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

Samuel A. Jacobs*, James J. Lee, Thomas J. George, James L. Wade, Philip J. Stella, Ding Wang, Ashwin R. Sama, Fanny Piette, Katherine L. Pogue-Geile, Rim S. Kim, Patrick G. Gavin, Corey Lipchik, Huichen Feng, Ying Wang, Melanie Finnigan, Brian F. Kiesel, Jan H. Beumer, Norman Wolmark, Peter C. Lucas, Carmen J. AllegraAshok Srinivasan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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 3þ3 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.

Original languageEnglish (US)
Pages (from-to)1612-1622
Number of pages11
JournalClinical Cancer Research
Issue number6
StatePublished - Mar 2021

ASJC Scopus subject areas

  • Medicine(all)


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