March 13, 2023
Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.
Liver cancers including hepatocellular carcinoma (HCC) and biliary tract or bile duct cancers (BTC) are rare but deadly, with only 20% and 9% of the patients surviving at 5 years respectively. In a welcome and much-needed development, studies show that the immunotherapy drug Durvalumab (tradename Imfinzi) in combination with standard therapies may significantly improve these numbers.
“For too long progress in the treatment of GI and liver cancers has lagged, leaving patients and physicians with too little hope for too long… We presented new data on treatments that give hope to improving quality of life and survival in patients with BTC and HCCs,” highlights Dr. Carlos Doti, Vice President, Head of Oncology US Medical Affairs at AstraZeneca.
The studies offer renewed hope to patients suffering from these cancers, which are expected to become more common over the next few decades.
“Our goal is to help people live longer and have a higher quality of life, especially those [patients] who have few treatment options. Ultimately, we’re not stopping until we eliminate BTC and HCC as a cause of death,” proclaims Dr. Doti.
Understanding Liver Cancer
The liver is one of the largest organs in the body. It has a variety of functions, including making bile, storing glycogen, and filtering out toxins from the blood. The liver is connected to the gallbladder and the intestines through tube-like structures called the bile ducts. These ducts have portions inside the liver, so-called intrahepatic, and portions outside the liver, which are termed extrahepatic. The liver itself or any portion of the bile duct can form cancerous tumors.
Hepatocytes are the main type of cells that forms the liver. Most liver cancers arise from hepatocytes and are termed HCCs. Liver cancer incidence is steadily rising, and it is the third leading cause of cancer deaths worldwide. Less commonly, cancers can start from the cells of the bile duct and are termed BTCs. Although less common than HCCs, these are equally deadly, with an average patient surviving for only 3 to 6 months after their diagnosis.
Therefore, new therapies, especially those that increase the life expectancy of these patients, are critically important. Durvalumab in combination with traditionally used medications has the potential to meet these needs, as shown in two important trials, the HIMALAYA, and the TOPAZ-1 clinical trials.
How Does Durvalumab Work?
Durvalumab is a human monoclonal antibody, which is a small molecule that binds to certain proteins on the surface of cancer cells. These include PD-1, PD-L1, and CD80 proteins that help cancer cells evade destruction by a patient’s native immune system. More specifically, PD-1 and CD80 are proteins expressed on several immune cells. These proteins can interact with PD-L1, a conjugate protein expressed by tumor cells, essentially rendering tumors invisible to and safe from the immune system. Had this interaction been prevented, the errant tumors cell could have been eliminated by the immune system. Durvalumab accomplishes just that, by binding to PD-L1 and preventing it from interacting with PD-1 and CD80 proteins.
Durvalumab has a versatile way of working, making it useful in many cancers such as HCCs, BTCs, and lung cancers.
Which Studies Demonstrate the Benefit of Combining Durvalumab With Other Drugs?
The HIMALAYA study, which recruited patients with HCC, combined durvalumab with tremelimumab. Tremelimumab, like durvalumab, is an immunotherapy drug that uses the patient’s own immune system in the fight against their cancers. It binds to CTLA-4, a protein expressed on some immune cells. This prevents CTLA-4 from interacting with CD80/86 proteins, which are proteins present on antigen-presenting cells, a specific kind of mediator immune cell, which primes the system to attack tumors that express the antigens. The conjugation is thwarted by tremelimumab, which enhances the immune system’s ability to eliminate cancer cells.
The TOPAZ 1 study included patients with BTCs and combined durvalumab with the chemotherapy drugs, gemcitabine and cisplatin. Chemotherapy works by disrupting tumor cell division. To grow and multiply, tumor cells divide and propagate very rapidly. Each time they divide, they copy their DNA and give one copy to each “daughter” cell. Chemotherapy disrupts this process of DNA replication, which then kills the dividing tumor cells. However, normal body cells also divide, and chemotherapy is not specific to just the cancer cells. Thus, it can affect healthy body tissues, which is what usually causes the side effects attributed to this treatment form.
Both the HIMALAYA and TOPAZ-1 trials were phase III clinical trials. A phase III clinical trial is the most rigorous test for any treatment or drug. A successful phase III trial offers physicians the highest level of evidence for the efficacy of a treatment for any disease.
The HIMALAYA trial had 1,324 patients with unresectable (non-operable) HCC who had not received any prior systemic therapy and could also not receive targeted therapies, such as radiation, to their cancerous lesions. These patients were spread out over 16 countries, including the U.S. The patients were randomly assigned to either receive Durvalumab and Tremelimumab (tradename Imjudo), termed the STRIDE regimen, or sorafenib, which is the standard treatment for such patients. The investigators were interested in the overall survival (OS) of patients assigned to each treatment category. OS is the length of time patients are alive after their initial diagnosis of cancer. With the STRIDE regimen, the overall survival at 36 months was 30.7%, while it was only 20.2% with sorafenib.
Some patients can develop antibodies to Durvalumab and Tremelimumab. These antibodies can potentially neuter these medications and reduce their overall benefit. Yet in the study, “the [treatment combination] continued to work and stayed effective, even in those patients who developed antibodies on treatment,” noted Dr. Doti.
The TOPAZ 1 study accrued 685 patients worldwide. These patients had unresectable, locally advanced, recurrent, or metastatic BTCs and had not received any prior treatment. These patients were randomly assigned to receive either chemotherapy alone or in combination with durvalumab. The main endpoint was overall survival. Patients who received chemotherapy alone survived an average of 11.5 months, while those who received the Durvalumab and chemotherapy combination lived an average of 12.8 months, a significant improvement.
TOPAZ-1 also investigated progression-free survival (PFS), which represents the time a patient is alive without a worsening of their disease. For the patients receiving the combination treatment, PFS was 7.2 months. Those who received chemotherapy alone achieved a PFS of only 5.7 months.
BTC cancer patients often develop infections due to their tumors obstructing their biliary tracts. This requires frequent antibiotic treatment. “Antibiotic use during the trial did not reduce the benefits of how [the treatment] works to stop the growth and spread of cancer,” emphasizes Dr. Doti. These patients also did well from their overall health perspective. Dr. Doti continues, “[these patients] needed less follow-up care… thereby reducing treatment burden.
How Safe are These Treatment Combinations?
For the TOPAZ1 study, 62.7% of the patients receiving the Durvalumab combination treatment while 64.9% of the patients receiving chemotherapy alone experienced side effects. This implies that most of the side effects come from chemotherapy. However, Durvalumab is not without its side effects. The most common side effects include fatigue, nausea, constipation, loss of appetite, abdominal pain, and fever.
For the HIMALAYA study, the side effects associated with the two treatments were comparable. Significant side effects were experienced by 50.5% of patients on the STRIDE regimen while 52.4% of the patients receiving sorafenib experienced similar side effects. Most common side effects with the STRIDE regimen include diarrhea, itchiness, muscle and bone pain, stomach pain, and tiredness.
Common side effects attributed to the use of durvalumab include fatigue, decreased appetite, stomach pain, constipation, diarrhea, or signs of a common cold. Serious side effects, although rare, can occur and include immune-mediated reactions, such as an inflammation of the lungs, gastrointestinal tract, liver, kidneys, or skin. Inflammation of other organs, such as the cardiovascular system, can occur but are far less common.
Are These Treatments Currently Available?
Based on the positive results of the two trials, the Food and Drug Administration has approved the STRIDE regimen as well as the Durvalumab and chemotherapy combination for patients with unresectable HCC and advanced BTCs. Therefore, as long as patients are an appropriate candidate for either regimen, they should be able to get it anywhere in the U.S.