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Clinical Trial
. 2025 Aug 9;95(1):80.
doi: 10.1007/s00280-025-04802-8.

NSABP FC-11: A phase II study of neratinib plus trastuzumab or neratinib plus cetuximab in patients with "quadruple wild-type" (KRAS/NRAS/BRAF/PIK3CA) metastatic colorectal cancer based on HER2 status: amplified, non-amplified (wild-type), or mutated

Tanner J Freeman #  1   2 , Thomas J George #  3   4 , Samuel A Jacobs #  3 , Greg Yothers  5   6 , Tatjana Kolevska  7 , Huichen Feng  3 , Corey Lipchik  3 , Sai Maley  3 , Nan Song  3 , Ashok Srinivasan  3   8 , Melanie Finnigan  3 , James L Wade 3rd  9 , Gary L Buchschacher Jr  10 , Tareq Al Baghdadi  11 , Asheesh Shipstone  12 , Daniel Lin  13 , Shannon L Puhalla  5   14 , Carmen J Allegra  3   4 , Norman Wolmark  3   14 , Katherine L Pogue-Geile  3
Affiliations
Clinical Trial

NSABP FC-11: A phase II study of neratinib plus trastuzumab or neratinib plus cetuximab in patients with "quadruple wild-type" (KRAS/NRAS/BRAF/PIK3CA) metastatic colorectal cancer based on HER2 status: amplified, non-amplified (wild-type), or mutated

Tanner J Freeman et al. Cancer Chemother Pharmacol. .

Abstract

Background: Patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC) treated with single-agent cetuximab (C) or panitumumab (P), have improved progression-free survival (PFS) and overall survival (OS) compared to best supportive care but an objective response rate (ORR) of only 13-17%. Preclinical and clinical data suggest that dual targeted therapy (e.g., neratinib [N] + C) may improve overall response rates in tumors that are wt for KRAS, NRAS, BRAF, and PIK3CA (quadruple-wt).

Methods: NSABP FC-11 is a multi-center, two-arm, phase II study in patients with quadruple-wt mCRC who had prior oxaliplatin and irinotecan treatment. Arm 1 treated patients with HER2 mutation, with or without prior C or P. Arm 2 treated HER2 non-amplified (14 evaluable) and HER2-amplified (1 evaluable) patients with N + C. The primary aim was PFS at cycle 6 (PFS6). Secondary aims included ORR, objective response, clinical benefit, and safety. Exploratory aims included molecular profiling for mutations, copy number, and RNA expression.

Results: Arm 1 closed early due to low accrual (n = 4) and is not reported. Arm 2 enrolled 21 patients; six discontinued treatment before first scan. Fifteen patients were evaluable with at least one follow-up scan with six demonstrating PFS6. With intention-to-treat (ITT) analysis, this cohort demonstrated an ORR/PFS6 of 28% (6/21). No grade 5 or otherwise unexpected adverse events were noted. Correlative molecular studies did not definitively define responders.

Conclusion: Arm 2 of FC-11 demonstrated an ORR/PFS6 of 28%, which compares favorably to single-agent treatment in this subset of patients.

Clinical trials registration: NCT03457896.

Keywords: Cetuximab; HER2; Metastatic colorectal cancer; Neratinib; Trastuzumab.

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Conflict of interest statement

Declarations. Competing interests: Tanner Freeman: No COIs. Thomas J. George: Consulting or Advisory Role (all to self): BillionToOne, Nihon Medi-Physics, KAHR Medical, Avammune Therapeutics, Exact Sciences, Summit Therapeutics, Arbele; Research Funding (all to institution): Bristol-Myers Squibb, Merck, AstraZeneca/MedImmune, Lilly, Bayer, Incyte, Ipsen, Genentech, Astellas Pharma, BioMed Valley Discoveries, GlaxoSmithKline, Amgen, OncoC4, BillionToOne, Jounce Therapeutics, Elicio Therapeutics, Seagen, Regeneron, Amal Therapeutics, Deciphera; Open Payments: https://openpaymentsdata.cms.gov/physician/321938. Greg Yothers: No COIs. Samuel A. Jacobs: No COIs. Tatjana Kolevska: No COIs. Huichen Feng: No COIs. Corey Lipchik: No COIs. Sai Maley: No COIs. Nan Song: No COIs. Ashok Srinivasan: Not related to oncology: Equity partner: AIF; BoD: Yamo Pharmaceuticals; Scientific Advisor: BioROSA. Melanie Finnigan: No COIs. James L. Wade, III: No COIs. Gary L Buchschacher, Jr: No COIs. Tareq Al baghdadi: Stock ownership (Bristol Myer Squibb); Advisory (Bristol Myer Squibb, AstraZeneca and Cardinal Health). Asheesh Shipstone: No COIs. Daniel Lin: Received honoraria for consulting for Exelixis, Astra Zeneca, and Agenus. These were unrelated to the study conduct. Shannon L. Puhalla: Consulting: AstraZeneca, Novartis, Abbvie, Pfizer, Celldex, Eisai, Puma Biotechnology; Research funding to institution: Abbvie, Novartis, Lilly, Pfizer, Incyte, Covance/Bayer, Puma Biotechnology, Roche/Genetech, AstraZeneca, Medivation. Carmen J. Allegra: No COIs. Norman Wolmark: Breast Cancer Research Foundation (Institution); The American Surgical Association (Travel).Katherine L. Pogue-Geile: No COIs. This work was supported in part by Puma Biotechnology, Inc; The Pennsylvania Department of Health CURE 2019 grant, SAP#4100085734; and NSABP Foundation, Inc. Ethical approval: The protocol was approved by the appropriate institutional review board; all patients provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki. Authors had full control of all primary data. Consent to participate: All patients provided written informed consent before enrollment in the study.

References

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