Background: Mutations in the KRAS gene result in a constitutively activated RAS-RAF-MEK-ERK (MAPK) pathway. In KRAS mutant tumors, the anti-tumor activity of MEK inhibitors is limited due to intrinsic resistance caused by feedback activation of upstream epidermal growth factor receptors (HER). This upstream activation not only reactivates MAPK, but also the phosphoinositide 3-kinase (PI3K)-AKT pathway in preclinical research. Based on these data, a phase I clinical trial was initiated with the combination of the orally administered pan-HER inhibitor afatinib and the MEK inhibitor selumetinib in patients with KRAS mutant and PIK3CA wildtype colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or pancreatic cancer to determine the recommended phase 2 regimen (RP2R). Methods: In this multicentre study, patients received escalating doses of afatinib and selumetinib according to a 3+3 design starting with 20 mg afatinib once daily (QD) continuously and 25 mg selumetinib twice daily (BID) in a 21 days on/7 days off schedule. Continuous and intermittent dosing were explored to assess optimal exposure and tolerability. The primary aim was determining the RP2R. Secondary objectives included assessment of anti-tumor activity and the analyses of pharmacokinetic and pharmacodynamic parameters for target inhibition. Clinicaltrials.gov identifier: NCT2450656. Results: In total, 26 mostly heavily pretreated patients with CRC (n=19), NSCLC (n=6) and pancreatic cancer (n=1) were enrolled among 5 dose-levels. Dose-limiting toxicities (DLTs) occurred in 6 patients and consisted of grade 3 diarrhea (n=3), decreased appetite (n=1), nausea/vomiting (n=1), dehydration (n=2) and mucositis (n=1). Clinical efficacy was limited with no responses according to RECIST v1.1 and stable disease for 221 days in a patient with NSCLC as best response. Conclusions: The RP2R was determined at 20 mg afatinib QD continuously and 25 mg selumetinib BID 21 days on/7 days off for continuous dosing. The 3 patients treated in the escalation cohort of the ongoing intermittent dose-level with 20 mg afatinib QD and 25 mg selumetinib BID 5 days on/2 days off, experienced no DLTs. Pending the latest safety results of the expansion cohort for this ongoing dose-level, the RP2R of intermittent dosing has not been established at the moment. Clinical trial information: NCT2450656.