Efficacy of disitamab vedotin-containing therapy in metastatic colorectal cancer: A case report

Abstract

BACKGROUND

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. In cases of metastatic CRC (mCRC) that are resistant to conventional chemotherapy-based treatments, the efficacy of available therapeutic options is typically low. CRC exhibiting overexpression or amplification of the human epidermal growth factor receptor 2 (HER2) gene has shown responsiveness to HER2-targeted therapies.

CASE SUMMARY

We present the case of a 69-year-old woman diagnosed with mCRC with an NRAS p.G12V mutation and microsatellite stability, identified through tumor sequencing, along with HER2 overexpression detected by immunohistochemistry. She exhibited an excellent response to disitamab vedotin-containing therapy. To our knowledge, this is the first reported case of mCRC with HER2 overexpression and an NRAS p.G12V mutation achieving a remarkable clinical response to anti-HER2 therapy.

CONCLUSION

Disitamab vedotin demonstrates promising anti-tumor effects in HER2-overexpressing mCRC, offering patients an additional treatment option.

Key Words: Disitamab vedotin; Human epidermal growth factor receptor 2; Overexpression; Metastatic colorectal cancer; Efficacy; Case report

Core Tip: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. In cases of metastatic CRC (mCRC) that is resistant to conventional chemotherapy, human epidermal growth factor receptor 2 (HER2)-targeted therapies have shown promise. We describe a 69-year-old woman with HER2-overexpressing mCRC, featuring an NRAS p.G12V mutation and microsatellite stability, who achieved an excellent response to disitamab vedotin treatment. This case is notable as it is the first recorded observation of a notable clinical response to anti-HER2 therapy in an mCRC patient with HER2 overexpression and an NRAS p.G12V mutation.

INTRODUCTION

Colorectal cancer (CRC) is a malignant tumor originating from the epithelial lining of the colon or rectum. It is the third most frequently diagnosed cancer and the third leading cause of cancer-related fatalities worldwide. Approximately 20% of patients with CRC present with metastatic disease at diagnosis, and up to 40% of those initially diagnosed with localized disease progress to recurrent disease. For patients with metastatic CRC (mCRC) that is resistant to chemotherapy-based regimens, available therapeutic options typically show limited effectiveness. In the realm of second-line treatment, targeted therapies, including epidermal growth factor receptor inhibitors, vascular endothelial growth factor antagonists, and immunotherapies, are selectively administered to patients with the corresponding biomarkers. Third-line treatments, such as regorafenib, fruquintinib, and trifluridine-tipiracil, have objective response rates (ORR) of less than 5%, offering a median overall survival benefit of only 1-2 months compared with placebo[1-3].

The human epidermal growth factor receptor 2 (HER2) serves as a significant oncogenic driver in both breast and gastric cancers and is increasingly recognized as a therapeutic target in mCRC. It is estimated that 3%-5% of patients with mCRC exhibit HER2-positive tumors[3-5]. Notably, this figure doubles to approximately 10% in cases where the tumors are RAS wild-type[4]. The prevalence of HER2 overexpression or amplification is affected by the site of the primary tumor location, showing a higher incidence in rectal cancers compared to colon cancers, and in left-sided tumors compared to right-sided ones[6,7]. HER2 overexpressed or amplified mCRC has exhibited positive responses to therapies specifically targeting HER2[8-10].

Disitamab vedotin is an innovative anti-HER2 antibody-drug conjugate, which comprises the novel anti-HER2 monoclonal antibody trastuzumab, linked to the cytotoxic agent monomethyl auristatin E via a cleavable linker[11]. This drug is specifically approved for the treatment of patients with HER2+ [immunohistochemistry (IHC) 2+/3+] locally advanced or metastatic gastric carcinoma/gastric and gastroesophageal junction carcinoma, as well as urothelial carcinoma, who have received at least two prior systemic chemotherapy regimens[12]. Here, we present a HER2-overexpressing (IHC3+) mCRC case responding significantly to disitamab vedotin-containing therapy.

CASE PRESENTATION

Chief complaints

A 69-year-old female patient was admitted to the hospital 20 days after onset of left lower abdominal pain on March 17, 2023.

History of present illness

The patient reported no history of present illness.

History of past illness

The patient reported no history of past illness.

Personal and family history

The patient reported no history of personal and family history.

Physical examination

Physical examination was not performed.

Laboratory examinations

Laboratory examinations were not performed.

Imaging examinations

The patient underwent colonoscopy and biopsy, which indicated sigmoid colon adenocarcinoma. Assessment and examination were performed after admission. No evidence of distant disease was found in a staging body computed tomography scan, but extensive locoregional infiltration was detected.

FINAL DIAGNOSIS

Based on biopsy and imaging findings, the patient was diagnosed with sigmoid colon adenocarcinoma (cT2-T3N2M0).

TREATMENT

The treatment process is summarized in Figure 1. Given the difficulty of performing curative surgery, the patient underwent four cycles of neoadjuvant chemotherapy using the CapeOX regimen, which included intravenous infusion of oxaliplatin (130 mg/m²) for 3 hours and oral administration of capecitabine (1000 mg/m²) twice daily on days 1-14 in 21-day cycles. Subsequently, she underwent curative surgery, with final pathology revealing stage IIIC (ypT3N2bM0, American Joint Committee on Cancer 8^th edition). Postoperative pathological analysis indicated moderately differentiated adenocarcinoma with proficient mismatch repair and HER2 overexpression (IHC3+). Unfortunately, one month after surgery, an abdominal computed tomography scan in November 2023 revealed multiple liver metastases (Figure 2A).

Figure 1 Treatment timeline. CapeOX regimen includes oxaliplatin and capecitabine. FOLFIRI regimen includes irinotecan, leucovorin, and fluorouracil. PD: Progressive disease; PR: Partial response.

Figure 2 Computed tomography images. A: Evidence of liver metastatic disease after surgery (November 2023); B: Liver metastasis progression after FOLFIRI plus bevacizumab regimen (March 2024); C: Partial remission of liver metastases after disitamab vedotin-containing therapy (June 2024); D: Continuous remission of liver metastases after disitamab vedotin-containing therapy (September 2024).

Tumor samples and peripheral blood plasma of the patient were sent for next generation sequencing and the results revealed NRAS p.G12V mutation, microsatellite stable status, and a tumor mutational burden of 7.9 mut/MB. Subsequently, the patient received FOLFIRI plus bevacizumab regimen on December 2023. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of intravenous infusion of irinotecan 180 mg/m² for one hour followed by intravenous infusion of leucovorin 400 mg/m² for 2 hours, an intravenous bolus of fluorouracil 400 mg/m², and continuous infusion of fluorouracil 2400 mg/m² for 46 hours. After four cycles chemotherapy, imaging studies on March 2024 revealed an enlargement of the liver metastatic lesions, indicating progressive disease (Figure 2B). The patient was then started on two cycles of intravenous infusion of disitamab vedotin 2 mg/kg in 14-day cycles combined with oral fruquintinib (4 mg once daily, days 1-21) and trifluridine-tipiracil (35 mg/m², twice daily on days 1-5 and days 8-12) in 28-day cycles. A repeat computed tomography scan after every two to three months of treatment showed significant improvement in liver disease sites on June 2024 and September 2024 (Figure 2C and D).

Changes in carcinoembryonic antigen (CEA) levels are shown in Figure 2. In December 2023, upon the initial diagnosis of liver metastasis, the patient’s CEA level was 30.9 ng/mL. After four cycles of FOLFIRI plus bevacizumab regimen, the CEA level increased to 224.0 ng/mL by March 2024. However, following six cycles of disitamab vedotin combined with fruquintinib and trifluridine-tipiracil, a significant decline in the CEA (from 224.0 ng/mL to 9.29 ng/mL) was observed on September 2024 (Figure 3). For the liver metastasis foci, a partial response was achieved based on the Modified Response Evaluation Criteria in Solid Tumors.

Figure 3 Changes in serum carcinoembryonic antigen levels (ng/mL) from December 2023 to November 2024. CEA: Carcinoembryonic antigen.

OUTCOME AND FOLLOW-UP

To date, the patient has completed 6 cycles of treatment, with a progression-free survival (PFS) of 7 months, and continues receiving treatment. There were no significant adverse events during treatment.

DISCUSSION

The overall 5-year survival rate for mCRC patients is 15%. In recent years, and despite some advances, the overall efficacy of chemotherapy for mCRC has reached a plateau. In a placebo-controlled phase 3 trial including 800 patients with refractory mCRC, the median PFS for cases treated with trifluridine-tipiracil monotherapy was 2.0 months, and the ORR was 1.6%[2]. Of note, the efficacy of the anti-angiogenic drug fruquintinib is also limited. In a placebo-controlled clinical trial involving 416 patients with refractory mCRC, the ORR and median PFS for patients treated with fruquintinib were 4.7% and 3.71 months, respectively[3].

HER2 amplification occurs in approximately 10% of RAS wild-type mCRC[4,5] and is associated with resistance to epidermal growth factor receptor-based treatment[13,14]. As per HER2-positive metastatic colorectal cancer diagnostic criteria, HER2 overexpression is defined as a 3+ HER2 score in > 50% of CRC cells as determined by IHC or a 3+ HER2 score in 10%-50% of CRC cells by IHC with positive amplification confirmed by fluorescent in situ hybridization in ≥ 50% of CRC cells[15]. The HER2 oncogene, when amplified or overexpressed, triggers excessive ligand-independent stimulation of mitogenic signals, resulting in unchecked cell proliferation and eventual tumor development[16]. Comprehensive studies on dual HER2 inhibition using trastuzumab-based combination therapies have consistently documented ORRs ranging from approximately 10% to 32%[5,8-10,17-19]. The MOUNTAINEER trial, evaluating dual HER2 inhibition with tucatinib plus trastuzumab, represents the most extensive prospective study to date assessing a chemotherapy-free treatment approach targeting HER2 in individuals with chemotherapy refractory, HER2-positive mCRC. Phase 2 results reported an ORR of 38.1% and median duration of response of 12.4 months, with favorable tolerability[20].

As in the above clinical trial, most clinical studies of HER2-positive mCRC to date included patients with RAS wild-type tumors, with only a few investigations addressing populations with dual HER2-positive and RAS-mutant status[9,10]. RAS mutation is considered to be associated with resistance to anti-HER2 therapy[9]. Accordingly, in HER2-amplified mCRC, a lower ORR to anti-HER2 drugs was observed in patients with RAS-mutated (8%) compared to those with RAS wild-type (40%) tumors[10]. Interestingly, the patient reported herein had both HER2 overexpression and NRAS p.G12V mutation, and achieved a significant clinical response after two months of treatment with a combination of disitamab vedotin, fruquintinib, and trifluridine-tipiracil. This may suggest that the combination of chemotherapy and anti-angiogenic therapy could potentially reverse the resistance to anti-HER2 drugs caused by RAS mutation.

CONCLUSION

Disitamab vedotin demonstrates promising anti-tumor effects in HER2-overexpressing mCRC, offering patients additional treatment options.