption of drug. * Subject has another past or active malignancy which requires treatment. Prior carcinoma in situ or non-melanoma skin cancer after curative resection are permitted. * Subject has any condition which, in the investigator's opinion, makes the subject unsuitable for study participation. * Subject has received potent CYP 3A4 inhibitors within 7 days prior to first dose of study drug or proton pump inhibitors such as omeprazole within 14 days prior to first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Assessed by Independent Radiologic Review (IRR) | From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months) | PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by IRR. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response (OR) | From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months) | Percentage of participants with OR was defined as the proportion of participants with best overall response as complete response (CR) or partial response (PR) without confirmation based on the RECIST v1.1 as assessed by the blinded IRR. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. |
| PFS as Assessed by the Investigator | From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months) | PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on RECIST V1.1, as assessed by local investigator. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available. |
| Percentage of Participants With Disease Control | From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months) | Percentage of participants with disease control was defined as the proportion of participants whose best overall response was rated as CR, PR or stable disease (SD) among all analyzed participants based on RECIST V1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug. |
| Duration of Response (DOR) | From date of first response up to data cut-off date 09 May 2017 (approximately 15 months) | DOR was defined as the time from the date of the first response CR/PR (whichever was first recorded) as assessed by IRR to the date of radiographical progression or date of censoring. If a participant had not progressed, the participant was censored at the date of last radiological assessment or at the date of first CR/PR if no post-baseline radiological assessment was available. Results are based Kaplan-Meier estimate. |
| Percentage of Deaths | From date of randomization up to data cut-off date 21 Dec 2017 (approximately 22 months) | All events of death after the first study drug administration were included. |
| Functional Assessment of Cancer Therapy - EGFR Inhibitors Subscale (FACT-EGFRI-18) Questionnaire | Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months) | ACT-EGFRI-18 is an 18-item Likert-scaled questionnaire, used to assess the effect of EGFR inhibitors on quality of life (QoL). The questionnaire is arranged in three HRQL dimensions: physical (seven items), social/emotional (six items), and functional well-being (five items). The response scores ranged from 0 to 4, and the response categories include not at all, a little bit, somewhat, quite a bit, and very much. Negatively worded items (e.g., My skin bleeds easily or My skin condition affects my mood) are reverse-scored, so that participants who experience a higher impact of symptom burden on HRQL receive a lower score (range 0-72). |
| European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 (EORTC-QLQ-LC13) | Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months) | The EORTC-QLQ-LC13 is a validated module of the EORTC-QLQ-Core 30, which includes module items that evaluate symptoms such as cough, hemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling hands or feet, hair loss and pain. The total score for the questionnaire ranges from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology or problems. |
| European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) | Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months) | EORTC-QLQ-LC30 is a 30-item cancer-specific questionnaire with multitrait scaling was used to create five functional domain scales: Physical, Role, Emotional, Social and Cognitive; two items evaluate global QoL; in addition, three symptom scales assess Fatigue, Pain and Emesis; and six single items assess other symptoms. The total score ranges from 0 to 100, with a high score for a functional scale representing a high/healthy level of functioning and a high score for a symptom scale or item representing a high level of symptomatology or problems. |
| EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months) | The EQ-5D is a generic preference-based measure that indirectly measures the utility for health that generates an index-based summary score based upon societal preference weights. The EQ-5D-5L consists of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual analog scale (VAS) for health status. Each item has 5 response levels ranging from level 1 (no problem or none) to level 5 (unable to perform activity). The VAS ranges from 0 (worst health status) and 100 (best health status). |
| Number of Participants With Adverse Events (AEs) | From first dose of study drug up to 30 days after last dose of study drug taken up to data cut-off 09 May 2017 | Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug. AEs were considered serious (SAEs) if the AE resulted in death, was life threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization. |
Countries
Australia, Belgium, Canada, Chile, France, Germany, Hungary, Italy, Japan, Malaysia, Netherlands, Peru, Portugal, Romania, Russia, Singapore, South Korea, Spain, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
First-line participants with locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma NSCLC with EGFR activating mutation (exon 19 deletion or exon 21 L858R) with or without a T790M mutation who had not previously been treated with an EGFR inhibitors were enrolled in 201 sites in 23 countries.
Pre-assignment details
Eligible participants were stratified according to the following: Eastern Cooperative Oncology Group (ECOG) performance status (0, 1 or 2), Epidermal growth factor receptor (EGFR) mutation status (exon 19 deletion or mutations in exon 21 \[L858R\]), Tyrosine kinase inhibitor (TKI) chosen (erlotinib or gefitinib) and race (Asian versus non-Asian).
Participants by arm
| Arm | Count |
|---|---|
| ASP8273 Participants received 300 mg of ASP8273 orally once daily in 28-day cycles until one of the discontinuation criteria was met (developed radiological progressive disease, required to receive local or systemic anti-cancer treatment, developed unacceptable toxicity, participant pregnancy, investigator decision, required to receive significant surgical procedure, participant protocol deviation or noncompliance, participant decline of further treatment and participant lost to follow-up). | 267 |
| Erlotinib or Gefitinib Participants received 150 mg of erlotinib or 250 mg of gefitinib orally once daily in 28-day cycles until one of the discontinuation criteria was met (developed radiological progressive disease, required to receive local or systemic anti-cancer treatment, developed unacceptable toxicity, participant pregnancy, investigator decision, required to receive significant surgical procedure, participant protocol deviation or noncompliance, participant decline of further treatment and participant lost to follow-up). | 263 |
| Total | 530 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 29 | 24 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Miscellaneous | 5 | 4 |
| Overall Study | Noncompliance with Study Drug | 0 | 1 |
| Overall Study | Progressive Disease | 61 | 82 |
| Overall Study | Protocol Deviation | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 157 | 142 |
| Overall Study | Withdrawal by Subject | 12 | 8 |
Baseline characteristics
| Characteristic | Total | ASP8273 | Erlotinib or Gefitinib |
|---|---|---|---|
| Age, Continuous | 65.8 Years STANDARD_DEVIATION 11.1 | 66.6 Years STANDARD_DEVIATION 10.6 | 65.0 Years STANDARD_DEVIATION 11.5 |
| ECOG Performance Status at Randomization Grade 0 | 206 Participants | 103 Participants | 103 Participants |
| ECOG Performance Status at Randomization Grade 1 | 307 Participants | 155 Participants | 152 Participants |
| ECOG Performance Status at Randomization Grade 2 | 17 Participants | 9 Participants | 8 Participants |
| EGFR Mutation Status at Randomization Exon 19 Deletion | 296 Participants | 149 Participants | 147 Participants |
| EGFR Mutation Status at Randomization Exon 21 L858R | 234 Participants | 118 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 12 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 489 Participants | 244 Participants | 245 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 11 Participants | 7 Participants |
| Investigator Prerandomization Selected TKI at Randomization Erlotinib | 304 Participants | 153 Participants | 151 Participants |
| Investigator Prerandomization Selected TKI at Randomization Gefitinib | 226 Participants | 114 Participants | 112 Participants |
| Race (Asian vs Non-Asian) at Randomization Asian | 325 Participants | 163 Participants | 162 Participants |
| Race (Asian vs Non-Asian) at Randomization Non-Asian | 205 Participants | 104 Participants | 101 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 325 Participants | 162 Participants | 163 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 17 Participants | 9 Participants | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 177 Participants | 89 Participants | 88 Participants |
| Sex: Female, Male Female | 324 Participants | 171 Participants | 153 Participants |
| Sex: Female, Male Male | 206 Participants | 96 Participants | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 39 / 265 | 35 / 262 |
| other Total, other adverse events | 240 / 265 | 253 / 262 |
| serious Total, serious adverse events | 84 / 265 | 67 / 262 |
Outcome results
Primary
Progression Free Survival (PFS) as Assessed by Independent Radiologic Review (IRR)
PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by IRR. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available.
Time frame: From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months)
Population: The analysis population was the full analysis set (FAS), which consisted of all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ASP8273 | Progression Free Survival (PFS) as Assessed by Independent Radiologic Review (IRR) | 9.26 months |
| Erlotinib or Gefitinib | Progression Free Survival (PFS) as Assessed by Independent Radiologic Review (IRR) | 9.59 months |
Comparison: Comparison between ASP8273 and Erlotinib or Gefitinib treatment groups was performed using log-rank test stratified by ECOG (0 and 1 vs 2), EGFR mutation type (exon 19 deletion or exon 21 L858R) and TKI chosen by the site (erlotinib or gefitinib) before randomization. Comparison was tested at 1-sided significance level of 0.025. Hazard ratio based on Cox proportional hazards model. Assuming proportional hazards, HR \< 1 indicated a reduction in hazard rate in favor of ASP8273 treatment group.p-value: 0.99295% CI: [1.086, 2.391]Log Rank
Secondary
Duration of Response (DOR)
DOR was defined as the time from the date of the first response CR/PR (whichever was first recorded) as assessed by IRR to the date of radiographical progression or date of censoring. If a participant had not progressed, the participant was censored at the date of last radiological assessment or at the date of first CR/PR if no post-baseline radiological assessment was available. Results are based Kaplan-Meier estimate.
Time frame: From date of first response up to data cut-off date 09 May 2017 (approximately 15 months)
Population: The analysis population was the FAS. Only participants with best overall response as CR or PR (without confirmation) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ASP8273 | Duration of Response (DOR) | 9.17 months |
| Erlotinib or Gefitinib | Duration of Response (DOR) | 9.03 months |
Comparison: Comparison between ASP8273 and Erlotinib or Gefitinib treatment groups was performed using log-rank test stratified by ECOG (0 and 1 vs 2), EGFR mutation type (exon 19 deletion or exon 21 L858R) and TKI chosen by the site (erlotinib or gefitinib) before randomization. Comparison was tested at 1-sided significance level of 0.025. Hazard ratio based on Cox proportional hazards model. Assuming proportional hazards, HR \< 1 indicated a reduction in hazard rate in favor of ASP8273 treatment group.p-value: 0.7895% CI: [0.661, 2.548]Log Rank
Secondary
European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30)
EORTC-QLQ-LC30 is a 30-item cancer-specific questionnaire with multitrait scaling was used to create five functional domain scales: Physical, Role, Emotional, Social and Cognitive; two items evaluate global QoL; in addition, three symptom scales assess Fatigue, Pain and Emesis; and six single items assess other symptoms. The total score ranges from 0 to 100, with a high score for a functional scale representing a high/healthy level of functioning and a high score for a symptom scale or item representing a high level of symptomatology or problems.
Time frame: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)
Population: The analysis population was the SAF, with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASP8273 | European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) | 53.77 units on a scale | Standard Deviation 11.49 |
| Erlotinib or Gefitinib | European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) | 52.01 units on a scale | Standard Deviation 11.26 |
Secondary
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 (EORTC-QLQ-LC13)
The EORTC-QLQ-LC13 is a validated module of the EORTC-QLQ-Core 30, which includes module items that evaluate symptoms such as cough, hemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling hands or feet, hair loss and pain. The total score for the questionnaire ranges from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology or problems.
Time frame: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)
Population: The analysis population was the SAF, with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASP8273 | European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 (EORTC-QLQ-LC13) | 18.93 units on a scale | Standard Deviation 4.42 |
| Erlotinib or Gefitinib | European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 (EORTC-QLQ-LC13) | 18.78 units on a scale | Standard Deviation 4.69 |
Secondary
EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L)
The EQ-5D is a generic preference-based measure that indirectly measures the utility for health that generates an index-based summary score based upon societal preference weights. The EQ-5D-5L consists of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual analog scale (VAS) for health status. Each item has 5 response levels ranging from level 1 (no problem or none) to level 5 (unable to perform activity). The VAS ranges from 0 (worst health status) and 100 (best health status).
Time frame: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)
Population: The analysis population was the SAF, with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ASP8273 | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Mobility | 1.78 Units on a scale | Standard Deviation 0.96 |
| ASP8273 | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Self-care | 1.28 Units on a scale | Standard Deviation 0.68 |
| ASP8273 | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Usual Activities | 1.71 Units on a scale | Standard Deviation 0.94 |
| ASP8273 | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Pain/Discomfort | 1.79 Units on a scale | Standard Deviation 0.86 |
| ASP8273 | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Anxiety/Depression | 1.61 Units on a scale | Standard Deviation 0.77 |
| ASP8273 | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | VAS | 69.44 Units on a scale | Standard Deviation 19.17 |
| Erlotinib or Gefitinib | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Anxiety/Depression | 1.54 Units on a scale | Standard Deviation 0.76 |
| Erlotinib or Gefitinib | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Mobility | 1.48 Units on a scale | Standard Deviation 0.85 |
| Erlotinib or Gefitinib | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Pain/Discomfort | 1.71 Units on a scale | Standard Deviation 0.83 |
| Erlotinib or Gefitinib | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Self-care | 1.19 Units on a scale | Standard Deviation 0.6 |
| Erlotinib or Gefitinib | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | VAS | 72.36 Units on a scale | Standard Deviation 17.19 |
| Erlotinib or Gefitinib | EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Usual Activities | 1.54 Units on a scale | Standard Deviation 0.83 |
Secondary
Functional Assessment of Cancer Therapy - EGFR Inhibitors Subscale (FACT-EGFRI-18) Questionnaire
ACT-EGFRI-18 is an 18-item Likert-scaled questionnaire, used to assess the effect of EGFR inhibitors on quality of life (QoL). The questionnaire is arranged in three HRQL dimensions: physical (seven items), social/emotional (six items), and functional well-being (five items). The response scores ranged from 0 to 4, and the response categories include not at all, a little bit, somewhat, quite a bit, and very much. Negatively worded items (e.g., My skin bleeds easily or My skin condition affects my mood) are reverse-scored, so that participants who experience a higher impact of symptom burden on HRQL receive a lower score (range 0-72).
Time frame: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)
Population: The analysis population was the SAF, with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ASP8273 | Functional Assessment of Cancer Therapy - EGFR Inhibitors Subscale (FACT-EGFRI-18) Questionnaire | 2.79 units on a scale | Standard Deviation 4.97 |
| Erlotinib or Gefitinib | Functional Assessment of Cancer Therapy - EGFR Inhibitors Subscale (FACT-EGFRI-18) Questionnaire | 9.34 units on a scale | Standard Deviation 10.57 |
Secondary
Number of Participants With Adverse Events (AEs)
Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug. AEs were considered serious (SAEs) if the AE resulted in death, was life threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization.
Time frame: From first dose of study drug up to 30 days after last dose of study drug taken up to data cut-off 09 May 2017
Population: The analysis population was SAF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ASP8273 | Number of Participants With Adverse Events (AEs) | TEAE | 251 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | TEAE Leading to Dose Reduction | 51 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE Leading to Dose Reduction | 51 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | TEAE Leading to Dose Interruption | 95 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE Leading to Dose Interruption | 83 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE | 235 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | Serious TEAE | 84 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | Drug-Related Serious TEAE | 46 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | TEAE Leading to Death | 14 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE Leading to Death | 1 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | TEAE Leading to Treatment Withdrawal | 39 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE Leading to Treatment Withdrawal | 27 participants |
| ASP8273 | Number of Participants With Adverse Events (AEs) | Death | 39 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE Leading to Death | 1 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | TEAE Leading to Death | 17 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | Serious TEAE | 67 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | TEAE Leading to Dose Reduction | 51 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE Leading to Treatment Withdrawal | 17 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE Leading to Dose Reduction | 50 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | Drug-Related Serious TEAE | 18 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | TEAE Leading to Dose Interruption | 74 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | TEAE Leading to Treatment Withdrawal | 28 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE Leading to Dose Interruption | 55 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | TEAE | 261 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | Death | 35 participants |
| Erlotinib or Gefitinib | Number of Participants With Adverse Events (AEs) | Drug-Related TEAE | 246 participants |
Secondary
Percentage of Deaths
All events of death after the first study drug administration were included.
Time frame: From date of randomization up to data cut-off date 21 Dec 2017 (approximately 22 months)
Population: The analysis population was the safety analysis set (SAF), which consisted of all participants who took at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP8273 | Percentage of Deaths | 14.7 percentage of participants |
| Erlotinib or Gefitinib | Percentage of Deaths | 13.4 percentage of participants |
Secondary
Percentage of Participants With Disease Control
Percentage of participants with disease control was defined as the proportion of participants whose best overall response was rated as CR, PR or stable disease (SD) among all analyzed participants based on RECIST V1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug.
Time frame: From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP8273 | Percentage of Participants With Disease Control | 62.2 percentage of participants |
| Erlotinib or Gefitinib | Percentage of Participants With Disease Control | 66.2 percentage of participants |
Comparison: Comparison between ASP8273 and Erlotinib or Gefitinib treatment groups was performed using stratified Cochran-Mantel-Haenszel (CMH) test, stratified by ECOG (0 and 1 vs 2), EGFR mutation type (exon 19 deletion or exon 21 L858R) and TKI chosen by the site (erlotinib or gefitinib) before randomization. Comparison was tested at 1-sided significance level of 0.025.p-value: 0.839Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Objective Response (OR)
Percentage of participants with OR was defined as the proportion of participants with best overall response as complete response (CR) or partial response (PR) without confirmation based on the RECIST v1.1 as assessed by the blinded IRR. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.
Time frame: From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP8273 | Percentage of Participants With Objective Response (OR) | 33.0 percentage of participants |
| Erlotinib or Gefitinib | Percentage of Participants With Objective Response (OR) | 47.9 percentage of participants |
Comparison: Comparison between ASP8273 and Erlotinib or Gefitinib treatment groups was performed using stratified Cochran-Mantel-Haenszel (CMH) test, stratified by ECOG (0 and 1 vs 2), EGFR mutation type (exon 19 deletion or exon 21 L858R) and TKI chosen by the site (erlotinib or gefitinib) before randomization. Comparison was tested at 1-sided significance level of 0.025.p-value: 1Cochran-Mantel-Haenszel
Secondary
PFS as Assessed by the Investigator
PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on RECIST V1.1, as assessed by local investigator. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available.
Time frame: From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months)
Population: The analysis population was the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ASP8273 | PFS as Assessed by the Investigator | 7.43 months |
| Erlotinib or Gefitinib | PFS as Assessed by the Investigator | 10.12 months |
Comparison: Comparison between ASP8273 and Erlotinib or Gefitinib treatment groups was performed using log-rank test stratified by ECOG (0 and 1 vs 2), EGFR mutation type (exon 19 deletion or exon 21 L858R) and TKI chosen by the site (erlotinib or gefitinib) before randomization. Comparison was tested at 1-sided significance level of 0.025. Hazard ratio based on Cox proportional hazards model. Assuming proportional hazards, HR \< 1 indicated a reduction in hazard rate in favor of ASP8273 treatment group.p-value: 0.99895% CI: [1.165, 2.406]Log Rank