A Case of Locally Advanced Gastric Cancer Treated with Nivolumab, Trastuzumab, Plus Chemotherapy in a Neoadjuvant Setting
Gastric cancer remains one of the most challenging malignancies worldwide, particularly in its advanced stages. The integration of neoadjuvant chemotherapy has shown promise in downstaging tumors and improving patient survival. This case report highlights the successful treatment of a locally advanced gastric cancer patient using a combination of nivolumab, trastuzumab, and chemotherapy in a neoadjuvant setting.
Case Presentation
A 70-year-old Chinese man presented to the Department of Medical Oncology in June 2017 with complaints of abdominal distension and weakness. Initial laboratory tests revealed moderate anemia, with a hemoglobin level of 61 g/L. A gastroscopy and subsequent biopsy confirmed the diagnosis of a moderately to poorly differentiated adenocarcinoma. Immunohistochemistry (IHC) indicated human epidermal growth factor receptor 2 (HER2) 2+ positivity, which was further confirmed by fluorescence in situ hybridization (FISH) to show HER2 gene amplification.
Computed tomography (CT) imaging revealed a mass-like lesion measuring 67 mm by 53 mm located on the lesser curvature of the stomach. The mass was fused with regional lymph nodes and the pancreas. Additionally, several swollen lymph nodes were observed, including a para-aortic lymph node measuring 24 mm in diameter. Based on these findings, the clinical stage was determined to be T4bN3bM0, classifying the tumor as unresectable.
Treatment Strategy
Given the advanced stage of the disease and the HER2 overexpression, a multidisciplinary team decided to initiate a neoadjuvant regimen combining chemotherapy, trastuzumab, and nivolumab. The treatment plan included the following: trastuzumab administered as an 8 mg/kg intravenous (IV) bolus followed by 6 mg/kg IV every three weeks; oxaliplatin 150 mg IV on day 1; S-1 60 mg twice daily orally from day 1 to day 14; and nivolumab 200 mg IV on day 8, repeated every three weeks.
Treatment Response and Adjustments
After two cycles of treatment, the patient exhibited a partial remission according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). However, the patient developed grade 2 thrombocytopenia, prompting an adjustment in the treatment regimen for cycles 3 and 4. Nivolumab and trastuzumab were maintained, while the chemotherapy schedule was modified to every two weeks, with oxaliplatin 150 mg IV on day 1 and S-1 40 mg twice daily orally from day 1 to day 10.
After completing four cycles of treatment, the patient underwent a total gastrectomy (D2) with Roux-en-Y esophagojejunostomy and para-aortic lymph node resection in October 2017. Pathological examination of the resected specimen revealed no cancer cells in the dissected lymph nodes. The residual cancer in the stomach was diagnosed as a moderately differentiated adenocarcinoma, with IHC confirming HER2 2+ positivity. The pathological stage was ypT3N0, indicating a significant downstaging of the tumor.
Post-Operative Treatment and Follow-Up
Following surgery, the patient received four additional cycles of the same neoadjuvant regimen. During the 16-month follow-up period, the patient remained disease-free, demonstrating the efficacy of the combined treatment approach.
Molecular and Immunological Profiling
To further understand the underlying biology of the tumor, molecular and immunological profiling was conducted. Tumor mutational burden (TMB) was measured at 11.1 mutations per megabase (Mb), classifying it as TMB-medium. Microsatellite instability (MSI) testing revealed a microsatellite stable phenotype. Additionally, immunohistochemical analysis showed proficient expression of mismatch repair (MMR) proteins and the absence of programmed death-ligand 1 (PD-L1) expression.
Discussion
Cisplatin plus S-1 is widely regarded as the standard first-line treatment for advanced gastric cancer (AGC) in China. However, in this case, the patient’s moderate anemia, physical status, and HER2 overexpression necessitated a tailored approach. The decision to use a reduced dose of oxaliplatin and S-1, combined with trastuzumab, was based on these considerations. The addition of nivolumab, a programmed death-1 (PD-1) inhibitor, was informed by the promising results of the ATTRACTION-2 study, which demonstrated the anti-tumor activity of nivolumab in Asian patients with advanced or recurrent gastric/gastroesophageal junction cancer.
The successful downstaging of the tumor and the subsequent R0 resection highlight the potential of combining immune checkpoint inhibitors with targeted therapy and chemotherapy in the neoadjuvant setting for locally advanced gastric cancer. This case underscores the importance of a personalized treatment approach, taking into account the patient’s unique clinical and molecular characteristics.
Conclusion
This case report illustrates the feasibility and efficacy of a neoadjuvant regimen combining nivolumab, trastuzumab, and chemotherapy in the treatment of locally advanced gastric cancer. The significant tumor downstaging and successful surgical resection achieved in this patient provide a strong rationale for further investigation into this combination therapy in the peri-operative setting. Future studies are warranted to explore the broader applicability of this approach and to identify predictive biomarkers that can guide patient selection.
doi.org/10.1097/CM9.0000000000000241
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