Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer.
Afatinib
/ therapeutic use
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Benzimidazoles
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Colorectal Neoplasms
/ drug therapy
Humans
Lung
Lung Neoplasms
/ drug therapy
Mutation
Pancreatic Neoplasms
/ drug therapy
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
/ adverse effects
Proto-Oncogene Proteins p21(ras)
/ genetics
Afatinib
Colorectal cancer
KRAS
Non-small cell lung cancer
Pancreatic cancer
Selumetinib
Journal
The oncologist
ISSN: 1549-490X
Titre abrégé: Oncologist
Pays: England
ID NLM: 9607837
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
07
11
2020
accepted:
30
11
2020
pubmed:
10
12
2020
medline:
22
6
2021
entrez:
9
12
2020
Statut:
ppublish
Résumé
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. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33296125
doi: 10.1002/onco.13631
pmc: PMC8018304
doi:
Substances chimiques
AZD 6244
0
Benzimidazoles
0
KRAS protein, human
0
Protein Kinase Inhibitors
0
Afatinib
41UD74L59M
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
290-e545Informations de copyright
© AlphaMed Press; the data published online to support this summary are the property of the authors.
Références
JAMA. 2017 May 9;317(18):1844-1853
pubmed: 28492898
Cell Rep. 2014 Apr 10;7(1):86-93
pubmed: 24685132
Cell. 2017 Feb 23;168(5):817-829.e15
pubmed: 28215705
Cancer Chemother Pharmacol. 2015 Jan;75(1):17-23
pubmed: 25322874
Nat Med. 2018 Jul;24(7):961-967
pubmed: 29808006
Br J Cancer. 2020 Apr;122(8):1166-1174
pubmed: 32147669
Nat Cell Biol. 2018 Sep;20(9):1064-1073
pubmed: 30104724
Cancer Chemother Pharmacol. 2020 May;85(5):917-930
pubmed: 32274564
Cancer Cell. 2013 Jan 14;23(1):121-8
pubmed: 23245996
Ann Oncol. 2016 Nov;27(11):2103-2110
pubmed: 27601237