Changes to protocol: - Changes to members of the TMG - Clarification that assessments should be made in relation to trial registration not trial randomisation - Pre-chemotherapy blood requirements modified in line with drug modification guidelines - List of trial CRFs modified to include Adverse Event Form

Changes to protocol, patient information sheet, consent form, gp letter and patient cards: - Addition of two new treatment arms for squamous patients (gemcitabine/cisplatin and gemcitabine/paclitaxel) - Amendments to the rationale of the trial as well as inclusion of rationale for including new treatment arms for squamous group - Gemcitabine/Cisplatin and Gemcitabine/Paclitaxel chemotherapy regimens added - All dose modification tables amended according to guidelines on SmPC for Pemetrexed and new dose modification tables added for Gemcitabine doublets - Statistical considerations section updated to include data on Gemcitabine/Cisplatin and Gemcitabine/Paclitaxel in squamous patients - Inclusion of 4 new references Addition of uncommon adverse events listed in Appendix 7 from the updated SmPC for Pemetrexed and the SmPC for Gemcitabine - Biological trial summary updated to include testing for resistance to gemcitabine - Addition of excluding patients who have recently received a yellow fever vaccination - Changes to patient information sheet, consent form, gp letter and patient cards to reflect new trial design

Changes to the protocol, patient information sheet and consent form: - Platelet count for inclusion in the trial changed to >100x 109/L - Changes to the stratification factors for randomisation - Dose modification tables have been amended according to guidelines in the SmPC for Pemetrexed and Gemcitabine - The number of x-rays required for the trial has been reduced, i.e. at chemotherapy cycles 1, 3 and 5, as is standard practice in several centres. Having x-rays at cycles 2, 4 and 6 is now optional. - Adequate renal function is now defined as >60ml/min by EDTA or C&G. - Common toxicology criteria for adverse events (CTCAE) version 3.0 is now replaced by CTCAE version 4.0 - Clarification in the patient information sheet on what treatment non-squamous patients will receive inc. administration of vitamin B12 injections.

Amendment to protocol, patient information sheet and consent form: • Addition of 24 hour urine collection as a method of determining patient GFR value • Clarification of two exclusion criteria’s which apply to non-squamous patients only • Clarification that all trial drugs can be dose banded • Clarification that vitamin b12 and folic acid should be started 7 days before trial treatment • Addition of dose modifications for Gemcitabine arms of the trial in the presence of febrile neutropenia • Pharmacovigilance section of the protocol updated to reflect the CTC template protocol • Removal of choice to do PET-CT scanning rather than CT scanning • Maximum number of hours for fixation of patient tissue samples amended from 48 to 72

Amendment to labels for all IMPs and NIMPs.

Amendment to protocol, patient information sheet, pregnancy monitoring information sheet and consent form: • Further clarification of the end of trial timepoint • Section added clarifying trial activation process for sponsor • Guidance added to inclusion criteria regarding contraception and to exclusion criteria regarding renal function • Documents to be given to randomised patients added • Terminology revised in Pharmacovigilance section • Updated information in relation to SAE processing at the UCL CTC and clinical reviewing • Addition of a section covering incident reporting and serious breaches • Addition of a section covering trial monitoring and oversight • Addition of a section covering withdrawal of patients • Addition of a section covering trial closure • Clarifying which patient identifiable information will be collected by the UCL CTC • Patient information sheet updated with advice on pregnancy and contraception

Amendment to protocol: • Inclusion criteria amendment: Previous palliative radiotherapy to non-target lesions is allowed for pain relief prior to starting chemotherapy (in version 8.0 and previous protocol versions it could not be given in the 28 days prior to starting chemotherapy) • Addition that tumour samples obtained by EBUS cores and EBUS FNA cell blocks are allowed provided that the tumour cells are well preserved • Clarifications to wording to section 5.0 – Pharmacovigilance • Section 5.6 rewritten to refer to DSURs instead of ASRs • Update to pemetrexed secondary label and addition of a primary label

Amendment to protocol, PIS, consent form, GP letter and patient card in line with Urgent Safety Measure undertaken 07/09/2012: • Protocol: clarification EBUS FNA and FNA are examples of cytology; the following amended for consistency across protocol: provision of prescription to CTC prior to site activation and use of ALT or AST in incl/excl; procedure for reporting temp excursions added; update to DM section; insurance section clarified to reflect it is insurers decision to compensate and not UCL; list of expected AEs added for pem/cis and pem/pac. • PIS: ERCC1 amended to provide clarity and easier understanding for patients; duration of treatment corrected from 3 months to 4.5months; removal of AEs associated with gemcitabine; number of CTs corrected in section entitled ‘Risk associated with the CT scan’. The risk factor is correct for 4 scans; wording updated to reflect pem/cisp is now licensed for first line treatment; insurance section updated in line with above protocol change. • Consent form: updated to reflect the change in version of the PIS • GP letter: correction to GP letter to indicate a new biopsy is not required for participation in the trial • Label Change for Pemetrexed: removal of primary label. Commercial stock to be over labelled for the outer packaging only. The outer and inner package will stay together at all times.

Submission of results summary for patients and results summary cover letter for PI's.