Histological or Cytological Diagnosis of Locally Advanced or Metastatic NSCLC of Nonsquamous Histology and Not Amenable to Curative Therapy.
Conditions
Keywords
nonsquamous
Brief summary
This is a multicenter, randomized, Phase 2, open label, parallel trial to evaluate an effect of pemetrexed alone on nonsquamous non-small cell lung cancer (NSCLC) in a second-line setting (such as progression-free survival \[PFS\], disease control rate, best response rate, time to treatment failure \[TTTF\], overall survival \[OS\] and 1-year survival rates) compared to pemetrexed plus erlotinib combination.
Interventions
DRUGPemetrexed
500 mg/m² intravenous (iv) over 10 minutes on the first day of each 21-day cycle until disease progression (PD) or unacceptable toxicity
DRUGErlotinib
150 mg given orally (po), daily (QD), starting on the first day of the first cycle
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological or cytological diagnosis of locally advanced or metastatic NSCLC that is of nonsquamous histology and not amenable to curative therapy. * Failure of previous treatment with one prior platinum-based chemotherapy regimen. * Good performance status. * Adequate bone marrow reserve, renal and hepatic functions.
Exclusion criteria
* Serious concomitant systemic disease. * Inability to take oral medication. * Inability or unwillingness to take vitamin supplementation and corticosteroids. * Pregnancy / Breast-feeding. * Treatment with certain medicines that prevent blood from clotting.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline to date of measured PD or death from any cause. Maximum follow-up was from baseline to 32.2 months | PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria using computed tomography (CT) or magnetic resonance imaging (MRI) for objective determination of progressive disease (PD: ≤20% increase in sum of longest diameter of target lesion). For participants alive as of data cut-off date who did not have PD, PFS was censored at date of last CT/MRI. For participants who received subsequent systemic anticancer therapy (after study discontinuation) prior to PD or death, PFS censored at date of last CT/MRI prior to initiation of post discontinuation systemic anticancer therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Best Response of Complete Response (CR) or Partial Response (PR) (Response Rate) | Baseline to measured progressive disease. Maximum follow-up was from Baseline to 34 months | CR: Disappearance of all tumor lesions; PR: Either a) at least a 30% decrease in sum of LD of target lesions or b) complete disappearance of target lesions, with persistence (but not worsening) ≥1 nontarget lesions. In either case, no new lesions may have appeared. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD. PD: ≤20% increase in the sum of LD of target lesions. Response Rate (%) = (CR+PR)/number of participants in arm\*100. |
| Time to Treatment Failure (TTTF) | Baseline to first date among death from any cause, PD, or study treatment discontinuation for any reason other than protocol complete or satisfactory response. Maximum follow-up was from Baseline to 32.2 months | Defined as the time from randomization to death from any cause, first observation of PD, or study treatment discontinuation due to any reason other than protocol complete or satisfactory response. For participants who discontinued due to protocol complete or satisfactory response, or for participants not known to have discontinued as of the data cut-off date, TTTF was censored at the last contact date. |
| Percentage of Participants With Best Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Disease Control Rate) | Baseline to measured PD. Maximum follow-up was from Baseline to 34 months | Per RECIST: CR: Disappearance of all target lesions; PR: Either a) ≤30% decrease in sum of longest diameter (LD) of target lesions or b) complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesions. In either case, no new lesions may have appeared. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD. PD: ≤20% increase in sum of LD of target lesions. Disease Control Rate (%) = (SD+PR+CR)/number of participants in arm\*100. |
| Percentage of Participants Surviving at 1 Year | Baseline to date of death from any cause up to 1 year | Overall Survival (OS) rate at 1 year from the date of randomization was determined using the distribution of OS times and was estimated using the Kaplan-Meier method. |
| Number of Participants With Adverse Events (AEs) | Baseline up to 42.2 months | Summaries of serious AEs (SAEs) and all other non-serious AEs are located in the Reported Adverse Event Module. |
| Overall Survival (OS) | Baseline to date of death from any cause. Maximum follow-up was from Baseline to 42.6 months. | OS time is the duration from randomization to the date of death from any cause. For each participant who was not known to have died as of the data inclusion cut-off date, OS was censored at the date of last contact. |
Countries
Austria, Germany, Hungary, Spain, Sweden
Participant flow
Pre-assignment details
This is a 2-arm study; however, results for participant disposition and baseline characteristics are presented for 4 groups including each study arm (Pemetrexed and Pemetrexed + Erlotinib) by histology (Nonsquamous and Squamous). Efficacy results are presented for participants with nonsquamous histology only.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed (Nonsquamous) Pemetrexed: 500 mg/m² iv over 10 minutes on the first day of each 21-day cycle until PD or unacceptable toxicity | 83 |
| Pemetrexed + Erlotinib (Nonsquamous) Pemetrexed: 500 mg/m² iv over 10 minutes on the first day of each 21-day cycle until PD or unacceptable toxicity
Erlotinib: 150 mg given orally, Daily, starting on the first day of the first cycle | 76 |
| Pemetrexed (Squamous) Pemetrexed: 500 mg/m² intravenous (iv) over 10 minutes on the first day of each 21 day cycle until disease progression or unacceptable toxicity | 19 |
| Pemetrexed + Erlotinib (Squamous) Pemetrexed: 500 mg/m² iv over 10 minutes on the first day of each 21-day cycle until PD or unacceptable toxicity
Erlotinib: 150 mg given po, QD, starting on the first day of the first cycle | 26 |
| Total | 204 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 10 | 0 | 3 |
| Overall Study | Death due to adverse event | 0 | 0 | 1 | 2 |
| Overall Study | Death due to study disease | 6 | 4 | 1 | 1 |
| Overall Study | Death, study drug related | 0 | 1 | 0 | 0 |
| Overall Study | Entry criteria not met | 1 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 9 | 6 | 3 | 1 |
| Overall Study | Progressive disease | 58 | 43 | 13 | 18 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Sponsor decision | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Pemetrexed (Nonsquamous) | Pemetrexed + Erlotinib (Squamous) | Pemetrexed (Squamous) | Pemetrexed + Erlotinib (Nonsquamous) |
|---|---|---|---|---|---|
| Age Continuous | 62.3 years STANDARD_DEVIATION 9.96 | 59.8 years STANDARD_DEVIATION 10.25 | 66.1 years STANDARD_DEVIATION 8.58 | 63.9 years STANDARD_DEVIATION 9.33 | 63.5 years STANDARD_DEVIATION 9.7 |
| Basis for Diagnosis Cytological | 39 participants | 19 participants | 4 participants | 1 participants | 15 participants |
| Basis for Diagnosis Histopathological | 165 participants | 64 participants | 22 participants | 18 participants | 61 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Status 0 | 82 Participants | 33 Participants | 9 Participants | 7 Participants | 33 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Status 1 | 92 Participants | 39 Participants | 13 Participants | 7 Participants | 33 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Status 2 | 29 Participants | 11 Participants | 4 Participants | 5 Participants | 9 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Unknown | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Adenocarcinoma of the lung | 131 participants | 70 participants | 0 participants | 0 participants | 61 participants |
| Initial Pathological Diagnosis Bronchioalveolar carcinoma | 5 participants | 4 participants | 0 participants | 0 participants | 1 participants |
| Initial Pathological Diagnosis Large cell lung carcinoma | 15 participants | 6 participants | 0 participants | 0 participants | 9 participants |
| Initial Pathological Diagnosis Mixed cell (squamous/adenocarcinoma) | 2 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Initial Pathological Diagnosis Squamous cell carcinoma of the lung | 45 participants | 0 participants | 26 participants | 19 participants | 0 participants |
| Initial Pathological Diagnosis Unknown | 6 participants | 2 participants | 0 participants | 0 participants | 4 participants |
| Pack-years, smokers only More than 15 pack-years | 148 participants | 60 participants | 25 participants | 15 participants | 48 participants |
| Pack-years, smokers only Unknown | 36 participants | 18 participants | 0 participants | 3 participants | 15 participants |
| Pack-years, smokers only Up to 15 pack-years | 20 participants | 5 participants | 1 participants | 1 participants | 13 participants |
| Race/Ethnicity, Customized African | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Caucasian | 202 participants | 82 participants | 26 participants | 19 participants | 75 participants |
| Race/Ethnicity, Customized East Asian | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native American | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized West Asian | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Austria | 11 participants | 4 participants | 0 participants | 2 participants | 5 participants |
| Region of Enrollment Germany | 102 participants | 44 participants | 15 participants | 6 participants | 37 participants |
| Region of Enrollment Hungary | 34 participants | 12 participants | 4 participants | 4 participants | 14 participants |
| Region of Enrollment Spain | 41 participants | 18 participants | 7 participants | 7 participants | 9 participants |
| Region of Enrollment Sweden | 16 participants | 5 participants | 0 participants | 0 participants | 11 participants |
| Sex: Female, Male Female | 66 Participants | 34 Participants | 2 Participants | 0 Participants | 30 Participants |
| Sex: Female, Male Male | 138 Participants | 49 Participants | 24 Participants | 19 Participants | 46 Participants |
| Smoking status Current smoker | 54 participants | 25 participants | 7 participants | 7 participants | 15 participants |
| Smoking status Ex-smoker | 126 participants | 44 participants | 19 participants | 12 participants | 51 participants |
| Smoking status Never smoked | 24 participants | 14 participants | 0 participants | 0 participants | 10 participants |
| Stage of Disease at Study Entry Stage I | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Stage of Disease at Study Entry Stage II | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Stage of Disease at Study Entry Stage IIIA | 6 participants | 3 participants | 0 participants | 2 participants | 1 participants |
| Stage of Disease at Study Entry Stage IIIB | 30 participants | 10 participants | 5 participants | 4 participants | 11 participants |
| Stage of Disease at Study Entry Stage IV | 168 participants | 70 participants | 21 participants | 13 participants | 64 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 91 / 102 | 98 / 102 |
| serious Total, serious adverse events | 43 / 102 | 53 / 102 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria using computed tomography (CT) or magnetic resonance imaging (MRI) for objective determination of progressive disease (PD: ≤20% increase in sum of longest diameter of target lesion). For participants alive as of data cut-off date who did not have PD, PFS was censored at date of last CT/MRI. For participants who received subsequent systemic anticancer therapy (after study discontinuation) prior to PD or death, PFS censored at date of last CT/MRI prior to initiation of post discontinuation systemic anticancer therapy.
Time frame: Baseline to date of measured PD or death from any cause. Maximum follow-up was from baseline to 32.2 months
Population: Includes Nonsquamous population only.~In Pemetrexed arm, 13 (15.7%) participants censored overall: 12 (14.5%) because of receiving subsequent systemic anticancer therapy.~In Pemetrexed + Erlotinib arm, 16 (21.1%) participants censored overall: 9 (11.8%) because of receiving subsequent systemic anticancer therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed (Nonsquamous) | Progression Free Survival (PFS) | 2.9 months |
| Pemetrexed + Erlotinib (Nonsquamous) | Progression Free Survival (PFS) | 3.2 months |
p-value: 0.004795% CI: [0.438, 0.897]Log Rank
Secondary
Number of Participants With Adverse Events (AEs)
Summaries of serious AEs (SAEs) and all other non-serious AEs are located in the Reported Adverse Event Module.
Time frame: Baseline up to 42.2 months
Population: All participants who received at least 1 dose of study drug were analyzed for safety. Nonsquamous and squamous populations are combined.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed (Nonsquamous) | Number of Participants With Adverse Events (AEs) | serious adverse events | 43 participants |
| Pemetrexed (Nonsquamous) | Number of Participants With Adverse Events (AEs) | other adverse events | 91 participants |
| Pemetrexed + Erlotinib (Nonsquamous) | Number of Participants With Adverse Events (AEs) | serious adverse events | 53 participants |
| Pemetrexed + Erlotinib (Nonsquamous) | Number of Participants With Adverse Events (AEs) | other adverse events | 98 participants |
Secondary
Overall Survival (OS)
OS time is the duration from randomization to the date of death from any cause. For each participant who was not known to have died as of the data inclusion cut-off date, OS was censored at the date of last contact.
Time frame: Baseline to date of death from any cause. Maximum follow-up was from Baseline to 42.6 months.
Population: Pemetrexed arm: 17 (20.5%) participants censored Pemetrexed + Erlotinib arm: 28 (36.8%) participants censored
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed (Nonsquamous) | Overall Survival (OS) | 7.8 months |
| Pemetrexed + Erlotinib (Nonsquamous) | Overall Survival (OS) | 11.8 months |
p-value: 0.01995% CI: [0.465, 0.981]Log Rank
Secondary
Percentage of Participants Surviving at 1 Year
Overall Survival (OS) rate at 1 year from the date of randomization was determined using the distribution of OS times and was estimated using the Kaplan-Meier method.
Time frame: Baseline to date of death from any cause up to 1 year
Population: Includes nonsquamous population only.~On the Pemetrexed arm, 17 participants were censored overall and on the Pemetrexed + Erlotinib arm, 28 participants were censored overall.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed (Nonsquamous) | Percentage of Participants Surviving at 1 Year | 34.1 Percentage participants with OS ≥1 year |
| Pemetrexed + Erlotinib (Nonsquamous) | Percentage of Participants Surviving at 1 Year | 49.4 Percentage participants with OS ≥1 year |
Secondary
Percentage of Participants With Best Response of Complete Response (CR) or Partial Response (PR) (Response Rate)
CR: Disappearance of all tumor lesions; PR: Either a) at least a 30% decrease in sum of LD of target lesions or b) complete disappearance of target lesions, with persistence (but not worsening) ≥1 nontarget lesions. In either case, no new lesions may have appeared. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD. PD: ≤20% increase in the sum of LD of target lesions. Response Rate (%) = (CR+PR)/number of participants in arm\*100.
Time frame: Baseline to measured progressive disease. Maximum follow-up was from Baseline to 34 months
Population: Includes nonsquamous population only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed (Nonsquamous) | Percentage of Participants With Best Response of Complete Response (CR) or Partial Response (PR) (Response Rate) | 10.8 percentage of participants |
| Pemetrexed + Erlotinib (Nonsquamous) | Percentage of Participants With Best Response of Complete Response (CR) or Partial Response (PR) (Response Rate) | 17.1 percentage of participants |
p-value: 0.1808Fisher Exact
Secondary
Percentage of Participants With Best Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Disease Control Rate)
Per RECIST: CR: Disappearance of all target lesions; PR: Either a) ≤30% decrease in sum of longest diameter (LD) of target lesions or b) complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesions. In either case, no new lesions may have appeared. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD. PD: ≤20% increase in sum of LD of target lesions. Disease Control Rate (%) = (SD+PR+CR)/number of participants in arm\*100.
Time frame: Baseline to measured PD. Maximum follow-up was from Baseline to 34 months
Population: Includes nonsquamous population only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed (Nonsquamous) | Percentage of Participants With Best Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Disease Control Rate) | 51.8 percentage of participants |
| Pemetrexed + Erlotinib (Nonsquamous) | Percentage of Participants With Best Response of Stable Disease (SD), Partial Response (PR) or Complete Response (CR) (Disease Control Rate) | 55.3 percentage of participants |
p-value: 0.3909Fisher Exact
Secondary
Time to Treatment Failure (TTTF)
Defined as the time from randomization to death from any cause, first observation of PD, or study treatment discontinuation due to any reason other than protocol complete or satisfactory response. For participants who discontinued due to protocol complete or satisfactory response, or for participants not known to have discontinued as of the data cut-off date, TTTF was censored at the last contact date.
Time frame: Baseline to first date among death from any cause, PD, or study treatment discontinuation for any reason other than protocol complete or satisfactory response. Maximum follow-up was from Baseline to 32.2 months
Population: Includes nonsquamous population only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed (Nonsquamous) | Time to Treatment Failure (TTTF) | 2.4 months |
| Pemetrexed + Erlotinib (Nonsquamous) | Time to Treatment Failure (TTTF) | 3.0 months |
p-value: 0.003495% CI: [0.457, 0.887]Log Rank