Pembrolizumab Plus Lenvatinib in EBV-Associated Advanced Intrahepatic Cholangiocarcinoma: Case Study

Abstract

Advanced intrahepatic cholangiocarcinoma is a treatment challenge with a poor prognosis and limited therapeutic options. The potential utility of an immune checkpoint inhibitor plus an anti-angiogenic drug-pembrolizumab plus lenvatinib-is still unknown. We present the case of a female patient aged 60 years with Epstein-Barr virus-associated advanced intrahepatic cholangiocarcinoma who had progressed after first-line treatment. She then received a combination of pembrolizumab and lenvatinib; these treatments led to an impressively long survival for 20 months and partial response to imaging studies. This case reports the first such combination therapy in patients with advanced iCCA and EBV, and the medical line of treatment for the same has dwindling options. Perhaps, more research on the function of EBV in iCCA could be needed as a potential biomarker of responsive candidates for immunotherapy.

Introduction

Intrahepatic cholangiocarcinoma is an extremely rare and aggressive bile duct carcinoma originating from bile duct epithelial cells inside the liver. Advanced iCCA has a poor prognosis with very few treatment options, which makes the management of advanced iCCA one of the important clinical challenges at present. The incidence of this disease is growing and so is the call for new innovative therapeutic approaches. Though gemcitabine and cisplatin remain the first-line drugs used, their efficacy is very low with advanced disease. Therefore, there is a dire need to look at new combinations of therapy.

Recent research has shown that immunotherapy might have a definite role in the treatment of cancer, especially in combination with drugs inhibiting angiogenesis, such as lapatinib. A PD-1 inhibitor, pembrolizumab, appears promising in several malignancies, although further research will be required to assess its efficacy for iCCA. In addition, the issue of EBV and its use as a marker of iCCA, as well as its role in influencing the response to immunotherapy, should be further addressed. This is the first documented case of pembrolizumab combined with lenvatinib used in a patient with EBV-associated advanced iCCA, shedding light on a potentially effective treatment.

Case Presentation

Patient Profile

A 60-year-old female was referred to our oncology department upon a diagnosis of advanced iCCA. She had a history of hypertension and no other significant comorbidities. She came with nonspecific complaints such as fatigue and weight loss which, according to imaging studies, was an intrahepatic mass.

Diagnosis

Diagnosis and further investigations Following biopsy confirmation, she was diagnosed with iCCA, which further investigations revealed to be EBV-positive in the tumor tissue, and hence, her condition came into the category of EBV-associated advanced iCCA (EBVaiCCA). Due to advanced disease characterized by both local invasion and metastasis to the liver, she began her first line of therapy with a combination of gemcitabine and cisplatin. However, after four cycles, the patient's disease began to advance, as witnessed in imaging studies that showed increased tumor burden.

Treatment Approach

Considering the progression of the disease after first-line therapy, a multidisciplinary team discussed available second-line options. According to developing evidence that demonstrates the combination of pembrolizumab and lenvatinib in other malignancies, we believe that this is an appropriate treatment option for the patient.

She was thus commenced on pembrolizumab 200 mg every three weeks, and lenvatinib 12 mg daily. The patient tolerated treatment with monitoring for the adverse effects that occurred, including hypertension, diarrhea, and abnormalities in liver functions, among other things. Importantly, she tolerated side effects well which were quickly addressed by modification of supportive care.

Response to Therapy

About eight weeks after the initiation of combination therapy, follow-up imaging studies showed a partial response with marked reductions in the size of her tumors and symptomatic improvement including relief from fatigue and improvement in appetite. She did report an obvious improvement in quality of life, as measured by standardized questionnaires, with objective improvements in physical functioning and general well-being.

Her disease stabilized for a short period, and then the progression resumed, so a decision needed to be made to transfer her over into more palliative care, where controlling the symptoms and keeping the patient's quality of life as stable as possible would be the focus.

Discussion

This case represents a groundbreaking exploration of pembrolizumab combined with lenvatinib for a patient with EBV-associated advanced iCCA. The promising response observed in this patient highlights the potential of combining immunotherapy with anti-angiogenic therapy in managing a notoriously difficult-to-treat malignancy.

The Role of EBV in iCCA

EBV is a well-established oncogenic virus associated with various malignancies, including lymphoproliferative disorders and nasopharyngeal carcinoma. The presence of EBV in tumor cells can enhance the tumor's immunogenicity, potentially rendering them more susceptible to immune checkpoint inhibitors like pembrolizumab. In this case, the patient’s EBV-positive status may have contributed to the favorable response to the combination therapy, suggesting a role for EBV as a biomarker for predicting treatment outcomes in iCCA.

Immunotherapy and Anti-Angiogenic Therapy

The combination of pembrolizumab and lenvatinib leverages two distinct mechanisms: pembrolizumab enhances the immune response against tumor cells, while lenvatinib targets the tumor vasculature, inhibiting angiogenesis and improving oxygenation within the tumor microenvironment. This synergistic effect may improve treatment outcomes and warrant further investigation in larger cohorts.

Future Implications

While this case offers hope for patients with advanced EBVaiCCA, it also underscores the necessity for ongoing clinical trials to validate these findings. Establishing the efficacy of pembrolizumab and lenvatinib in a broader patient population will be crucial in developing standardized treatment protocols. Additionally, further research is needed to elucidate the predictive value of EBV as a biomarker for immunotherapy response in iCCA.

Conclusion

Even if this represents the first reported case of the association of EBV with advanced iCCA, it still shows the significant potential that pembrolizumab and lenvatinib offer when given in combination as an extremely promising therapeutic approach for patients harboring EBV-associated advanced iCCA. An overall survival of 20 months in such a patient further supports further research on the treatment combination as well as the role of EBV as a biomarker for predicting responses in immunotherapy. The patient here acts as an icon of hope, as continued efforts are focused on optimizing effective systemic therapies in this advanced form of iCCA.

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