TY - JOUR
T1 - 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
AU - van Geel, Robin M J M
AU - van Brummelen, Emilie M J
AU - Eskens, Ferry A L M
AU - Huijberts, Sanne C F A
AU - de Vos, Filip Y F L
AU - Lolkema, Martijn P J K
AU - Devriese, Lot A
AU - Opdam, Frans L
AU - Marchetti, Serena
AU - Steeghs, Neeltje
AU - Monkhorst, Kim
AU - Thijssen, Bas
AU - Rosing, Hilde
AU - Huitema, Alwin D R
AU - Beijnen, Jos H
AU - Bernards, René
AU - Schellens, Jan H M
N1 - Funding Information:
Funding information Pfizer Inc. funded this study and provided the investigational drugs dacomitinib and PD-0325901.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/4/14
Y1 - 2020/4/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85081749954&partnerID=8YFLogxK
U2 - 10.1038/s41416-020-0776-z
DO - 10.1038/s41416-020-0776-z
M3 - Article
C2 - 32147669
SN - 0007-0920
VL - 122
SP - 1166
EP - 1174
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 8
ER -