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 accessOne-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 CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Novel biomarkers for patient stratification in colorectal cancer: A review of definitions, emerging concepts, and data.World J Gastrointest Oncol. 2018; 10: 145-158
- 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
- HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression.PLoS One. 2014; 9: e98528
- HER2/neu testing in primary colorectal carcinoma.Br J Cancer. 2014; 111: 1977-1984
- 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
- 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
- Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas.Clin Cancer Res. 2015; 21: 5519-5531
- Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.Sci Transl Med. 2011; 3: 99ra86
- Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing.PLoS Genet. 2014; 10e1004271
- 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
- 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
- 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
- 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
- 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
- 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
- HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China.PeerJ. 2020; 8: e8602
- 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
- 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
- Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.Ann Oncol. 2014; 25: 1995-2001
- Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer.Ann Oncol. 2018; 29: 1108-1119
- Clinicopathologic Characteristics of HER2-positive metastatic colorectal cancer and detection of HER2 in plasma circulating tumor DNA.Clin Colorectal Cancer. 2019; 18: 175-182
- Dynamic monitoring of HER2 amplification in circulating DNA of patients with metastatic colorectal cancer treated with cetuximab.Annals of Oncology. 2019; 30: v200
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).
- 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
- HER2 activating mutations are targets for colorectal cancer treatment.Cancer Discov. 2015; 5: 832-841
Article Info
Publication History
Published online: July 15, 2022
Accepted:
July 11,
2022
Received in revised form:
June 29,
2022
Received:
May 16,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier Inc.
