Durvalumab, marketed as Imfinzi, and tremelimumab, known as Imjudo, are two separate immunotherapy drugs now used together to treat advanced liver cancer. This combination represents a significant step forward for adult patients diagnosed with unresectable hepatocellular carcinoma (HCC). HCC is the most common form of liver cancer, and for many patients with advanced disease, therapeutic options have historically been limited. The introduction of this dual regimen provides a new systemic approach to harnessing the body’s own defenses against this aggressive cancer.
Context of Liver Cancer Treatment
Hepatocellular carcinoma often arises in a liver already damaged by chronic disease, such as hepatitis or cirrhosis. Many patients are not candidates for curative treatments like surgical removal or liver transplant by the time of diagnosis. For decades, the therapeutic landscape for advanced HCC was dominated by systemic treatments that mainly slowed cancer progression. These older therapies often provided limited long-term survival advantages and sometimes came with challenging side effects.
Immunotherapy aims to re-engage the patient’s own immune system, specifically T-cells, to recognize and destroy cancer cells. The shift toward this treatment type has been particularly impactful in advanced cancers where traditional methods have reached their limit. This dual therapy combines two different strategies to overcome the cancer’s ability to hide from the immune system, creating a more robust anti-tumor immune attack than either agent could achieve alone.
How Dual Immunotherapy Works
This combined approach relies on targeting two separate regulatory pathways, known as immune checkpoints, that cancer cells exploit to evade destruction. The first pathway involves cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which acts like a brake on the initial activation of T-cells in the lymph nodes. Tremelimumab is an anti-CTLA-4 antibody that blocks this inhibitory signal, effectively releasing the initial brake and “priming” the immune system to recognize the tumor. This promotes the proliferation and activation of T-cells, preparing them for the fight.
The second pathway involves the programmed death-ligand 1 (PD-L1) protein, which cancer cells display on their surface to send an “all-clear” signal to the T-cells that have already reached the tumor site. Durvalumab is an anti-PD-L1 antibody that blocks this signal, preventing the cancer cell from turning off the T-cell. This two-pronged strategy, where tremelimumab primes the immune response and durvalumab sustains the attack, is designed to generate a more powerful and durable anti-tumor effect.
The Treatment Schedule and Delivery
The specific dosing regimen for this combination is often referred to as the STRIDE regimen, which stands for Single Tremelimumab Regular Interval Durvalumab. Both medications are administered intravenously (IV) in a clinical setting. The combination uses a single, high dose of tremelimumab to kickstart the immune system. This initial “priming” dose is given only once, along with the first dose of durvalumab.
Following this, the treatment shifts to a maintenance phase using only durvalumab. Durvalumab is then given every four weeks, continuing the blockade of the PD-L1 pathway to sustain the anti-tumor activity. Patients typically receive tremelimumab first, infused over about an hour, followed by the infusion of durvalumab on the same day.
Measuring Effectiveness in Clinical Trials
The approval of this dual immunotherapy combination was based on the results of the Phase 3 HIMALAYA trial, a large, randomized study comparing the regimen against the older standard treatment, sorafenib. The primary measure of success in the trial was Overall Survival (OS). The combination demonstrated a statistically and clinically significant improvement in OS compared to sorafenib.
Patients who received the durvalumab and tremelimumab combination had a median OS of 16.4 months, compared to 13.8 months for those who received sorafenib. This translated to a 22% reduction in the risk of death for patients on the dual immunotherapy. An estimated 30.7% of patients treated with the combination were still alive at three years, compared to 20.2% of patients treated with sorafenib.
The Objective Response Rate (ORR) was also significantly higher with the immunotherapy combination. The ORR for the dual regimen was 20.1%, a substantial increase compared to the 5.1% observed in the sorafenib group. This clinical evidence led to the U.S. Food and Drug Administration (FDA) approval of this regimen for adult patients with unresectable HCC.
Recognizing and Managing Treatment Side Effects
The side effects of the durvalumab and tremelimumab combination are related to the immune system becoming overactive, leading to inflammation in various organs. These are referred to as immune-related adverse events (irAEs). Common irAEs reported in clinical trials include:
- Inflammation of the colon (colitis)
- Inflammation of the lungs (pneumonitis)
- Inflammation of the liver (hepatitis)
- Inflammation of endocrine glands, such as the thyroid or pituitary
Patients may experience symptoms such as rash, diarrhea, fatigue, and muscle pain. The overall rate of severe side effects (Grade 3 or 4) for the combination was comparable to that of sorafenib in the HIMALAYA trial. Importantly, the combination did not increase the risk of severe liver toxicity or bleeding. Management often involves temporarily pausing the immunotherapy and administering corticosteroids to reduce the inflammation. Close monitoring and prompt communication with the healthcare team are essential for safely navigating this treatment.