Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer.
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Benzamides
/ administration & dosage
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Colorectal Neoplasms
/ drug therapy
Diphenylamine
/ administration & dosage
ErbB Receptors
/ antagonists & inhibitors
Female
Humans
Lung Neoplasms
/ drug therapy
Male
Middle Aged
Mitogen-Activated Protein Kinase Kinases
/ antagonists & inhibitors
Mutation
Neoplasms
/ drug therapy
Pancreatic Neoplasms
/ drug therapy
Proto-Oncogene Proteins p21(ras)
/ genetics
Quinazolinones
/ administration & dosage
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
12
11
2019
accepted:
17
02
2020
revised:
10
02
2020
pubmed:
10
3
2020
medline:
31
12
2020
entrez:
10
3
2020
Statut:
ppublish
Résumé
Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER). In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336). Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC. Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.
Sections du résumé
BACKGROUND
Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER).
METHODS
In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336).
RESULTS
Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC.
CONCLUSIONS
Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.
Identifiants
pubmed: 32147669
doi: 10.1038/s41416-020-0776-z
pii: 10.1038/s41416-020-0776-z
pmc: PMC7156736
doi:
Substances chimiques
Benzamides
0
KRAS protein, human
0
Quinazolinones
0
dacomitinib
5092U85G58
mirdametinib
86K0J5AK6M
Diphenylamine
9N3CBB0BIQ
ErbB Receptors
EC 2.7.10.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Banques de données
ClinicalTrials.gov
['NCT02039336']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1166-1174Références
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