Immunotherapy has emerged as a transformative approach in cancer treatment, harnessing the body’s own immune system to fight malignant cells. This field has opened new avenues for patients with various cancers, particularly those with historically challenging prognoses. Hepatocellular carcinoma (HCC) represents a significant global health concern, and the development of innovative treatment strategies for this aggressive cancer is a major focus in oncology.
Hepatocellular Carcinoma: A Brief Overview
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, originating from the main liver cells called hepatocytes. The liver, located beneath the rib cage on the right side of the abdomen, performs many functions, including aiding digestion and removing waste products. HCC often develops in individuals with pre-existing chronic liver conditions, with cirrhosis being a common underlying factor.
Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of HCC, accounting for over 70% of cases worldwide. Other contributing factors include excessive alcohol consumption, non-alcoholic fatty liver disease (NAFLD) linked to obesity and diabetes, and certain inherited liver diseases. Diagnosing HCC can be challenging as symptoms may not appear until later stages.
How Durvalumab and Tremelimumab Work
Durvalumab and tremelimumab are distinct yet complementary immunotherapy drugs, specifically categorized as immune checkpoint inhibitors. These drugs aim to counteract cancer cells’ evasive tactics by unleashing the immune system’s natural ability to detect and destroy them.
Durvalumab functions as a programmed death-ligand 1 (PD-L1) inhibitor. PD-L1 is a protein found on the surface of some cancer cells and immune cells within the tumor environment. When PD-L1 binds to its receptor, PD-1, on T-cells (a type of immune cell), it sends an “off” signal that prevents the T-cells from attacking the cancer. By blocking this interaction, durvalumab allows T-cells to become active and recognize and target the tumor.
Tremelimumab, on the other hand, is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor. CTLA-4 is another protein found on the surface of T-cells that acts as a natural “brake” on the immune response, helping to prevent the immune system from becoming overactive. By blocking CTLA-4, tremelimumab enhances T-cell activation and proliferation, further boosting the immune system’s ability to mount an anti-tumor response.
The Combination Strategy for HCC
The rationale behind combining durvalumab and tremelimumab for hepatocellular carcinoma (HCC) is rooted in their complementary mechanisms of action. Combining them aims to create a more robust and sustained anti-tumor immune response by simultaneously releasing these inhibitory signals. This dual blockade can lead to increased T-cell activation and proliferation, potentially overcoming the immunosuppressive environment often found within HCC tumors.
Clinical evidence from studies like the HIMALAYA trial has supported the use of this combination for HCC. The HIMALAYA study, a phase 3 randomized international trial, compared the combination of durvalumab plus tremelimumab (known as the STRIDE regimen) against sorafenib. The STRIDE regimen involves a single, higher priming dose of tremelimumab followed by regular interval doses of durvalumab.
The HIMALAYA trial demonstrated that the durvalumab and tremelimumab combination significantly improved overall survival compared to sorafenib in patients with unresectable HCC. The median overall survival was 16.4 months for the combination arm, compared to 13.8 months for the sorafenib arm. Furthermore, long-term follow-up data from the HIMALAYA study have shown durable responses, with approximately 25% of patients treated with the combination still alive at 4 years, compared to 15% with sorafenib. These outcomes highlight the significance of this combination as a first-line treatment option for advanced, unresectable HCC.
Patient Considerations: Efficacy and Side Effects
Patients considering durvalumab and tremelimumab combination therapy for unresectable hepatocellular carcinoma (HCC) can expect certain outcomes regarding efficacy and potential side effects. At 24 months, the overall survival rate was approximately 40.5% with the combination, compared to 32.6% with sorafenib. These survival benefits extended to 36 months, with an estimated overall survival rate of 30.7% for the combination versus 20.2% for sorafenib.
The combination has shown an objective response rate of about 20.1%. The median time to response was relatively short, around 1.86 months. Importantly, patient-reported outcomes from the HIMALAYA study indicated that the combination was associated with delayed worsening of disease-related symptoms like fatigue, appetite loss, and abdominal pain, as well as improved overall quality of life compared to sorafenib.
Immune checkpoint inhibitors can cause side effects, referred to as immune-related adverse events (irAEs), because they result from the activated immune system affecting healthy tissues. In the HIMALAYA trial, common side effects with the durvalumab and tremelimumab combination included diarrhea (around 26.5%), pruritus (itching, about 22.9%), and rash (approximately 22.4%). Liver injury, characterized by elevated liver enzyme levels, occurred in about 12.4% of patients, with approximately 5% being Grade 3 or higher. Other reported irAEs included hypothyroidism, colitis, and pneumonitis.
Most irAEs tend to occur early in treatment. While serious irAEs can occur, severe events leading to treatment discontinuation were less common, around 5.7%. Patient eligibility for this therapy generally includes those with:
Unresectable HCC who have not received prior systemic therapy.
Barcelona Clinic Liver Cancer (BCLC) stage B (if not eligible for locoregional therapy) or stage C.
Child-Pugh class A liver function.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Close monitoring and appropriate management of side effects are important for patient safety and to ensure continued treatment benefit.