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
Recommended Citation
Jacobs SA, Lee JJ, George TJ, Wade JL, Stella PJ, Wang D, Sama A, Piette F, Pogue-Geile KL, Kim RS, Gavin PG, Lipchik C, Feng H, Wang Y, Finnigan M, Kiesel B, Beumer JH, Wolmark N, Lucas PC, Allegra CJ, and Srinivasan A. 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. Clin Cancer Res 2020.
Document Type
Article
Publication Date
11-17-2020
Publication Title
Clinical cancer research
Abstract
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.
EXPERIMENTAL DESIGN: 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 120mg, 160mg, 200mg, and 240mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies.
RESULTS: Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240mg 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 7/16 (44%). HER2 amplification (CISH) was detected in 2/21 (9.5%) treatment-naïve tumors and 4/16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared to matched enrollment biopsies, 6/8 (75%) blood samples showed concordance for HER2 CNV in cfDNA. 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 240mg/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.
PubMed ID
33203645
