Part B. - Removed the requirement for subjects with wild-type EGFR from the inclusion criteria. - Updated the inclusion criteria to ensure dose would be adjusted for subject’s renal function for both carboplatin and cisplatin. - Clarified that subjects who had more than 28 days between doses of farletuzumab or placebo should be discontinued from study treatment. - Clarified Farletuzumab or Placebo Visit; in the event that the dose of chemotherapy was delayed during Combination Therapy, farletuzumab (2.5 mg/kg) or placebo IV would be administered. There were to be no additional farletuzumab or placebo dose modifications. - Updated farletuzumab/placebo dosing during maintenance as Monotherapy 7.5 mg/kg Q3W. Clarified that the dose could be re-calculated more frequently than when weight changed more than 10% per site guidelines. - Clarified that treatment with other nonstudy monoclonal antibodies and tyrosine kinase inhibitors (TKIs) while on study was not allowed; use of granulocyte colony stimulating factors by study subjects was not allowed for prophylaxis. - Clarified that tumor histology would be verified by the site to ensure adenocarcinoma of the lung. EGFR testing would be completed retrospectively if the status was unknown. Deleted the requirement for central pathologist confirmation of histology. - Added central laboratory assessment of tumor expression of FRA for all subjects. Subjects with no FRA expression were excluded from the study. - Clarified that subjects with confirmation of newly diagnosed evidence of disease would discontinue study treatment (Combination Therapy or Monotherapy) but move on to Follow-up; subjects would not discontinue the study.

Part C. - Removed post-infusion electrocardiogram (ECG); removed laboratory assessment of lactate dehydrogenase and phosphorus. - Emphasized that exploratory biomarker substudy was not compulsory and required additional subject consent. - Corrected the initial infusion rate 0.2 mL/min, progressed at 0.2 mL/min every 5 min to 1 mL/min; suggested the rate of increase 0.2 mL/min every 5 minutes. - Clarified CT/MRI scanning window during all time points; ±7 days. - Clarified the collection of scans when subjects discontinued study treatment without evidence of radiographic or clinical disease progression or study termination by the sponsor. - Clarified data capture during Follow-up as any additional systemic therapy received for Stage IV adenocarcinoma of the lung and survival status. - Clarified other protocol-approved measures of disease progression, and added symptomatic deterioration, as reasons for discontinuation. - Added the definition of Per Protocol Analysis Set; changed the cut-off for PFS primary analysis to 70 events. - Clarified that independent read would be the read of reference for ORR. - Added details of safety analyses by Data and Safety Monitoring Board (DSMB); changed time point to the 12th subject dosed.

Part A. - Updated the protocol title to reflect the updated protocol design. - Removed the maintenance component of pemetrexed from the Introduction and from the study design as the benefit was not unequivocally proven in multiple clinical studies. Subjects experiencing clinical benefit after at least 4, but no more than 6, cycles of chemotherapy were to go on to receive farletuzumab or placebo monotherapy per their original randomization assignment. - Updated the study design to simplify proof of concept evaluation of farletuzumab with standard of care chemotherapy for Stage IV non-small cell lung cancer (NSCLC), adenocarcinoma. The study would assess PFS after all cycles of chemotherapy were completed. - Removed “docetaxel” and added “cisplatin” as appropriate to reflect the current chemotherapeutic regimens. - Removed the exclusion of EGFR mutations as there was currently no Food and Drug Administration (FDA) approved, universally agreed upon, method of mutation detection. Tumor samples collected in the context of this study would be assayed retrospectively for EGFR mutations by a central laboratory for exploratory purposes only. Therapeutic decisions would not be made based on the EGFR mutation assay developed for the purposes of this clinical study. - Changed the randomization ratio to 1:1 and decreased sample size by 45 subjects to allow data analysis to be performed sooner. The randomization stratification factor was changed from region to chemotherapy regimen to ensure consistency across chemotherapy regimens selected. - Added new exploratory endpoints: red blood cell folate level, homocysteine level, & circulating tumor cells, and associated collections and assessments. - Added a safety analysis specifically aimed at evaluating any significant increase in toxicity or treatment intolerability due to the novel combination of pemetrexed and farletuzumab to the study design. - Updated the number of subjects to be randomized (120).

- Updated rationales for change in protocol-approved chemotherapy regimen - Deleted the requirement for EGFR wild type - Updated the statistical design.

Part A. - Additional safety information was added as a result of the ongoing DSMB reviews. - Added the definition of clinical progression throughout to address subjects who have definitive progressive disease (PD) other than by RECIST 1.1. - Deleted PFS after Combination Therapy as a secondary objective; this was now included as part of the primary analysis for PFS. - Changed “disease stabilization” to PFS throughout in correlation analyses since PFS was the primary endpoint and OS was the key secondary endpoint. - Clarified that all doses of farletuzumab, placebo and chemotherapy would be administered on Day 1 of the week specified. - Clarified that the investigator would choose which one of the 3 protocol-approved chemotherapy regimens would be administered to each subject. - Provided the option of administering carboplatin at AUC 5 or 6 as clinically indicated. - Clarified the timing of the DSMB safety review as the first 6 subjects who received farletuzumab in combination with a pemetrexed-containing chemotherapy regimen. - Corrected study duration to be approximately 29 months. - Removed limitation on alkaline phosphatase (ALK-P) from inclusion criteria to allow subjects with bone metastasis to be included. Clarified the definition of surgically sterile.

Part B. - Clarified timing of the end of palliative radiation in relationship to the first dose of farletuzumab or placebo in the exclusion criteria as being prior to first dose. Clarified the required timing of completion for radiotherapy, surgery, steroid and anticonvulsant treatment completion as being at least 14 days prior to the first dose. Clarified exclusion of “other” immunotherapies with the exception of low-dose steroids. Added exclusion for allergic reaction to “any components of farletuzumab”. - Changed serum and urine FRA sampling time point to Cycle 4 Week 1 Day 1. Changed RBC folate and total homocysteine sampling time points to Cycle 1 Week 1 Day 1. - Deleted sampling for serum FRA, urine FRA, RBC folate, total homocysteine, CTC, and biomarkers from the Monotherapy phase. Updated quantities of blood and urine to be collected. - Changed the maximum rate of infusion from 1 mL/min to 2 mL/min, and specified that if 2 mL/min was well tolerated, subsequent infusions could be started at that rate. - Clarified the inclusion of positive fluid cytology as a protocol-approved measure of progression. - Clarified the timing of screening evaluations - Clarified determination of sample size for OS power and provided rationale for same. Added the OS interim futility analysis and clarified the timing for same. Futility considerations were to be based on conditional power with a suggested boundary of 2% (conditional power at estimated effect size), corresponding to an approximate OS HR futility boundary of 1.0. - Instead of an additional secondary endpoint of ‘PFS at the end of Chemotherapy’, the analysis was presented as part of the primary analysis, but at a pre-specified time point, to eliminate any bias associated with the timing of the completion of the Chemotherapy. - Additional safety monitoring milestones were included, as well as the proposed milestone for an OS futility analysis. -Updated the assay for determination of FRA.

- The assessment of the primary endpoint (PFS by RECIST v.1.1) was changed from “as assessed by independent central radiology” to “as assessed by investigator review.” Originally, the study design called for analysis of PFS based on RECIST v.1.1 assessment by central radiographic review after the 70th event of disease progression or death. Approximately 6 months after the last subject was enrolled, a blinded assessment was performed to assess the extent of discordance between the investigator RECIST assessments and those of the independent central reviewers. Based on these results and on simulations performed to extrapolate the projected timeline to reach the study target of 70 PFS events by independent central review, it became evident that it would likely take significant additional study time, even beyond the projected follow-up for the OS endpoint, to reach this target; in fact, this extrapolation suggested that the target may never be reached with a sample size of 130 subjects. Therefore the primary endpoint was changed to investigator assessment of PFS by RECIST v.1.1, while maintaining the PFS assessment by independent central review as a key sensitivity analysis. - The primary Cox model was changed to an unstratified model so that the estimation and testing methodologies would be consistent. - Switched from an event-driven, independent PFS endpoint (70 events) to a duration driven, investigator-assessed PFS endpoint (minimum of 6 months follow-up).