Advanced Non-Small Cell Lung Cancer
Conditions
Keywords
Advanced Non-Small Cell Lung Cancer of Nonsquamous Histology, Advanced Lung Cancer, Non-Small Cell Lung Cancer, Lung Cancer
Brief summary
The purpose of this study is to compare the regimens of pemetrexed, carboplatin with pemetrexed maintenance and paclitaxel, carboplatin, bevacizumab with bevacizumab maintenance in participants with Stage IV nonsquamous non-small cell lung cancer.
Detailed description
This is a multicenter, randomized, open-label, Phase III trial. Eligible participants will be randomized in a 1:1 ratio to receive pemetrexed and carboplatin followed by pemetrexed or paclitaxel, carboplatin, and bevacizumab followed by bevacizumab as their study treatment. Participants randomized to Pemetrexed + Carboplatin + Pemetrexed will receive folic acid, vitamin B12, and dexamethasone as stated in the pemetrexed label. Before administration of paclitaxel, participants randomized to Paclitaxel + Carboplatin + Bevacizumab will receive premedication (dexamethasone, diphenhydramine, and cimetidine or ranitidine) as recommended in the paclitaxel label.
Interventions
DRUGPemetrexed
Induction therapy: 500 milligrams/square meter (mg/m²) given intravenously every 21 days for 4 cycles. Maintenance therapy: 500 mg/m² given intravenously every 21 days until disease progression or treatment discontinuation.
DRUGCarboplatin
Induction Therapy (every 21 days for 4 cycles): Area Under the Curve (AUC) 6 \[maximum possible dose of 900 milligrams (mg)\] intravenously infused over 30 minutes.
DRUGPaclitaxel
Induction Therapy (every 21 days for 4 cycles): 200 mg/m² intravenously infused over 3 hours
BIOLOGICALBevacizumab
Induction therapy: 15 milligrams/kilogram (mg/kg) given intravenously every 21 days for 4 cycles. Maintenance therapy: 15 mg/kg given intravenously every 21 days until disease progression or treatment discontinuation.
Sponsors
Eli Lilly and Company
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
* a histologic or cytologic diagnosis of advanced non-small cell lung cancer (NSCLC) \[Stage IV from the American Joint Committee on Cancer Staging Criteria (AJCC) staging system, version 7.0, including both M1a and M1b\], other than predominantly squamous cell histology, that is not amenable to curative therapy. Participants may not have received any prior systemic chemotherapy, immunotherapy, targeted therapy, or biological therapy, including adjuvant therapy, for any stage of NSCLC. * prior radiation therapy is allowed to \< 25% of the bone marrow; however, prior radiation to the whole pelvis not allowed. * good performance status. * adequate organ function. * estimated life expectancy of at least 12 weeks.
Exclusion criteria
* known central nervous system (CNS) disease, other than treated brain metastasis. * major surgical procedure, open biopsy, open pleurodesis, or significant traumatic injury within 28 days prior to study or have an anticipated need for major surgery during the study. * core biopsy or other minor surgical procedure, excluding placement of vascular access device, closed pleurodesis, thoracentesis, and mediastinoscopy, within 7 days prior to study. * history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis. * currently receiving ongoing treatment with full-dose warfarin or equivalent * significant vascular disease within 6 months prior to Day 1 of Cycle 1. * evidence of bleeding diathesis or coagulopathy. * serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the participant's ability to adhere to the protocol. * serious cardiac condition, such as myocardial infarction, angina, or heart disease. * inadequately controlled hypertension. * any prior history of hypertensive crisis or hypertensive encephalopathy. * serious, nonhealing wound, active ulcer, or untreated bone fracture. * another active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within the last 5 years. * previously received treatment with paclitaxel, carboplatin, pemetrexed, or bevacizumab (prior intravitreal administration of bevacizumab does not preclude study participation). * pregnant or breast-feeding. * history of stroke or transient ischemic attack within 6 months prior to study. * known sensitivity to any component of paclitaxel, carboplatin, pemetrexed, or bevacizumab. * history of hemoptysis within 3 months prior to randomization. * unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). * unwilling to take folic acid or vitamin B12 supplementation. * clinically significant third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage. Participants with M1a disease with pleural effusions are eligible if the effusions can be adequately controlled.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival Without Grade 4 Toxicity (G4PFS) as Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | Randomization to measured progressive disease or treatment discontinuation up to 39.49 months | G4PFS was defined as the duration from the date of randomization to the earliest occurrence date of one of the following three events: Common Terminology Criteria (CTC) grade 4 adverse events (G4AEs), or progressive disease (PD) or death from any cause, whichever occurred earlier. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants who had no G4AEs, or PD, or death at the time of the data inclusion cutoff, PFS was censored at their last objective progression-free disease assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Randomization to measured progressive disease up to 39.49 months | PFS was defined as the duration from the date of randomization to the date of progressive disease (PD) or death from any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PD was ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last objective progression-free disease assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy. |
| Overall Survival (OS) | Randomization to date of death from any cause up to 39.49 months | OS was defined as the duration from the date of randomization to the date of death from any cause. For participants who were alive at the time of the data inclusion cutoff, OS was censored at the last date the participant was known to be alive. |
| Percentage of Participants With Complete Response or Partial Response (Overall Tumor Response Rate) | Baseline to date of objective progressive disease up to 39.49 months | Overall Response rate (ORR) was the percentage of participants with a confirmed complete response (CR) or partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR was the disappearance of all target and non-target lesions; PR was a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions. ORR was calculated as a total number of participants with CR or PR from the start of study treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100. |
| Disease Control Rates Defined as Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | Baseline to date of objective progressive disease up to 39.49 months | Disease control rate was the percentage of participants with a confirmed CR, PR or SD, as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR was the disappearance of all target and non-target lesions; PR was a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesion; SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Disease control rate was calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated, then multiplied by 100. |
Countries
United States
Participant flow
Pre-assignment details
Completers included participants who died, participants with progressive disease and those who got randomized but didn't receive any treatment.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed + Carboplatin Induction therapy: pemetrexed 500 milligrams/square meter (mg/m²) given intravenously plus carboplatin area under the curve (AUC) 6 \[maximum possible dose of 900 milligrams (mg)\] intravenously infused over 30 minutes for four 21-day cycles.
Maintenance therapy: pemetrexed 500 mg/m² given intravenously every 21 days until disease progression or treatment discontinuation. | 182 |
| Paclitaxel + Carboplatin + Bevacizumab Induction therapy: paclitaxel 200 mg/m² intravenously infused over 3 hours plus carboplatin AUC 6 (maximum possible dose of 900 mg) intravenously infused over 30 minutes plus bevacizumab 15 milligrams/kilogram (mg/kg) given intravenously for four 21-day cycles.
Maintenance therapy: bevacizumab 15 mg/kg given intravenously every 21 days until disease progression or treatment discontinuation. | 179 |
| Total | 361 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Pemetrexed + Carboplatin | Total | Paclitaxel + Carboplatin + Bevacizumab |
|---|---|---|---|
| Age, Continuous | 64.8 years STANDARD_DEVIATION 9.62 | 64.7 years STANDARD_DEVIATION 9.22 | 64.6 years STANDARD_DEVIATION 8.82 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 9 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 178 Participants | 352 Participants | 174 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 31 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 165 Participants | 322 Participants | 157 Participants |
| Region of Enrollment United States | 182 Participants | 361 Participants | 179 Participants |
| Sex: Female, Male Female | 77 Participants | 152 Participants | 75 Participants |
| Sex: Female, Male Male | 105 Participants | 209 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 167 / 171 | 160 / 166 |
| serious Total, serious adverse events | 76 / 171 | 64 / 166 |
Outcome results
Primary
Progression Free Survival Without Grade 4 Toxicity (G4PFS) as Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0
G4PFS was defined as the duration from the date of randomization to the earliest occurrence date of one of the following three events: Common Terminology Criteria (CTC) grade 4 adverse events (G4AEs), or progressive disease (PD) or death from any cause, whichever occurred earlier. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants who had no G4AEs, or PD, or death at the time of the data inclusion cutoff, PFS was censored at their last objective progression-free disease assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy.
Time frame: Randomization to measured progressive disease or treatment discontinuation up to 39.49 months
Population: All randomized participants. The number of participants censored was 30 for pemetrexed + carboplatin group and 35 for paclitaxel + carboplatin + bevacizumab group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed + Carboplatin | Progression Free Survival Without Grade 4 Toxicity (G4PFS) as Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | 3.91 months |
| Paclitaxel + Carboplatin + Bevacizumab | Progression Free Survival Without Grade 4 Toxicity (G4PFS) as Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | 2.86 months |
p-value: 0.176Log Rank
Secondary
Disease Control Rates Defined as Complete Response (CR), Partial Response (PR), and Stable Disease (SD)
Disease control rate was the percentage of participants with a confirmed CR, PR or SD, as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR was the disappearance of all target and non-target lesions; PR was a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesion; SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Disease control rate was calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated, then multiplied by 100.
Time frame: Baseline to date of objective progressive disease up to 39.49 months
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed + Carboplatin | Disease Control Rates Defined as Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | 59.9 percentage of participants |
| Paclitaxel + Carboplatin + Bevacizumab | Disease Control Rates Defined as Complete Response (CR), Partial Response (PR), and Stable Disease (SD) | 57.0 percentage of participants |
p-value: 0.575Pearson Chi-square Test
Secondary
Overall Survival (OS)
OS was defined as the duration from the date of randomization to the date of death from any cause. For participants who were alive at the time of the data inclusion cutoff, OS was censored at the last date the participant was known to be alive.
Time frame: Randomization to date of death from any cause up to 39.49 months
Population: All randomized participants. The number of participants censored was 52 for pemetrexed + carboplatin group and 56 for paclitaxel + carboplatin + bevacizumab group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed + Carboplatin | Overall Survival (OS) | 10.51 months |
| Paclitaxel + Carboplatin + Bevacizumab | Overall Survival (OS) | 11.66 months |
p-value: 0.615Log Rank
Secondary
Percentage of Participants With Complete Response or Partial Response (Overall Tumor Response Rate)
Overall Response rate (ORR) was the percentage of participants with a confirmed complete response (CR) or partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR was the disappearance of all target and non-target lesions; PR was a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions. ORR was calculated as a total number of participants with CR or PR from the start of study treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100.
Time frame: Baseline to date of objective progressive disease up to 39.49 months
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed + Carboplatin | Percentage of Participants With Complete Response or Partial Response (Overall Tumor Response Rate) | 23.6 percentage of participants |
| Paclitaxel + Carboplatin + Bevacizumab | Percentage of Participants With Complete Response or Partial Response (Overall Tumor Response Rate) | 27.4 percentage of participants |
p-value: 0.414Pearson Chi-square Test
Secondary
Progression Free Survival (PFS)
PFS was defined as the duration from the date of randomization to the date of progressive disease (PD) or death from any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PD was ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last objective progression-free disease assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy.
Time frame: Randomization to measured progressive disease up to 39.49 months
Population: All randomized participants. The number of participants censored was 35 for pemetrexed + carboplatin group and 49 for paclitaxel + carboplatin + bevacizumab group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed + Carboplatin | Progression Free Survival (PFS) | 4.44 months |
| Paclitaxel + Carboplatin + Bevacizumab | Progression Free Survival (PFS) | 5.45 months |
p-value: 0.61Log Rank