Advertisement

Dual HER2 Targeted Therapy With Pyrotinib and Trastuzumab in Refractory HER2 Positive Metastatic Colorectal Cancer: A Result From HER2-FUSCC-G Study

  • Author Footnotes
    † These authors contributed equally to this work.
    Jinjia Chang
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center; Shanghai, 200032, China

    Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally to this work.
    Midie Xu
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
    Search for articles by this author
  • Chenchen Wang
    Affiliations
    Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center; Shanghai, 200032, China

    Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
    Search for articles by this author
  • Dan Huang
    Affiliations
    Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
    Search for articles by this author
  • Zhe Zhang
    Affiliations
    Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center; Shanghai, 200032, China

    Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
    Search for articles by this author
  • Zhiyu Chen
    Affiliations
    Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center; Shanghai, 200032, China

    Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
    Search for articles by this author
  • Xiaodong Zhu
    Correspondence
    Address for correspondence: Xiaodong Zhu, MD, PhD and Wenhua Li, MD, PhD, Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270# DongAn Road, Shanghai, China.
    Affiliations
    Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center; Shanghai, 200032, China

    Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
    Search for articles by this author
  • Wenhua Li
    Correspondence
    Address for correspondence: Xiaodong Zhu, MD, PhD and Wenhua Li, MD, PhD, Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270# DongAn Road, Shanghai, China.
    Affiliations
    Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center; Shanghai, 200032, China

    Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally to this work.

      Abstract

      Background

      Dual-HER2 targeted therapy has led to a promising antitumor effect in HER2 positive cancers including gastrointestinal cancer. The present data focus on patients with HER2 positive colorectal cancer who received pyrotinib and trastuzumab after failure to standard second-line treatment.

      Methods

      Patients diagnosed of HER2 positive refractory or metastatic colorectal cancer were enrolled to receive trastuzumab in combination with pyrotinib as third-line and beyond therapy. Trastuzumab was given as a loading dose at 8 mg/kg followed by 6mg/kg once every 3 weeks, and oral pyrotinib as 400 mg per day until progression. ORR was set as the primary endpoint. PFS and OS were set as a secondary endpoints. This trial is registered with Clinical Trial.gov, NCT04960943, and is ongoing.

      Results

      Between February 2020 to December 2021, 16 patients including 14 with RAS wild-type status were enrolled in this cohort. ORR was 50.0% in the overall population, and 57.1% in RAS wild-type patients. At a median follow-up of 11.2 months, median PFS and OS were 7.53 and 16.8 months, respectively. The RAS/BRAF wild-type patients had prolonged survival (PFS: 7.53 vs. 1.63 months, P = .02; OS: NR vs.4.13 months, P = .001) compared with RAS/BRAF mutant patients. The most common treatment-emergent adverse event (TEAE) reported is diarrhea. Five (31.3%) patients reported grade 3 TEAEs, and no death was reported.

      Conclusions

      Trastuzumab in combination with pyrotinib demonstrated encouraging antitumor activity that translated to prolonged survival benefit in HER2 positive refractory or mCRC patients who are RAS wild-type with acceptable tolerance.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Colorectal Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Chand M
        • Keller DS
        • Mirnezami R
        • et al.
        Novel biomarkers for patient stratification in colorectal cancer: A review of definitions, emerging concepts, and data.
        World J Gastrointest Oncol. 2018; 10: 145-158
        • Richman SD
        • Southward K
        • Chambers P
        • et al.
        HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.
        J Pathol. 2016; 238: 562-570
        • Seo AN
        • Kwak Y
        • Kim DW
        • et al.
        HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression.
        PLoS One. 2014; 9: e98528
        • Ingold Heppner B
        • Behrens HM
        • Balschun K
        • et al.
        HER2/neu testing in primary colorectal carcinoma.
        Br J Cancer. 2014; 111: 1977-1984
        • Bruzzi M
        • Auclin E
        • Lo Dico R
        • et al.
        Influence of molecular status on recurrence site in patients treated for a stage iii colon cancer: a post hoc analysis of the PETACC-8 trial.
        Ann Surg Oncol. 2019; 26: 3561-3567
        • Bertotti A
        • Migliardi G
        • Galimi F
        • et al.
        A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer.
        Cancer Discov. 2011; 1: 508-523
        • Leto SM
        • Sassi F
        • Catalano I
        • et al.
        Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas.
        Clin Cancer Res. 2015; 21: 5519-5531
        • Yonesaka K
        • Zejnullahu K
        • Okamoto I
        • et al.
        Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.
        Sci Transl Med. 2011; 3: 99ra86
        • Mohan S
        • Heitzer E
        • Ulz P
        • et al.
        Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing.
        PLoS Genet. 2014; 10e1004271
        • Sartore-Bianchi A
        • Trusolino L
        • Martino C
        • et al.
        Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2016; 17: 738-746
        • Meric-Bernstam F
        • Hurwitz H
        • Raghav KPS
        • et al.
        Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study.
        Lancet Oncol. 2019; 20: 518-530
        • Siena S
        • Di Bartolomeo M
        • Raghav K
        • et al.
        Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2021; 22: 779-789
        • Ma F
        • Ouyang Q
        • Li W
        • et al.
        Pyrotinib or Lapatinib combined with Capecitabine in HER2-positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a randomized, phase ii study.
        J Clin Oncol. 2019; 37: 2610-2619
        • Xu B
        • Yan M
        • Ma F
        • et al.
        Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.
        Lancet Oncol. 2021; 22: 351-360
        • Wenzhen Zhu
        • Jianchao Wu
        • Min Cui
        • et al.
        Durable clinical benefit from pyrotinib combined with carboplatin in HER2-positive relapsed breast cancer previously treated with taxanes, anthracyclines, and trastuzumab.
        Ann Palliat Med. 2020; Sep;9(5): 3684-3689
        • Zhang X
        • Wu J
        • Wang L
        • et al.
        HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China.
        PeerJ. 2020; 8: e8602
        • Yang Z
        • Yang N
        • Ou Q
        • et al.
        Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients.
        Clin Cancer Res. 2018; 24: 3097-3107
        • Kulukian A
        • Lee P
        • Taylor J
        • et al.
        Preclinical activity of HER2-selective tyrosine kinase inhibitor tucatinib as a single agent or in combination with trastuzumab or docetaxel in solid tumor models.
        Mol Cancer Ther. 2020; 19: 976-987
        • Missiaglia E
        • Jacobs B
        • D'Ario G
        • et al.
        Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.
        Ann Oncol. 2014; 25: 1995-2001
        • Siena S
        • Sartore-Bianchi A
        • Marsoni S
        • et al.
        Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer.
        Ann Oncol. 2018; 29: 1108-1119
        • Wei Q
        • Zhang Y
        • Gao J
        • et al.
        Clinicopathologic Characteristics of HER2-positive metastatic colorectal cancer and detection of HER2 in plasma circulating tumor DNA.
        Clin Colorectal Cancer. 2019; 18: 175-182
        • Strickler J.H.
        • Zemla T.
        • Ou F.-S.
        • et al.
        Dynamic monitoring of HER2 amplification in circulating DNA of patients with metastatic colorectal cancer treated with cetuximab.
        Annals of Oncology. 2019; 30: v200
      1. al. SJZTOF. Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): initial results from the MOUNTAINEER trial. Annal Oncol 2019;30,(200).

        • Li HS
        • Yang LL
        • Zhang MY
        • Cheng K
        • Chen Y
        • Liu JY.
        Remarkable Response of EGFR- and HER2-amplified metastatic colon cancer to pyrotinib after failed multiline treatments: a case report and literature review.
        Front Oncol. 2020; 10548867
        • Kavuri SM
        • Jain N
        • Galimi F
        • et al.
        HER2 activating mutations are targets for colorectal cancer treatment.
        Cancer Discov. 2015; 5: 832-841