Global amendment 1: Clarifications, corrections, and administrative changes, or updates to background information were made. In addition the following was implemented: - cardiac assessments (electrocardiogram (ECG) and left ventricular ejection fraction (LVEF)) were to be performed only if clinically indicated. Left ventricular dysfunction has been associated with HER2 inhibition. Based on the available clinical trial data, there as no suggestion that afatinib caused an adverse effect on cardiac contractility. However, afatinib had not been studied in patients with abnormal LVEF or those with significant cardiac history. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during afatinib treatment, should be considered. In patients that developed relevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEF assessment should be considered.; - reporting of serious adverse events (SAEs) after the follow-up period was clarified. The investigator did not need to actively monitor patients for AEs once the clinical trial had ended. However, if the investigator became aware of an SAE that occurred after the patient had completed the clinical trial (including any protocol required residual effect period (REP) and / or follow-up), it was to be reported by the investigator to the sponsor if considered relevant by the investigator;

Global amendment 1 (continued) - new safety information was added: patients who presented with symptoms of keratitis, such as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye were to be referred promptly to an ophthalmic specialist. If a diagnosis of ulcerative keratitis was confirmed, treatment with afatinib was to be interrupted or discontinued. If keratitis was diagnosed, the benefits and risks of continuing treatment with afatinib were to be carefully considered. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is a risk factor for keratitis and ulceration; -acceptable methods of birth control were to be used for 28 days after the end of active treatment (rather than 14 days as originally specified).

Global amendment 2: In addition to clarifications, corrections, and administrative changes, or updates to background information, the following main changes, were implemented: the duration of treatment was updated to ensure an on-going supply to patients who have not yet met the criteria for ceasing study treatment and to allow completion of the trial; a planned interim analysis was added.

Global amendment 3: In addition to clarifications, corrections, and administrative changes, or updates to background information, the following main changes, were implemented: shipment of medication to patients’ homes (or dispensing enough medication for 2 cycles) was permitted to allow flexibility in visit conduct in case required due to pandemic or other exceptional situations to ensure patients safety by ensuring continuous treatment; the risk assessment was updated in line with updates to the Investigator Brochure, to note that gastrointestinal perforation, including fatalities, had been reported during treatment with afatinib in 0.2% of patients across all randomised controlled clinical trials. In the majority of cases, gastrointestinal perforation was associated with other known risk factors, including concomitant medications such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), or anti-angiogenic agents, an underlying history of gastrointestinal ulceration, underlying diverticular disease, age, or bowel metastases at sites of perforation. Patients who develop gastrointestinal perforation while taking afatinib, should permanently discontinue treatment.