Combination therapies represent a significant advancement in oncology, moving beyond single-agent treatments to multi-pronged attacks on cancer. This approach involves pairing drugs that work in different ways to enhance their overall effectiveness. One such strategy is the combination of a targeted therapy, cabozantinib, with immunotherapy. This pairing fights cancer by simultaneously disrupting its internal growth signals and dismantling its ability to hide from the body’s immune system.
The Role of Cabozantinib in Cancer Treatment
Cabozantinib is a type of targeted drug known as a tyrosine kinase inhibitor (TKI). Tyrosine kinases are proteins that act as on/off switches for many cellular functions, including cell growth. In cancer cells, some of these kinases can become stuck in the “on” position, leading to uncontrolled proliferation. Cabozantinib works by blocking the signals from several of these proteins, cutting off the communication lines that tumors use to expand.
The drug’s primary action involves inhibiting angiogenesis, the formation of new blood vessels that tumors need to grow. It accomplishes this by blocking a receptor called VEGFR, which is important in blood vessel development. By cutting off this blood supply, cabozantinib starves the tumor of the oxygen and nutrients it needs to survive, which helps to slow or stop tumor growth.
Beyond its anti-angiogenic effects, cabozantinib also targets other tyrosine kinases, including MET and AXL. These proteins are involved in tumor cell survival, invasion, and the development of resistance to other cancer treatments. By inhibiting MET and AXL, cabozantinib helps to counteract the cancer’s ability to spread to other parts of the body and overcome the effects of therapy.
The Function of Immunotherapy
Immunotherapy is a class of treatment that harnesses the power of the body’s own immune system to fight cancer. A common form used in combination with cabozantinib involves drugs known as immune checkpoint inhibitors. These treatments are designed to overcome cancer’s ability to evade detection by the immune system. T-cells, a type of immune cell, constantly patrol the body for threats, but cancer cells can exploit natural “checkpoints” to avoid being attacked.
Cancer cells can display proteins on their surface, such as PD-L1. When T-cells, which have a corresponding PD-1 protein, interact with these PD-L1 proteins, it sends a “don’t attack” signal to the T-cell. This interaction allows the cancer cell to hide from the immune system.
Immune checkpoint inhibitors work by blocking this deceptive signal. These drugs prevent the PD-1 and PD-L1 proteins from interacting. With the checkpoint blocked, T-cells are able to recognize the cancer cells as foreign and launch a targeted attack against the tumor.
The Synergistic Action of the Combination Therapy
The power of this combination comes from the way cabozantinib reshapes the area immediately surrounding the tumor, known as the tumor microenvironment. This microenvironment is a complex ecosystem of blood vessels, immune cells, and structural components that can either help or hinder cancer growth. An unaltered tumor microenvironment is often immunosuppressive, meaning it actively prevents the immune system from mounting an effective attack.
Cabozantinib helps to create a more pro-inflammatory and less immunosuppressive microenvironment. It achieves this by reducing the population of suppressive immune cells, such as regulatory T-cells and myeloid-derived suppressor cells, that dampen the anti-cancer immune response. It also promotes the infiltration of cancer-killing T-cells into the tumor.
This alteration of the tumor microenvironment sets the stage for immunotherapy to be more effective. Cabozantinib “prepares the battlefield” by breaking down the tumor’s defenses and creating a more favorable setting for an immune attack. Once the environment is primed, the immune checkpoint inhibitors can work more efficiently, unmasking the cancer cells and allowing the newly infiltrated T-cells to recognize and destroy them.
Cancers Treated With Cabozantinib and Immunotherapy
The combination of cabozantinib and immunotherapy has become a standard treatment for certain cancers, with advanced renal cell carcinoma (RCC), a type of kidney cancer, being a primary example. Its approval was based on the CheckMate 9ER clinical trial, which showed the combination of cabozantinib and the immunotherapy drug nivolumab led to significantly better outcomes for patients compared to treatment with a single targeted therapy agent. The study showed improvements in progression-free survival and overall survival, establishing this combination as a first-line treatment option for many patients with advanced RCC.
In addition to RCC, this combination is also being explored for other cancers. Research has shown promise in treating hepatocellular carcinoma (HCC), the most common type of liver cancer, and urothelial carcinoma, which affects the bladder and urinary tract. Clinical trials continue to investigate the effectiveness of this pairing in other malignancies, such as endometrial cancer.
Managing Combined Side Effects
Combining cabozantinib and immunotherapy can lead to a unique set of side effects that may include issues from both drugs or new effects specific to the combination. Side effects commonly associated with cabozantinib can include diarrhea, fatigue, high blood pressure, and hand-foot syndrome, which causes redness and discomfort in the hands and feet. These effects are managed with supportive care, such as medication to control blood pressure or dose adjustments, and require careful monitoring.
Because immunotherapy activates the immune system, it can sometimes cause it to attack healthy tissues in the body. These immune-related adverse events can affect various organs, leading to skin rashes, colitis (inflammation of the colon), pneumonitis (inflammation of the lungs), or other inflammatory conditions.
Close communication between the patient and their healthcare team allows for prompt intervention for any side effects. This may involve pausing treatment or administering medications to suppress the immune system, such as corticosteroids. Effective management is a key part of ensuring that patients can continue to benefit from this combination therapy.