Neratinib-Plus-Cetuximab in Quadruple-WT ( KRAS, NRAS, BRAF, PIK3CA ) Metastatic Colorectal Cancer Resistant to Cetuximab or Panitumumab: NSABP FC-7, A Phase Ib Study.

Autor:	Jacobs SA; NSABP Foundation, Inc., Pittsburgh, Pennsylvania. Samuel.jacobs@nsabp.org ashok.srinivasan@nsabp.org., Lee JJ; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.; UPMC, Pittsburgh, Pennsylvania., George TJ; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; University of Florida, Gainesville, Florida., Wade JL 3rd; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; Cancer Care Specialists of Illinois, Decatur, Illinois., Stella PJ; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; St. Joseph Mercy Health System, Ann Arbor, Michigan., Wang D; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; Henry Ford Cancer Institute, Detroit, Michigan., Sama AR; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania., Piette F; International Drug Development Institute (IDDI), Louvain la Neuve, Belgium., Pogue-Geile KL; NSABP Foundation, Inc., Pittsburgh, Pennsylvania., Kim RS; NSABP Foundation, Inc., Pittsburgh, Pennsylvania., Gavin PG; NSABP Foundation, Inc., Pittsburgh, Pennsylvania., Lipchik C; NSABP Foundation, Inc., Pittsburgh, Pennsylvania., Feng H; NSABP Foundation, Inc., Pittsburgh, Pennsylvania., Wang Y; NSABP Foundation, Inc., Pittsburgh, Pennsylvania., Finnigan M; NSABP Foundation, Inc., Pittsburgh, Pennsylvania., Kiesel BF; UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.; UPMC, Pittsburgh, Pennsylvania., Beumer JH; UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.; UPMC, Pittsburgh, Pennsylvania., Wolmark N; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; UPMC, Pittsburgh, Pennsylvania., Lucas PC; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Allegra CJ; NSABP Foundation, Inc., Pittsburgh, Pennsylvania.; University of Florida, Gainesville, Florida., Srinivasan A; NSABP Foundation, Inc., Pittsburgh, Pennsylvania. Samuel.jacobs@nsabp.org ashok.srinivasan@nsabp.org.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Mar 15; Vol. 27 (6), pp. 1612-1622. Date of Electronic Publication: 2020 Nov 17.
DOI:	10.1158/1078-0432.CCR-20-1831
Abstrakt:	Purpose: In metastatic colorectal cancer (mCRC), HER2 ( ERBB2 ) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment. Patients and Methods: Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies. Results: Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. HER2 amplification (chromogenic in situ IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for HER2 CNV in circulating cell-free DNA. Five SD patients had HER2 amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples. Conclusions: The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. HER2 amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu