Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer

Abstract

Lessons Learned Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d. Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined. Background Antitumor effects of MEK inhibitors are limited in KRAS‐mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3‐kinase–AKT pathway. Therefore, this phase I trial was initiated with the pan‐HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild‐type tumors. Methods Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy. Results Twenty‐six patients were enrolled with colorectal cancer (n = 19), non‐small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose‐limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response. Conclusion Afatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.

Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now?

“…In peripheral blood mononuclear cells, inhibition of phosphorylated ERK needs a specified concentration for both selumetinib and afatinib. Although the study reported limited clinical efficacy for the two drugs, several side effects have been reported after oral administration [ 190 ]. Folprecht G et al conducted a clinical study that included 47 patients with mCRC who received EKB-569, an EGFR tyrosine kinase inhibitor, in combination with irinotecan, 5-FU, and leucovorin (FOLFIRI).…”

Disease Modeling on Tumor Organoids Implicates AURKA as a Therapeutic Target in Liver Metastatic Colorectal Cancer

“…Dual inhibition of EGFR–MEK by AfaSel treatment has been proven to be applicable in a phase I study on KRAS-mutant CRC, although drug doses had to be lowered when compared with the maximal single-agent dose to avoid drug toxicity. 43 The AURKA inhibitor alisertib (+cytotoxic treatment) passed a phase I clinical trial without showing unexpected side effects, albeit at the lowest drug dose investigated. 44 Our data suggest that relatively low doses of AfaSel and alisertib, when applied in a triple combination, can induce apoptosis in KRAS-mutant CRC–PDTOs.…”

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

“…In the present study, OnkoKB, CiViC, and My Cancer Genome were considered, and the predicted drug effects took into account that a tumor might develop a resistance to drug treatment. A further caveat is that it remains unclear if, for example, OnkoKB target level 1 agents such as the MEK inhibitor Selumetinib, which has proved very successful in neurofibromatosis, might also help the 10% of ACC patients bearing NF1 alterations: to date, Selumetinib produced no significant result in NSCLC [ 73 , 74 ], uveal melanoma [ 75 ] and other cancers [ 76 ], despite NF1 mutations.…”