Study of AVE0005 (VEGF Trap) in Locally Advanced or Metastatic Platinum- and Erlotinib- Resistant Non-small-cell-lung Adenocarcinoma

OR was either complete response (CR) or partial response (PR) based on RECIST or modified RECIST. CR was the disappearance of all target/nor-target lesions; and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with reference to the baseline sum LD (According to modified RECIST, to calculate LD for cavitated lesions, the longest cavitation diameters were subtracted from the LD of cavitated target lesions). Assessments were made by the Investigator, and confirmed by repeat tumor imaging 4-6 weeks after documentation of the initial response.

Time frame: up to 2.5 years from initial treatment

Population: Simon's cohort: The first 84 evaluable participants, based on Simon's two-stage study design that required 84 evaluable participants to maintain a targeted 90% power.

OR was either complete response (CR) or partial response (PR) based on RECIST or modified RECIST. CR was the disappearance of all target/nor-target lesions; and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with reference to the baseline sum LD (According to modified RECIST, to calculate LD for cavitated lesions, the longest cavitation diameters were subtracted from the LD of cavitated target lesions). Assessments were made by the IRC, and confirmed by repeat tumor imaging 4-6 weeks after documentation of the initial response.

Time frame: up to 2.5 years from initial treatment

Population: Simon's cohort: The first 84 evaluable participants, based on Simon's two-stage study design that required 84 evaluable participants to maintain a targeted 90% power.

DR was the time interval from the first complete response (CR) or partial response (PR) to the date of tumor progression or death from any cause, whichever was earlier. The duration of response was calculated only for those participants who achieved CR or PR.

Time frame: up to 2.5 years from initial treatment

Population: No modified RECIST responses, as confirmed by the IRC review, were observed. Only 2 responders were reported by the Investigators. Therefore, the analyses for duration of response was not performed.

Median free and VEGF-bound trough concentrations were determined at the end of each cycle beyond Cycle 2 (Steady-state) for each participant. Plasma free aflibercept levels were estimated by a validated direct ELISA, with an LOQ of 15.6 ng/mL. Plasma VEGF-bound aflibercept levels were also estimated by a separate validated direct ELISA with an LOQ of 43.9 ng/mL. Mean ± SD (coefficient of variation \[CV%\]) values were estimated from the median values calculated for each participant.

Time frame: At the end of each treatment cycle (up to 2.5 years)

Population: All participants who received at least part of 1 dose of study treatment and had evaluable blood samples on Day 1 of Cycle 3 for measurement of VEGF-bound aflibercept.

HRQL was assessed with the Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS) questionnaire, which was completed by the participants on Day 1 of Cycle 1 only (for baseline value), then on Day 14 of each even-numbered cycle to evaluate the participants symptoms. The questionnaire scored 7 symptoms: shortness of breath, weight loss, clarity in thinking, coughing, appetite, chest tightness, ease of breathing, on a 0-4 scale. The total FACT-LCS score ranged from 0-28 (where 28 was related to the worst outcome). To calculate a change, the baseline score was subtracted from the score obtained after treatment. A negative value implied an improvement in HRQL.

Time frame: Baseline to 2.5 years

Population: All registered participants with available questionnaires at the timepoint assessed.

Anti-drug antibodies in a participant's serum sample were assayed with an anti-drug ELISA assay, with a lower limit of quantitation of 238.4 ng/mL for an undiluted human serum sample. Serum for anti-drug antibody analysis was collected pre-dose on every fourth cycle after Cycle 1 Day 1 (at 8 week intervals), at end of treatment (EOT), and during post-treatment follow-up 60 days after the last dose.

Time frame: up to 2.5 years after initial treatment

Population: All participants who received at least part of 1 dose of study treatment and had evaluable blood samples.

Participants with abnormal laboratory results for * Liver and renal function (Alkaline phosphatase, Alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], Creatinine, Hyperbilirubinemia), * Electrolytes (Hypercalcemia, Hypocalcemia, Hypokalemia, Hypernatremia, Hyponatremia, Hypophosphatemia) * Metabolism (Hypoalbuminemia, Hyperglycemia, Hypoglycemia) * Hematology (Partial thromboplastin time, Anemia, Lymphopenia, Neutropenia, Thrombocytopenia, Leukopenia)

Time frame: Up to 2.5 years

Population: All participants who received at least part of 1 dose of study treatment.

All AEs regardless of seriousness or relationship to study treatment, spanning from the first administration of study treatment until 60 days after the last administration of study treatment, were recorded, and followed until resolution or stabilization. The number of participants with all treatment emergent adverse events (TEAE), serious adverse events (SAE), TEAE leading to death, and TEAE leading to permanent treatment discontinuation are reported.

Time frame: up to 60+/-5 days after treatment discontinuation, or or until TEAE was resolved or stabilized (Collected till 18 July 2008)

Population: All participants who received at least part of 1 dose of study treatment.

OS was the time interval between registration to the date of death from any cause. The median time for OS was estimated from Kaplan-Meier Plots. A participant was to be censored for the OS analysis if the participant was alive by the study cut-off date. The censoring date was either the date that the participant was last known to be alive or the date of study cut-off, whichever came earlier.

Time frame: up to 2.5 years from initial treatment

Population: All registered participants. 38 participants were censored for OS.

Plasma free aflibercept levels after the first aflibercept infusion were estimated by a validated direct measured by enzyme-linked immunosorbent assay (ELISA), with a limit of quantification (LOQ) of 15.6 ng/mL.

Time frame: Day 1 of the first infusion of Aflibercept (cycle 1)

Population: All participants who received at least part of 1 dose of study treatment and had evaluable blood samples.

PFS time was interval from the date of registration to the date of tumor progression (by RECIST or modified RECIST), or death from any cause, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots. Progression was at least a 20% increase in the sum of the longest diameter (LD) of tumors, compared to smallest sum LD recorded since treatment started, or the appearance of one or more new tumors. If a participant did not progress or die, the date was censored to the date of last valid tumor assessment or the date of data cut-off, whichever was earlier.

Time frame: up to 2.5 years from initial treatment

Population: All registered participants. 18 participants were censored.

PFS time was interval from the date of registration to the date of tumor progression (by RECIST or modified RECIST), or death from any cause, whichever was earlier. If a participant did not progress or die, the date was censored to the date of last valid tumor assessment or the date of data cut-off, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots. Progression was at least a 20% increase in the sum of the longest diameter (LD) of tumors, compared to smallest sum LD recorded since treatment started, or the appearance of one or more new tumors.

Time frame: up to 2.5 years from initial treatment

Population: All registered participants. 17 participants were censored.