Durable Response to Nivolumab Combined With Metformin in Advanced Pancreatic Cancer: A Case Report With Seven Years of Follow-Up

Abstract

We report a case of poorly differentiated pancreatic cancer that showed an exceptional response to combination therapy with nivolumab and metformin. A 58-year-old man presented with epigastric pain and was diagnosed with locally advanced pancreatic cancer with para-aortic lymph node metastasis. After disease progression following modified FOLFIRINOX therapy (a combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin), the patient was enrolled in a phase Ib clinical trial of nivolumab (3 mg/kg biweekly) combined with metformin (750 mg/day). Post-treatment imaging showed marked tumor shrinkage with normalization of the tumor markers. During treatment, the patient was diagnosed with early-stage lung cancer and underwent successful left S1+S2 segmentectomy with temporary suspension of immunotherapy. The therapeutic response of pancreatic cancer has been sustained for seven years, with minimal residual disease. This unprecedented response duration is particularly noteworthy considering his microsatellite stability, which typically predicts a limited response to immune checkpoint inhibition. This case demonstrates an exceptional response to nivolumab and metformin combination therapy in poorly differentiated pancreatic cancer. The remarkable durability of the response suggests the need for further investigation to identify patients most likely to benefit from this therapeutic approach.

Keywords: immune checkpoint inhibitors; immunotherapy; metformin; nivolumab; pancreatic cancer.

Figure 1. Imaging findings on initial examination

(A) Contrast-enhanced computed tomography (CT) revealed a 60-mm hypovascular pancreatic head tumor (arrow) invading the common hepatic artery, proper hepatic artery, and portal vein. (B) A para-aortic lymph node was enlarged to 10 mm, suggesting metastasis (arrowhead). (C) No lung lesion was observed at first.

Figure 2. Pathological findings

(A) The pancreatic tumor tissue collected by ultrasonography-guided fine-needle aspiration (EUS-FNA) demonstrated poorly differentiated adenocarcinoma with increased chromatin forming solid nests with invasive growth patterns on hematoxylin-eosin staining. (B) Immunohistochemical staining was negative for chromogranin A. (C) Synaptophysin was also negative. (D) The Ki-67 index was > 70%.

Figure 3. Clinical course and treatment response

The initial computed tomography (CT) scan revealed locally advanced pancreatic cancer with paraaortic lymph node metastasis. After disease progression on modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), nivolumab combined with metformin therapy was initiated, achieving marked tumor shrinkage sustained for seven years. The graph shows the changes in tumor markers (carcinoembryonic antigen; CEA) corresponding to the treatment response. CT images demonstrate a dramatic reduction in the size of the primary tumor and metastatic lymph node (arrow).

Figure 4. CT findings at 40 months

(A, B) The diameter of the pancreatic cancer and para-aortic lymph node (arrow) has been continuing to shrink. (C) An 11-mm ground-glass opacity was observed in the upper lobe of the left lung (arrowhead). (D, E) A CT-guided lung tumor biopsy revealed the presence of thyroid transcription factor-1 (TTF-1)-positive adenocarcinoma with alveolar epithelial replacement.