Non-small Cell Lung Cancer
Conditions
Brief summary
This study will compare overall survival in participants with Stage IIIB or IV nonsquamous non-small cell lung cancer.
Interventions
DRUGPemetrexed
Induction therapy 500 milligram per meter squared (mg/m\^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days
DRUGPaclitaxel
Induction therapy 200 mg/m\^2 IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days
DRUGCarboplatin
Induction therapy area under the concentration curve (AUC) 6 IV every 21 days for up to 4 cycles of 21 days
BIOLOGICALBevacizumab
Induction therapy 15 milligrams per kilogram (mg/kg) IV every 21 days for up to 4 cycles of 21 days
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
* You must sign an informed consent document for clinical research. * You must have Stage IIIB or Stage IV nonsquamous non-small cell lung cancer. * You must not have received any prior treatment for your disease. * Prior radiation therapy is allowed to \< 25% of the bone marrow; however, prior radiation to the whole pelvis is not allowed. If you have had radiation therapy to the chest, you are not eligible to participate. * You must be at least 18 years of age or older. * You must have measureable tumor lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) or disease can be evaluated on computed tomography (CT) scan. * Your test results assessing the function of blood forming tissue, kidneys and liver must be satisfactory. * Women must be sterile, postmenopausal or on contraception and men must be sterile (for example post-vasectomy) or on contraception.
Exclusion criteria
* You cannot have clinically significant third-space fluid collections (e.g. ascites or pleural effusions that cannot be controlled by drainage or other procedures). * You cannot have Non-small Cell Lung Carcinoma (NSCLC) of predominantly squamous cell histology. * You cannot have known central nervous system (CNS) disease, other than stable, treated brain metastasis. * You cannot have undergone a surgical procedure, open biopsy, open pleurodesis, or significant traumatic injury within 28 days of starting the study treatment, or have an anticipated need for major surgery during the study. * You cannot have a history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis. * You are currently receiving ongoing treatment with full-dose warfarin or equivalent. * You cannot have significant vascular disease, serious cardiac conditions (such as heart attack), stroke or transient ischemic attack within 6 months of the trial. * You cannot have evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation). * You cannot have inadequately controlled hypertension, or a history of hypertensive crisis or hypertensive encephalopathy. * You cannot have a serious, nonhealing wound, active ulcer, or untreated bone fracture. * You cannot have another form of cancer, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within the last 5 years. * You cannot have received an investigational treatment within 30 days prior to the trial. * You cannot have previously received treatment with paclitaxel, carboplatin, pemetrexed, or bevacizumab. * You cannot be pregnant or breast-feeding. * You cannot have a known sensitivity to any component of paclitaxel, carboplatin, pemetrexed, or bevacizumab. * You cannot have a history of hemoptysis (coughing blood) within 3 months prior to the trial. * You are unable to stop taking aspirin more than 1.3 grams per day or other nonsteroidal anti-inflammatory drugs (NSAIDs). * You are unable or unwilling to take folic acid or vitamin B12 supplementation. * You are unable to take corticosteroids. * You have any other on-going illnesses including active infections that may not allow you to adhere to the requirements of the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Baseline to date of death from any cause (up to 37.06 months) | Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progressive Disease | Baseline to measured progressive disease (up to 37.06 months) | Time to progressive disease was defined as the time from randomization to the first date of objective disease progression. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier. |
| Percentage of Participants With a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate) | Baseline to measured progressive disease (up to 37.06 months) | Disease Control Rate (DCR) is the number of participants with a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared with baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions. Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions compared with the smallest sum of the longest diameter recorded since the start of treatment or the appearance of 1 or more new lesion(s). Stable Disease (SD) was defined as small changes that did not meet above criteria. |
| Progression Free Survival Time | Baseline to measured progressive disease or date of death from any cause (up to 33.54 months) | Progression free survival (PFS) is defined as the time from date of randomization to the date of objective disease progression or death due to any cause. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier. |
| Safety and Toxicity Profile of Study Treatments | Baseline to study endpoint (up to 37.06 months) | Safety and toxicity profile was defined as serious and other non-serious adverse events. A summary of serious and all other non-serious adverse events is located in the Reported Adverse Event module. |
| Duration of Hospitalizations Per Participant | Baseline to study endpoint (up to 37.06 months) | Length of hospitalization in participants hospitalized during the study or within 30 days of discontinuation regardless of whether the hospitalization was or was not due to study drug. |
| Number of Participants Who Received a Transfusion | Baseline to study endpoint (up to 37.06 months) | — |
| Number of Participants Receiving Concomitant Medication | Baseline to study endpoint (up to 37.06 months) | — |
| Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - General (FACT-G) | Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) | The FACT-G is a validated instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item questionnaire and is organized into subscales, each designed to assess a QOL domain: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items. Each item uses a 5 point rating scale (0=not at all and 4=equals very much). FACT-G Total is the sum of the scores of all 4 subscales and ranges from 0 to 108. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction. |
| Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L) | Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) | FACT-L is a valid instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item FACT-General (G) and 9-item lung cancer subscale (LCS). FACT-G is organized into subscales: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items. Each item uses a 5 point rating scale (0=not at all and 4=equals very much). FACT-L Total Score=4 subscales + LCS and ranges from 0 to 144. Trial Outcome Index-Lung (TOI-L)=PWB+FWB+LCS and ranges from 0 to 92. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction. |
| Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx) | Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days) | FACT/GOG-Ntx is a validated instrument used to measure quality of life (QOL) in participants with cancer and neurotoxicity (Ntx) consisting of 27-item FACT-General (G) and 11-item Ntx subscale. FACT-G is organized into domain subscales: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items; each uses a 5 point rating scale (0=not at all and 4=equals very much). FACT/GOG-Ntx Total Score=sum 5 subscales and ranges from 0-152. Ntx Trial Outcome Index (TOI-Ntx)=PWB+FWB+NTX and range from 0-100. For all FACT scales, higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction. |
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Pemetrexed | Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose) | — |
| Pharmacokinetics (PK): Elimination Half-life (t1/2) for Pemetrexed | Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose) | — |
| Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Pemetrexed | Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose) | — |
| Percentage of Participants With a Complete Response (CR) and Partial Response (PR) (Overall Response Rate) | Baseline to measured progressive disease (up to 37.06 months) | Overall Response Rate (ORR) is the number of participants with a Complete Response (CR) and Partial Response (PR) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared to baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions. |
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum | Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose) | Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form. |
| Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum | Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose) | Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form. |
| Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum | Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose) | Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form. |
| Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms | Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose) | Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form. |
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Bevacizumab | Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose) | — |
| Pharmacokinetics (PK): Elimination Half-life (t1/2) for Bevacizumab | Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose) | — |
| Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) Bevacizumab | Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose) | — |
| Pharmacokinetics (PK): Bevacizumab Clearance (CL) | Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose) | — |
| Translational Research: Number of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations | Baseline | Epidermal Growth Factor Receptor (EGFR) mutations were measured by polymerase chain reaction (PCR). |
| Translational Research: Overall Survival (OS) Based on Nuclear Thyroid Transcription Factor-1 (TTF-1) Expression Regardless of Study Treatment | Baseline to date of death from any cause (up to 37.06 months) | Nuclear Thyroid Transcription Factor-1 (TTF-1) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TTF-1 Positive have an H score \>0 and TTF-1 Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive. |
| Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | Baseline to date of death from any cause (up to 37.06 months) | Cytoplasmic and nuclear Thymidylate Synthase (TS) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic and nuclear staining, and H score was calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TS Positive have an H score \>0 and TS Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive. |
| Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | Baseline to date of death from any cause (up to 37.06 months) | Cytoplasmic and membrane Folate Receptor Alpha (FR-α) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic or membrane staining, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). FR-α Positive have an H score \>0 and FR-α Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive. |
| Pharmacokinetics (PK): Pemetrexed Clearance (CL) | Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose) | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pem/Carbo/Bev Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab
Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days
Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.
Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m\^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days
Pemetrexed: Maintenance therapy 500 mg/m\^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation
Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days | 472 |
| Pac/Carbo/Bev Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab
Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m\^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days
Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days
Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.
Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days | 467 |
| Total | 939 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Induction Period | Adverse Event | 27 | 38 |
| Induction Period | Deaths Due to Study Disease | 9 | 9 |
| Induction Period | Deaths Not Due to Study Disease | 19 | 14 |
| Induction Period | Entry Criterion Not Met | 12 | 11 |
| Induction Period | Lost to Follow-up | 1 | 1 |
| Induction Period | Physician Decision | 21 | 20 |
| Induction Period | Progressive Disease | 73 | 55 |
| Induction Period | Protocol Violation | 1 | 2 |
| Induction Period | Withdrawal by Subject | 15 | 19 |
| Maintenance Period | Adverse Event | 42 | 26 |
| Maintenance Period | Death due to study disease | 3 | 3 |
| Maintenance Period | Death not due to study disease | 2 | 5 |
| Maintenance Period | Entry Criterion Not Met | 0 | 2 |
| Maintenance Period | Other | 1 | 1 |
| Maintenance Period | Physician Decision | 25 | 20 |
| Maintenance Period | Progressive Disease | 186 | 224 |
| Maintenance Period | Protocol Violation | 1 | 3 |
| Maintenance Period | Withdrawal by Subject | 34 | 14 |
Baseline characteristics
| Characteristic | Total | Pac/Carbo/Bev | Pem/Carbo/Bev |
|---|---|---|---|
| Age, Customized <=65 years | 485 participants | 236 participants | 249 participants |
| Age, Customized >65 years | 454 participants | 231 participants | 223 participants |
| Histological Category for Subgroup Analyses Adenocarcinoma | 743 participants | 365 participants | 378 participants |
| Histological Category for Subgroup Analyses Large Cell Carcinoma | 23 participants | 15 participants | 8 participants |
| Histological Category for Subgroup Analyses Other or Indeterminant | 172 participants | 86 participants | 86 participants |
| Histological Category for Subgroup Analyses Unknown | 1 participants | 1 participants | 0 participants |
| Histological Subtype Adenocarcinoma, Lung | 727 participants | 360 participants | 367 participants |
| Histological Subtype Bronchioalveolar Carcinoma | 7 participants | 3 participants | 4 participants |
| Histological Subtype Large Cell Lung Carcinoma | 23 participants | 15 participants | 8 participants |
| Histological Subtype NSCLC Not Otherwise Specified | 86 participants | 39 participants | 47 participants |
| Histological Subtype NSCLC Poorly Differentiated | 86 participants | 47 participants | 39 participants |
| Histological Subtype Predominantly Adenocarcinoma | 9 participants | 2 participants | 7 participants |
| Histological Subtype Unknown | 1 participants | 1 participants | 0 participants |
| Previously Treated Brain Metastasis No | 835 participants | 415 participants | 420 participants |
| Previously Treated Brain Metastasis Yes | 104 participants | 52 participants | 52 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 29 participants | 14 participants | 15 participants |
| Race/Ethnicity, Customized Black or African American | 94 participants | 52 participants | 42 participants |
| Race/Ethnicity, Customized Caucasian | 805 participants | 396 participants | 409 participants |
| Race/Ethnicity, Customized Information not provided | 4 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Multiple race/ethnicities | 5 participants | 3 participants | 2 participants |
| Region of Enrollment United States | 939 participants | 467 participants | 472 participants |
| Sex: Female, Male Female | 439 Participants | 218 Participants | 221 Participants |
| Sex: Female, Male Male | 500 Participants | 249 Participants | 251 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 430 / 442 | 433 / 443 |
| serious Total, serious adverse events | 188 / 442 | 181 / 443 |
Outcome results
Primary
Overall Survival
Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time frame: Baseline to date of death from any cause (up to 37.06 months)
Population: All randomized participants using the intent-to-treat principle. Number of participants censored: n=131, 127 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pem/Carbo/Bev | Overall Survival | 12.55 months |
| Pac/Carbo/Bev | Overall Survival | 13.40 months |
p-value: 0.9489695% CI: [0.86, 1.16]Log Rank
Secondary
Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - General (FACT-G)
The FACT-G is a validated instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item questionnaire and is organized into subscales, each designed to assess a QOL domain: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items. Each item uses a 5 point rating scale (0=not at all and 4=equals very much). FACT-G Total is the sum of the scores of all 4 subscales and ranges from 0 to 108. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time frame: Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)
Population: The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT-G data, using the intent-to-treat principle.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - General (FACT-G) | 0.51 units on a scale | Standard Error 0.54 |
| Pac/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - General (FACT-G) | 0.18 units on a scale | Standard Error 0.54 |
p-value: 0.667Mixed Models Analysis
Secondary
Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx)
FACT/GOG-Ntx is a validated instrument used to measure quality of life (QOL) in participants with cancer and neurotoxicity (Ntx) consisting of 27-item FACT-General (G) and 11-item Ntx subscale. FACT-G is organized into domain subscales: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items; each uses a 5 point rating scale (0=not at all and 4=equals very much). FACT/GOG-Ntx Total Score=sum 5 subscales and ranges from 0-152. Ntx Trial Outcome Index (TOI-Ntx)=PWB+FWB+NTX and range from 0-100. For all FACT scales, higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time frame: Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)
Population: The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT/GOG-Ntx data, using the intent-to-treat principle.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pem/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx) | FACT/GOG-Ntx Total Score (n=393, 389) | -0.60 units on a scale | Standard Error 0.7 |
| Pem/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx) | Ntx Trial Outcome Index (TOI-Ntx)(n=393, 390) | -2.79 units on a scale | Standard Error 0.55 |
| Pac/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx) | FACT/GOG-Ntx Total Score (n=393, 389) | -5.48 units on a scale | Standard Error 0.7 |
| Pac/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx) | Ntx Trial Outcome Index (TOI-Ntx)(n=393, 390) | -7.60 units on a scale | Standard Error 0.55 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
Secondary
Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L)
FACT-L is a valid instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item FACT-General (G) and 9-item lung cancer subscale (LCS). FACT-G is organized into subscales: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items. Each item uses a 5 point rating scale (0=not at all and 4=equals very much). FACT-L Total Score=4 subscales + LCS and ranges from 0 to 144. Trial Outcome Index-Lung (TOI-L)=PWB+FWB+LCS and ranges from 0 to 92. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time frame: Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)
Population: The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT-L, using the intent-to-treat principle.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pem/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L) | FACT-L Total Score (n=397, 392) | 1.88 units on a scale | Standard Error 0.65 |
| Pem/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L) | Trial Outcome Index-Lung (TOI-L) (n=396, 394) | -0.38 units on a scale | Standard Error 0.5 |
| Pac/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L) | FACT-L Total Score (n=397, 392) | 1.66 units on a scale | Standard Error 0.66 |
| Pac/Carbo/Bev | Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L) | Trial Outcome Index-Lung (TOI-L) (n=396, 394) | -0.40 units on a scale | Standard Error 0.5 |
p-value: 0.815Mixed Models Analysis
p-value: 0.978Mixed Models Analysis
Secondary
Duration of Hospitalizations Per Participant
Length of hospitalization in participants hospitalized during the study or within 30 days of discontinuation regardless of whether the hospitalization was or was not due to study drug.
Time frame: Baseline to study endpoint (up to 37.06 months)
Population: All randomized participants who received at least 1 dose of study drug and had at least one hospitalization while on study or within 30 days of discontinuation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Duration of Hospitalizations Per Participant | 9.4 days | Standard Deviation 9.8 |
| Pac/Carbo/Bev | Duration of Hospitalizations Per Participant | 8.0 days | Standard Deviation 6.7 |
Secondary
Number of Participants Receiving Concomitant Medication
Time frame: Baseline to study endpoint (up to 37.06 months)
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pem/Carbo/Bev | Number of Participants Receiving Concomitant Medication | 406 participants |
| Pac/Carbo/Bev | Number of Participants Receiving Concomitant Medication | 421 participants |
Secondary
Number of Participants Who Received a Transfusion
Time frame: Baseline to study endpoint (up to 37.06 months)
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pem/Carbo/Bev | Number of Participants Who Received a Transfusion | 116 participants |
| Pac/Carbo/Bev | Number of Participants Who Received a Transfusion | 44 participants |
Secondary
Percentage of Participants With a Complete Response (CR) and Partial Response (PR) (Overall Response Rate)
Overall Response Rate (ORR) is the number of participants with a Complete Response (CR) and Partial Response (PR) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared to baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions.
Time frame: Baseline to measured progressive disease (up to 37.06 months)
Population: All randomized participants using the intent-to-treat principle
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pem/Carbo/Bev | Percentage of Participants With a Complete Response (CR) and Partial Response (PR) (Overall Response Rate) | 34.1 percentage of participants |
| Pac/Carbo/Bev | Percentage of Participants With a Complete Response (CR) and Partial Response (PR) (Overall Response Rate) | 33.0 percentage of participants |
p-value: 0.72997Fisher Exact
Secondary
Percentage of Participants With a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate)
Disease Control Rate (DCR) is the number of participants with a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared with baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions. Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions compared with the smallest sum of the longest diameter recorded since the start of treatment or the appearance of 1 or more new lesion(s). Stable Disease (SD) was defined as small changes that did not meet above criteria.
Time frame: Baseline to measured progressive disease (up to 37.06 months)
Population: All randomized participants using the intent-to-treat principle
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pem/Carbo/Bev | Percentage of Participants With a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate) | 65.9 percentage of participants |
| Pac/Carbo/Bev | Percentage of Participants With a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate) | 69.8 percentage of participants |
p-value: 0.20892Fisher Exact
Secondary
Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) Bevacizumab
Time frame: Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)
Population: Randomized participants who received study drug and had evaluable AUC(0-∞) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) Bevacizumab | 3070 microgram*day per milliliter (μg•day/mL) | Geometric Coefficient of Variation 29 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) Bevacizumab | 3160 microgram*day per milliliter (μg•day/mL) | Geometric Coefficient of Variation 33 |
Secondary
Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Pemetrexed
Time frame: Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)
Population: Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable AUC(0-∞) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Pemetrexed | 203 microgram*hour per milliliter (μg•hr/mL) | Geometric Coefficient of Variation 23 |
Secondary
Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum
Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time frame: Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)
Population: Randomized participants who received study drug and had evaluable AUC(0-∞) data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum | Total (Bound and Unbound) | 160 microgram*hour per milliliter (μg•hr/mL) | Geometric Coefficient of Variation 32 |
| Pem/Carbo/Bev | Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum | Unbound (n=17, 13) | 55.7 microgram*hour per milliliter (μg•hr/mL) | Geometric Coefficient of Variation 33 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum | Total (Bound and Unbound) | 182 microgram*hour per milliliter (μg•hr/mL) | Geometric Coefficient of Variation 24 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum | Unbound (n=17, 13) | 62.9 microgram*hour per milliliter (μg•hr/mL) | Geometric Coefficient of Variation 34 |
Secondary
Pharmacokinetics (PK): Bevacizumab Clearance (CL)
Time frame: Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)
Population: Randomized participants who received study drug and had evaluable CL data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Bevacizumab Clearance (CL) | 0.341 liters per day (L/day) | Geometric Coefficient of Variation 31 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Bevacizumab Clearance (CL) | 0.376 liters per day (L/day) | Geometric Coefficient of Variation 38 |
Secondary
Pharmacokinetics (PK): Elimination Half-life (t1/2) for Bevacizumab
Time frame: Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)
Population: Randomized participants who received study drug and had evaluable t1/2 data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Elimination Half-life (t1/2) for Bevacizumab | 14.8 days | Geometric Coefficient of Variation 36 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Elimination Half-life (t1/2) for Bevacizumab | 12.8 days | Geometric Coefficient of Variation 46 |
Secondary
Pharmacokinetics (PK): Elimination Half-life (t1/2) for Pemetrexed
Time frame: Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)
Population: Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable t1/2 data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Elimination Half-life (t1/2) for Pemetrexed | 2.88 hours (hr) | Geometric Coefficient of Variation 13 |
Secondary
Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum
Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time frame: Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)
Population: Randomized participants who received study drug and had evaluable t1/2 data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum | Total (Bound and Unbound) | 65.6 hours (hr) | Geometric Coefficient of Variation 69 |
| Pem/Carbo/Bev | Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum | Unbound (n=17, 13) | 2.03 hours (hr) | Geometric Coefficient of Variation 15 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum | Total (Bound and Unbound) | 86.4 hours (hr) | Geometric Coefficient of Variation 21 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum | Unbound (n=17, 13) | 1.95 hours (hr) | Geometric Coefficient of Variation 21 |
Secondary
Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Bevacizumab
Time frame: Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)
Population: Randomized participants who received study drug and had evaluable Cmax data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Bevacizumab | 276 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 18 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Bevacizumab | 302 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 20 |
Secondary
Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Pemetrexed
Time frame: Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)
Population: Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable Cmax data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Pemetrexed | 122 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 20 |
Secondary
Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum
Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time frame: Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)
Population: Randomized participants who received study drug and had evaluable Cmax data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum | Total (Bound and Unbound) | 18.4 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 24 |
| Pem/Carbo/Bev | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum | Unbound (n=18, 15) | 21.1 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 31 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum | Total (Bound and Unbound) | 17.8 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 33 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum | Unbound (n=18, 15) | 17.1 micrograms per milliliter (μg/mL) | Geometric Coefficient of Variation 34 |
Secondary
Pharmacokinetics (PK): Pemetrexed Clearance (CL)
Time frame: Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)
Population: Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable CL data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Pemetrexed Clearance (CL) | 72.1 milliliters per minute (mL/min) | Geometric Coefficient of Variation 25 |
Secondary
Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms
Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time frame: Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)
Population: Randomized participants who received study drug and had evaluable CL data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pem/Carbo/Bev | Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms | Total (Bound and Unbound) | 2.02 liters per hour (L/hr) | Geometric Coefficient of Variation 39 |
| Pem/Carbo/Bev | Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms | Unbound (n=17, 13) | 5.81 liters per hour (L/hr) | Geometric Coefficient of Variation 35 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms | Total (Bound and Unbound) | 1.87 liters per hour (L/hr) | Geometric Coefficient of Variation 28 |
| Pac/Carbo/Bev | Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms | Unbound (n=17, 13) | 5.36 liters per hour (L/hr) | Geometric Coefficient of Variation 47 |
Secondary
Progression Free Survival Time
Progression free survival (PFS) is defined as the time from date of randomization to the date of objective disease progression or death due to any cause. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier.
Time frame: Baseline to measured progressive disease or date of death from any cause (up to 33.54 months)
Population: All randomized participants using the intent-to-treat principle. Number of participants censored: n=127, 109 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pem/Carbo/Bev | Progression Free Survival Time | 6.04 months |
| Pac/Carbo/Bev | Progression Free Survival Time | 5.55 months |
p-value: 0.0120695% CI: [0.71, 0.96]Log Rank
Secondary
Safety and Toxicity Profile of Study Treatments
Safety and toxicity profile was defined as serious and other non-serious adverse events. A summary of serious and all other non-serious adverse events is located in the Reported Adverse Event module.
Time frame: Baseline to study endpoint (up to 37.06 months)
Population: All randomized participants who received at least 1 dose of study drug during the specified treatment phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pem/Carbo/Bev | Safety and Toxicity Profile of Study Treatments | Serious Adverse Events (SAEs) | 111 participants |
| Pem/Carbo/Bev | Safety and Toxicity Profile of Study Treatments | Other Adverse Events (AEs) | 432 participants |
| Pac/Carbo/Bev | Safety and Toxicity Profile of Study Treatments | Other Adverse Events (AEs) | 288 participants |
| Pac/Carbo/Bev | Safety and Toxicity Profile of Study Treatments | Serious Adverse Events (SAEs) | 83 participants |
| Pac/Carbo/Bev; Induction Phase | Safety and Toxicity Profile of Study Treatments | Serious Adverse Events (SAEs) | 123 participants |
| Pac/Carbo/Bev; Induction Phase | Safety and Toxicity Profile of Study Treatments | Other Adverse Events (AEs) | 431 participants |
| Pac/Carbo/Bev; Maintenance Phase | Safety and Toxicity Profile of Study Treatments | Serious Adverse Events (SAEs) | 68 participants |
| Pac/Carbo/Bev; Maintenance Phase | Safety and Toxicity Profile of Study Treatments | Other Adverse Events (AEs) | 296 participants |
Secondary
Time to Progressive Disease
Time to progressive disease was defined as the time from randomization to the first date of objective disease progression. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier.
Time frame: Baseline to measured progressive disease (up to 37.06 months)
Population: All randomized participants using the intent-to-treat principle. Number of participants censored: n=198, 172 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pem/Carbo/Bev | Time to Progressive Disease | 7.03 months |
| Pac/Carbo/Bev | Time to Progressive Disease | 6.04 months |
p-value: 0.00695% CI: [0.67, 0.94]Log Rank
Secondary
Translational Research: Number of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations
Epidermal Growth Factor Receptor (EGFR) mutations were measured by polymerase chain reaction (PCR).
Time frame: Baseline
Population: All randomized participants with EGFR data regardless of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pem/Carbo/Bev | Translational Research: Number of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations | EGFR mutation positive | 11 participants |
| Pem/Carbo/Bev | Translational Research: Number of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations | EGFR mutation negative | 121 participants |
Secondary
Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression
Cytoplasmic and membrane Folate Receptor Alpha (FR-α) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic or membrane staining, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). FR-α Positive have an H score \>0 and FR-α Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time frame: Baseline to date of death from any cause (up to 37.06 months)
Population: All randomized participants with FR-α Cytoplasm or Membrane H scores. Participants censored: FR-α Positive Cytoplasm n=21, 15 and Negative n=4, 3; FR-α Membrane Positive n=16, 8 and Negative n=9, 10 for Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | FR-α Cytoplasm Positive (H score > 0; n=64, 53) | 14.4 months |
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | FR-α Cytoplasm Negative (H score = 0; n=34, 29) | 12.0 months |
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | FR-α Membrane Positive (H score > 0; n=39, 22) | 19.2 months |
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | FR-α Membrane Negative (H score = 0; n=59, 60) | 12.9 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | FR-α Membrane Negative (H score = 0; n=59, 60) | 11.3 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | FR-α Cytoplasm Positive (H score > 0; n=64, 53) | 14.3 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | FR-α Membrane Positive (H score > 0; n=39, 22) | 15.5 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression | FR-α Cytoplasm Negative (H score = 0; n=34, 29) | 11.2 months |
p-value: 0.89195% CI: [0.622, 1.511]Regression, Cox
p-value: 0.0695% CI: [0.342, 1.023]Regression, Cox
p-value: 0.90595% CI: [0.49, 1.88]Regression, Cox
p-value: 0.45595% CI: [0.575, 1.281]Regression, Cox
Secondary
Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression
Cytoplasmic and nuclear Thymidylate Synthase (TS) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic and nuclear staining, and H score was calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TS Positive have an H score \>0 and TS Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time frame: Baseline to date of death from any cause (up to 37.06 months)
Population: All randomized participants with TS Cytoplasm and Nucleus H scores. Participants censored: TS Cytoplasm Positive n=23, 20 and Negative n=4, 1; TS Nucleus Positive n=17, 9 and Negative n=10, 12 for the Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | TS Cytoplasm Positive (H score > 0; n=90, 83) | 12.9 months |
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | TS Cytoplasm Negative (H score = 0; n=10, 6) | 18.2 months |
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | TS Nucleus Positive (H score > 0; n=68, 51) | 12.7 months |
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | TS Nucleus Negative (H score = 0; n=32, 38) | 19.2 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | TS Nucleus Negative (H score = 0; n=32, 38) | 12.4 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | TS Cytoplasm Positive (H score > 0; n=90, 83) | 12.4 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | TS Nucleus Positive (H score > 0; n=68, 51) | 12.4 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression | TS Cytoplasm Negative (H score = 0; n=10, 6) | 11.6 months |
p-value: 0.67395% CI: [0.654, 1.316]Regression, Cox
p-value: 0.28795% CI: [0.157, 1.729]Regression, Cox
p-value: 0.295% CI: [0.498, 1.157]Regression, Cox
p-value: 0.91595% CI: [0.54, 1.738]Regression, Cox
Secondary
Translational Research: Overall Survival (OS) Based on Nuclear Thyroid Transcription Factor-1 (TTF-1) Expression Regardless of Study Treatment
Nuclear Thyroid Transcription Factor-1 (TTF-1) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TTF-1 Positive have an H score \>0 and TTF-1 Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time frame: Baseline to date of death from any cause (up to 37.06 months)
Population: All randomized participants with TTF-1 H scores regardless of study treatment. Participants censored: n=38, 11 in the TTF-1 Nuclear Positive and Negative arms, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pem/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Nuclear Thyroid Transcription Factor-1 (TTF-1) Expression Regardless of Study Treatment | 14.9 months |
| Pac/Carbo/Bev | Translational Research: Overall Survival (OS) Based on Nuclear Thyroid Transcription Factor-1 (TTF-1) Expression Regardless of Study Treatment | 8.7 months |
p-value: <0.00195% CI: [0.338, 0.681]Regression, Cox