Approximately 3% of patients with metastatic colorectal cancer (mCRC) harbor human epidermal growth factor receptor 2 (HER-2) amplification. Due to the lack of established anti-ERBB2 treatment options, patients with HER-2-amplified mCRC rarely receive targeted therapy. Furthermore, traditional chemotherapy regimens are suboptimal for these patients, limiting advanced-stage treatment options to best supportive care or participation in clinical trials. This report describes a patient with HER-2-amplified, refractory mCRC who received salvage therapy with vedicizumab combined with pyrotinib. This regimen resulted in a partial response and ongoing progression-free survival of 6 months. This case study suggests that an anti-HER-2 regimen containing vedicizumab and pyrotinib may offer a potential salvage treatment option for patients with HER-2-amplified mCRC, but further validation is needed in larger cohort studies. Background: Colorectal cancer (CRC) is the second most lethal malignancy, accounting for 9.4% of all cancer-related deaths, with 20% of new cases presenting with metastatic disease at diagnosis. Currently, surgery offers only a limited number of long-term benefits for patients with metastatic colorectal cancer (mCRC) with liver or lung metastases. However, treatment remains challenging for most patients, with a 5-year survival rate of only 14%. Consequently, current research and treatment strategies are increasingly focused on the identification and application of molecular subtypes. The inherent heterogeneity of tumor molecular subtypes (including differences in KRAS, NRAS, and BRAF gene expression) highlights the need for differentiated treatment strategies for patients refractory to systemic chemotherapy. Evidence from existing clinical trials and case reports suggests that personalized treatment based on the unique molecular profiles of patients with mCRC can significantly improve survival outcomes. Therefore, tumor molecular profiling, the discovery of novel tumor markers, and the development of new anticancer drugs are crucial to achieving optimal survival benefits. Human epidermal growth factor receptor 2 (ERBB2, formerly known as HER-2), a member of the epidermal growth factor receptor family, plays a key role in regulating cell proliferation and differentiation. ERBB2 amplification is associated with the development of various malignancies, including breast, lung, and gastric cancers, and mutations in this gene are found in approximately 3% of mCRC cases. This mutation can lead to overactivation of signaling pathways such as MAPK/ERK and PI3K/Akt, thereby promoting tumor cell migration, proliferation, and adhesion. The US Food and Drug Administration (FDA) recently approved ERBB2-targeted drugs for the treatment of ERBB2-amplified breast and gastric cancers. However, there are no approved targeted therapies for ERBB2-amplified metastatic colorectal cancer (CRC), particularly refractory mCRC, and research is ongoing. In limited cohorts of the Phase II HERACLES-A and Mypathway trials, objective response rates (complete or partial response) of 20%-30% were observed in patients with ERBB2-amplified mCRC treated with trastuzumab combined with pertuzumab or lapatinib. Both drugs are established ERBB2-targeted agents in clinical practice, and these results demonstrate the potential value of anti-ERBB2 therapy for ERBB2-amplified mCRC. Disitamab vedotin is my country’s first independently developed ERBB2-targeted antibody-drug conjugate, approved by the US FDA and the China National Medical Products Administration. In June 2021, the drug was approved in China for the treatment of patients with locally advanced or metastatic gastric cancer with ERBB2 overexpression (IHC2+ or 3+), and was subsequently recommended for the treatment of other solid tumors expressing ERBB2 (including urothelial carcinoma, biliary tract cancer, non-small cell lung cancer and breast cancer). Its core mechanism is to deliver the anticancer agent monomethyl auristatin E (MMAE) to cells expressing HER2 receptors, enter the cells by endocytosis after anchoring to the cell membrane, and then release MMAE by active lysosomal enzymes. The released MMAE can destroy the intracellular microtubule structure and lead to tumor cell death. Pyrotinib is an irreversible dual pan-ErbB receptor tyrosine kinase inhibitor that effectively blocks the Ras/Raf/MEK/MAPK and PI3K/Akt signaling cascades by inhibiting the autophosphorylation of HER homo/heterodimers (Figure 1), mainly targeting EGFR and ERBB2 receptors.Resmetirom In Vitro This report presents a case of ER progression despite treatment with trastuzumab and lapatinib.Resmetirom References case of BB2-amplified mCRC. After in-depth discussion by a team of oncologists, an innovative anti-ERBB2 regimen of vedicizumab combined with pyrotinib was used to achieve partial remission. This treatment strategy effectively curbs disease progression and provides a new treatment option for ERBB2-amplified mCRC. ▲Figure 1 The main mechanism of vedicizumab and pyrotinib in ERBB2-amplified mCRC Case The patient was a 32-year-old female who was admitted to the hospital on September 29, 2023, due to hemoptysis and fatigue that lasted for more than two months. The patient denied a history of smoking and drinking and a family history of related diseases. On April 25, 2022, she underwent left hemicolectomy at the Second Affiliated Hospital of Zhejiang University School of Medicine. Postoperative pathology showed moderate to poorly differentiated adenocarcinoma in the left colon, infiltrating into the serosa, and metastasis was seen in 6 of 20 lymph nodes. Immunohistochemistry revealed positive pMMR, CDX-2, Her-2, 3+, synaptophysin, focally weakly positive, CD56, and Ki-67 (80%). Next-generation sequencing (NGS) revealed ERBB2 amplification (copy number 16.6), wild-type RAS/RAF/PI3KCA, and microsatellite stability (MSS). According to the 8th edition of the American Joint Committee on Cancer (AJCC) staging criteria, the patient was diagnosed with ERBB2-amplified metastatic colorectal cancer (mCRC), stage pT3N2M0. Postoperatively, the patient received eight cycles of adjuvant chemotherapy with the XELOX regimen (oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 orally twice daily on days 1-14, repeated every 3 weeks). A chest CT scan (September 29, 2023) performed for hemoptysis revealed multiple masses and nodules in both lungs, as well as enlarged lymph nodes in the mediastinum, bilateral hilum, neck, and left axilla (Figures 2A-D). Multiple metastases were also found in the right lobe of the liver, bilateral adrenal glands, lower abdomen, lungs, and brain. The patient’s performance status (PS) was 3. Based on the clinical presentation, medical history, and imaging studies, the patient was diagnosed with recurrent metastatic colorectal cancer (TNM stage IV). Supportive care was administered, including hemostatic and anti-infective measures, expectorant and acid suppression, analgesic therapy, and nutritional support. Based on the efficacy of the anti-ERBB2 regimen in the HERACLES-A study, salvage therapy with trastuzumab (8 mg/kg initially, then 6 mg/kg every 3 weeks) combined with lapatinib (1000 mg orally daily) was initiated on October 6, 2023. Figure 2. Chest CT scan during treatment shows changes in the primary lung lesion (red arrow). Three weeks later (November 1, 2023), the patient was readmitted to the hospital with chest tightness, extreme fatigue, and dyspnea (oxygen saturation 70%). A repeat chest CT scan showed progression of multiple lung metastases compared to the previous examination, with new bilateral pleural effusions (Figures 2E-H). Metastases at other sites remained stable. The PS score worsened to 4, and CEA and CA19-9 levels increased significantly (Figures 3A,B), indicating disease progression. Palliative care was initiated, including anti-infectives, pleural effusion management, oxygen therapy, and analgesia. Despite the failure of multiple lines of treatment, the patient and family strongly requested active treatment. After multidisciplinary discussion, an anti-ERBB2 salvage therapy regimen consisting of vedicizumab (2.5 mg/kg intravenously every 2 weeks) combined with pyrotinib (320 mg orally daily) was initiated on November 3, 2023. This regimen enhances anti-tumor efficacy by simultaneously targeting both the extracellular and intracellular domains of ERBB2. ▲Figure 3 Changes in tumor marker CEA during treatment CT evaluation on November 28, 2023 showed that after 2 cycles of targeted therapy, partial remission was achieved according to the Solid Tumor Response Evaluation Criteria v1.1 (Figure 2I-L). During the combined treatment, CEA and CA19-9 levels decreased significantly (Figure 3A, B), hemoptysis and fatigue symptoms continued to improve, and the PS score returned to 2. After completing 5 cycles of treatment, no serious adverse reactions such as blood toxicity, liver damage, lung damage or diarrhea occurred, only mild nausea and fatigue were seen.PMID:35108383 The patient’s condition is currently stable and he is still receiving follow-up treatment in the hospital. The treatment regimen and clinical characteristics are summarized in Figure 4. ▲Figure 4 Summary of patient treatment and discussion of clinical characteristics This article reports a case of a patient with ERBB2-amplified refractory metastatic colorectal cancer (mCRC) who achieved partial remission after receiving the salvage treatment regimen of vedicizumab combined with pyrotinib, and explains how this regimen was sustained.Continue to control disease progression. To the researchers’ knowledge, this is the first case in the world where vedicizumab combined with pyrotinib was used to treat ERBB2-amplified refractory mCRC and showed significant efficacy. The prognostic value of ERBB2 amplification in mCRC remains controversial. However, recent clinical trials have shown that some patients can achieve partial remission and survival benefits through anti-ERBB2 drugs (including various combinations of monoclonal antibodies, antibody-drug conjugates [ADCs], and tyrosine kinase inhibitors [TKIs]). The HERACLES-A study is a prospective, open-label, phase II trial that focuses on exploring ERBB2-targeted treatment strategies. The study used a salvage regimen of trastuzumab combined with lapatinib to treat 27 patients with KRAS wild-type HER2-positive mCRC. The results showed an objective response rate (ORR) of 28%, a median progression-free survival (PFS) of 4.7 months, and no grade 4 or 5 adverse events. The MOUNTAINEER trial, a global, open-label, phase II study, enrolled patients with HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer to evaluate the dual HER2-targeting combination of tucatinib and trastuzumab. This combination achieved an ORR of 38.1%. While adverse effects such as diarrhea, hypertension, and liver and kidney injury were reported, these were considered acceptable and manageable for patients with advanced cancer. Despite limited sample sizes, both studies provide important evidence for ERBB2-targeted therapy. Based on the results of the HERACLES-A study and the patient’s medical history, this case was initially treated with salvage therapy with trastuzumab and lapatinib. However, the patient developed significant pleural effusions, suggesting inadequate disease control. In this setting, selecting an effective subsequent line of treatment was challenging. Given the patient’s ERBB2 amplification, the mechanisms of action of vedicizumab and pyrotinib, and the patient’s strong preference for prolonged survival rather than supportive care, a salvage regimen of vedicizumab and pyrotinib was ultimately attempted, which unexpectedly demonstrated promising results. Although no prospective studies have yet validated the efficacy of vedicizumab combined with pyrotinib in patients with ERBB2-amplified metastatic CRC, studies have explored the efficacy of these two agents in treating HER2-positive tumors. Two recent single-arm studies (RC48-C005 and RC48-C009) reported results from vedicizumab in patients with HER2-positive metastatic urothelial carcinoma who had failed systemic chemotherapy. The median progression-free survival (PFS) and overall survival (OS) were 5.9 months (95% CI 4.3-7.2) and 14.2 months (95% CI 9.7-18.8), respectively. Furthermore, a patient with HER2 2+ advanced gastric cancer and systemic metastases who had failed first-line therapy achieved a 6-month progression-free survival (PFS) with vedicizumab. A recent prospective observational study demonstrated that pyrotinib, alone or in combination with trastuzumab, had a promising antitumor effect in patients with HER2-positive RAS wild-type metastatic CRC. In the pyrotinib plus trastuzumab subgroup, the median PFS was 8.6 months, and the ORR was 50.0%. In the pyrotinib monotherapy group, the median PFS and ORR were 5.5 months and 25.0%, respectively. Common adverse reactions in both drug-related trials and case series included diarrhea, peripheral sensory neuropathy, elevated aspartate aminotransferase (AST), leukopenia, hand-foot syndrome, and fatigue. However, the patient in this case experienced only mild nausea and fatigue, which may be related to the widespread metastatic disease characteristics of advanced colorectal cancer. The primary limitation of this case report is its single nature. While we speculate that the observed disease control may be attributable to the combination of vedicizumab and pyrotinib, further validation of this regimen in patients with ERBB2-amplified metastatic colorectal cancer is warranted through basic and clinical trials. In summary, this report reports a case of a female patient with refractory metastatic colorectal cancer harboring ERBB2 amplification. This patient achieved a partial response with salvage therapy with vedicizumab plus pyrotinib, achieving sustained disease control and significant improvement in tumor marker levels. Given the high objective response rate of ERBB2 targeted therapy in salvage treatment of colorectal cancer, it is recommended that future studies further explore and optimize ERBB2 targeted therapy.Wang J and Zheng Q (2025) Disitamab vedotin combined with pyrotinib as salvage treatment in Her-2-amplified treatment refractory metastatic colorectal cancer: a case report.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. 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