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- Title
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.
- Authors
van Geel, Robin M. J. M.; van Brummelen, Emilie M. J.; Eskens, Ferry A. L. M.; Huijberts, Sanne C. F. A.; de Vos, Filip Y. F. L.; Lolkema, Martijn P. J. K.; Devriese, Lot A.; Opdam, Frans L.; Marchetti, Serena; Steeghs, Neeltje; Monkhorst, Kim; Thijssen, Bas; Rosing, Hilde; Huitema, Alwin D. R.; Beijnen, Jos H.; Bernards, René; Schellens, Jan H. M.
- Abstract
<bold>Background: </bold>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).<bold>Methods: </bold>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).<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
British Journal of Cancer, 2020, Vol 122, Issue 8, p1166
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-0776-z