Change of timing of QoL & Patient self-reported symptoms and side effects assessment. Clarification to eligibility criteria for previous treatment with trastuzumab Addition of option of MUGA scans Addition of potential interactions between capecitabibe and other medication Amendment to haematological toxicities for clarification of inconsistencies and unnecessary information within the protocol Amendment to advice on trastuzumab delay of over 2 weeks for clarification of inconsistencies within protocol Update to timing of protocol defined schedule of events Update to assessments required prior to each treatment cycle (3 weekly) Addition of alternative location for patient interviews as clinic visits may not always be suitable for the patient.

Addition of PK sampling sub-study Correction to consent form statements

Addition of PK sampling sub-study Amendment to eligibility criteria to include amiodarone as an inclusion criteria and removal of this drug from concomitant therapy section. Update to exclusion criteria to clarify prior treatment with capecitabine in the metastaic setting is an exclusion criteria Update to permitted dose modifications of lapatinin cececitabine following discussions with LANTERN investigators Removal of requirement for as assessment of disease progression at 3 weekly treatment visits to clarify this is only necessary at 12 & 24 weeks post randomisation follow up visits.

Amendment to eligibility criteria to amend the definition of normal organ and bone marrow function and to remove this from the exclusion criteria. Clarification of pre-treatment investigations, concomitant therapy and dosing and frequency of treatment in section 9 of the protocol. Amendment to instructions for lapatinib and capecitabine dose modifications following adverse events Update to schedule of events to remove laboratory investigations.

Update to PIS/protocol to include a statement that if informed consent is obtained from the participant and the participant subsequently becomes unable to provide on-going informed consent by virtue of physical or mental incapacity, the consent previously given when capable remains legally valid. Participants who lose capacity after informed consent has been obtained will continue with protocol treatment and assessments in consultation with the Principal Investigator and participants care/ family with the participants best interests foremost in the decision making process. On going collection of safety and follow up data will continue via clinical care team for inclusion in the trial analysis in order to preserve the integrity of the trials intention to treat analysis and fulfil regulatory requirements specifically for pharmacovigilance purposes.

The timeframe for trastuzumab treatment was expanded from current only, to current, or prior (in the adjuvant or metastatic setting) treatment. The requirement for patients to have developed brain metastases whilst on trastuzumab treatment was also been removed. Eligibility criteria was expanded to include not only newly diagnosed brain metastases, but also progression of CNS metastases within the last 12 months. Clarified SARs / SUSARs will continue to be reported after 24 weeks for patients still on trial treatment. SAE collection to start from randomisation not registration. Pregnancies will be followed up until outcome is known. A number of new stratification factors added such as: •Type of local therapy (this has been expanded to include both types of therapy) •Timeframe of trastuzumab treatment and which setting (metastatic / adjuvant or both) •Timeframe of diagnosis of brain metastases / progression of brain metastases Treatment allocation section updated to reflect change of randomisation from stratified permuted block randomisation to minimisation. Update to Trastuzumab preparation & IMP Formulation and Storage. Some trial sites store reconstituted trastuzmab out of line with the SPC. Trastuzumab dose section updated to state that dose banding is permitted. Clarified guidance to be followed if a loading dose is required. Updated to state that in the case of a treatment delay future treatment is at the investigation of the investigator Trastuzumab dose section updated to state that dose banding is permitted. Clarified guidance to be followed if a loading dose is required. Updated to state that in the case of a treatment delay future treatment is at the investigation of the investigator. Redefined end of trial as 30 days after 24 week clinical rereview or 30 days after last lapatinib trial treatment administered (whichever date is later)