Non-Small Cell Lung Cancer (NSCLC)
Conditions
Brief summary
This is a randomized, open-label, multicenter, Phase 3 study, comparing efficacy and safety of eribulin with TPC in subjects with advanced and disease progression following at least two prior regimens for advanced disease, which should have included a platinum-based regimen.
Interventions
DRUGEribulin
Administration of eribulin mesylate at a dose of 1.4 mg/m2 i.v. over 2 to 5 minutes on Days 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.
DRUGTPC -Vinorelbine,Gemcitabine,Docetaxel, and Pemetrexed
* Vinorelbine 30 mg/m2 i.v. on Day 1, every 7 days * Gemcitabine 1250 mg/m2 i.v. on Days 1 and 8, every 21 days * Docetaxel 75 mg/m2 i.v. on Day 1 every 21 days * Pemetrexed 500 mg/m2 i.v. on Day 1 every 21 days (nonsquamous histology only).
Sponsors
Eisai 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
Inclusion: Subjects must meet all of the following criteria to be included in this study: 1. Histologically or cytologically confirmed diagnosis of NSCLC. 2. Documented evidence of advanced NSCLC not amenable to surgery or radiotherapy. 3. Confirmation of the presence or absence of EGFR mutations prior to study enrolment in all subjects. 4. Subjects must have received at least two prior regimens for advanced NSCLC, which should have included a platinum-based regimen and, in all subjects with tumors harbouring EGFR mutations, an EGFR TKI. 5. Radiographic evidence of disease progression on, or after, the last anti-cancer regimen prior to study entry. 6. Presence of measurable disease. 7. ECOG performance status of 0, 1, or 2. 8. Adequate bone marrow 9. Adequate renal function. 10. Adequate liver function. 11. Female subjects of child-bearing potential must agree to use two forms of highly effective contraception. 12. Male subjects and their female partners who are of child-bearing potential must agree to use two forms of highly effective contraception. 13. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol. 14. Males or females aged at least 18 years (or any age greater than 18 years as determined by country legislation) at the time of informed consent. Exclusion: Subjects who meet any of the following criteria will be excluded from this study: 1. Subjects who have received any anti-cancer therapy within 14 days, or five half-lives of the drug (whichever is longer), prior to randomization. 2. Subjects who have not recovered from toxicities as a result of prior anti-cancer therapy to less than Grade 2. 3. Subjects who have previously been treated, or participated in a study with eribulin, whether treated with eribulin or not. The TPC option must not include the same agent which the subject received in a prior regimen. 4. Peripheral neuropathy more than CTCAE Grade 2. 5. Significant cardiovascular impairment. 6. Subjects with a high probability of Long QT Syndrome, or QTc interval \>500 ms. 7. Subjects with brain or subdural metastases are not eligible, unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy. 8. Any serious concomitant illness. 9. Known HIV positive, or have an infection requiring treatment. 10. Any malignancy that required treatment, or has shown evidence of recurrence (except for NSCLC, non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) during the 5 years prior to study entry. 11. Female subjects must not be pregnant, and must not be breastfeeding. 12. Hypersensitivity to either HalB or HalB chemical derivatives or both, or to any of the excipients of the eribulin formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization (Day 1) until date of death from any cause, or 37 months | The OS was defined as the time in months from the date of randomization to the date of death, regardless of cause. In the absence of confirmation of death, the participants were censored either at the date that participant was last known to be alive or the date of study cut-off, whichever was earlier. The two treatment arms were compared using the log-rank test, stratified by histology, TPC option, and geographic region; and the treatment difference between eribulin mesylate and TPC was tested at a significance level of 0.05 (2-sided). Kaplan-Meier (K-M) survival probabilities for each arm were plotted over time. The treatment effect was estimated by fitting a Cox Proportional Hazards model to the OS times including treatment arm as a factor and histology, TPC option and geographic region as strata. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) | Randomization (Day 1) until date of disease progression or death (whichever occurred first), or 37 months | PFS was defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first. The difference in PFS (based on the tumor response evaluation as determined by the investigator) between eribulin mesylate and TPC was evaluated using the log rank test, stratified by histology, TPC option, and geographic region, tested at an alpha level of 0.05 (2-sided). PFS censoring rules will be defined in the SAP and follow Federal Department of Agriculture (FDA) guidance. |
| Objective Response Rate (ORR) | Randomization (Day 1) to CR or PR | The ORR was defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) per RECIST criteria. The ORR was estimated by study arm based on the tumor response evaluation as determined by the investigator, according to RECIST 1.1. Participants with unknown response were treated as non-responders. The statistical difference in ORR between treatment arms was evaluated using the Cochran-Mantel-Haenszel (CMH) chi-square test with histology, TPC option, and geographic region as strata, tested at an alpha level of 0.05 (2-sided). The 95 percent confidence interval (CI) was calculated using Clopper Pearson method. |
Countries
Australia, France, Germany, Hong Kong, Italy, Japan, Poland, Russia, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 735 participants were screened. Of these, 195 screen failed due to failure to meet inclusion/exclusion criteria, adverse events, withdrawal of consent, or other reason and were not randomized into the study. A total of 540 participants were randomized into the study. Of these, 3 were discontinued prior to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Eribulin Mesylate Eribulin mesylate (1.4 mg/m\^2) was administered IV over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days. | 270 |
| Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed TPC: Vinorelbine (30 mg/m\^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m\^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m\^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m\^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m\^2) was administered IV on Day 1 every 21 days (nonsquamous histology only). | 270 |
| Total | 540 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 28 | 24 |
| Overall Study | Clinical progression | 28 | 25 |
| Overall Study | Disease progression | 194 | 181 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Not treated | 1 | 2 |
| Overall Study | Other | 6 | 17 |
| Overall Study | Withdrawal by Subject | 11 | 15 |
| Overall Study | Withdrawn consent | 2 | 5 |
Baseline characteristics
| Characteristic | Arm A: Eribulin Mesylate | Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed | Total |
|---|---|---|---|
| Age, Continuous | 61.4 Years STANDARD_DEVIATION 9.62 | 60.8 Years STANDARD_DEVIATION 9.32 | 61.1 Years STANDARD_DEVIATION 9.47 |
| Sex: Female, Male Female | 107 Participants | 101 Participants | 208 Participants |
| Sex: Female, Male Male | 163 Participants | 169 Participants | 332 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 28 / 269 | 21 / 268 |
| other Total, other adverse events | 254 / 269 | 261 / 268 |
| serious Total, serious adverse events | 96 / 269 | 86 / 268 |
Outcome results
Primary
Overall Survival (OS)
The OS was defined as the time in months from the date of randomization to the date of death, regardless of cause. In the absence of confirmation of death, the participants were censored either at the date that participant was last known to be alive or the date of study cut-off, whichever was earlier. The two treatment arms were compared using the log-rank test, stratified by histology, TPC option, and geographic region; and the treatment difference between eribulin mesylate and TPC was tested at a significance level of 0.05 (2-sided). Kaplan-Meier (K-M) survival probabilities for each arm were plotted over time. The treatment effect was estimated by fitting a Cox Proportional Hazards model to the OS times including treatment arm as a factor and histology, TPC option and geographic region as strata.
Time frame: Randomization (Day 1) until date of death from any cause, or 37 months
Population: Full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Eribulin Mesylate | Overall Survival (OS) | 9.5 months |
| Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed | Overall Survival (OS) | 9.5 months |
Comparison: OS was compared between eribulin and TPC testing the following null hypothesis: H0: OS in Arm A (eribulin) is equal to OS in Arm B (TPC) against the alternative: H1: OS in Arm A (eribulin) is not equal to OS in Arm B (TPC).p-value: 0.134395% CI: [0.95, 1.41]Log Rank
Secondary
Objective Response Rate (ORR)
The ORR was defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) per RECIST criteria. The ORR was estimated by study arm based on the tumor response evaluation as determined by the investigator, according to RECIST 1.1. Participants with unknown response were treated as non-responders. The statistical difference in ORR between treatment arms was evaluated using the Cochran-Mantel-Haenszel (CMH) chi-square test with histology, TPC option, and geographic region as strata, tested at an alpha level of 0.05 (2-sided). The 95 percent confidence interval (CI) was calculated using Clopper Pearson method.
Time frame: Randomization (Day 1) to CR or PR
Population: Full analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Eribulin Mesylate | Objective Response Rate (ORR) | 12.2 percentage of participants |
| Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed | Objective Response Rate (ORR) | 15.2 percentage of participants |
Comparison: OS was compared between eribulin and TPC testing the following null hypothesis: H0: OS in Arm A (eribulin) is equal to OS in Arm B (TPC) against the alternative: H1: OS in Arm A (eribulin) is not equal to OS in Arm B (TPC).p-value: 0.3034Cochran-Mantel-Haenszel
Secondary
Progression Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST)
PFS was defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first. The difference in PFS (based on the tumor response evaluation as determined by the investigator) between eribulin mesylate and TPC was evaluated using the log rank test, stratified by histology, TPC option, and geographic region, tested at an alpha level of 0.05 (2-sided). PFS censoring rules will be defined in the SAP and follow Federal Department of Agriculture (FDA) guidance.
Time frame: Randomization (Day 1) until date of disease progression or death (whichever occurred first), or 37 months
Population: Full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Eribulin Mesylate | Progression Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) | 3.0 months |
| Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed | Progression Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) | 2.8 months |
Comparison: OS was compared between eribulin and TPC testing the following null hypothesis: H0: OS in Arm A (eribulin) is equal to OS in Arm B (TPC) against the alternative: H1: OS in Arm A (eribulin) is not equal to OS in Arm B (TPC).p-value: 0.394695% CI: [0.9, 1.32]Log Rank