Renal cell carcinoma is the most common type of kidney cancer, accounting for almost 95% of all cases. It develops in the parts of the kidneys responsible for transporting urine through the excretory system, and is usually treated by removing part of the kidney or the entire organ. However, if the cancer has spread to both kidneys or is not able to be surgically removed, then other options are necessary for treatment. A recent approach to treating this type of cancer is to use a combination of immunotherapy and small molecule drugs to leverage complimentary mechanisms and increase the probability of tumor suppression.
How does immunotherapy work?
Immunotherapy can take several forms, but in general it has to do with either activating or blocking a part of the body’s innate immune system to fight cancer. One group of cells in the immune system responsible for fighting infection and disease are called T cells. The activity of T cells is regulated by a number of checkpoints, which prevent the immune system from attacking the body’s own cells, but can also lead to preventing it from attacking tumors.
For example, T cells express a receptor protein on their surface called PD1. When another protein called PD-L1 binds to it, it suppresses the immune response. This happens normally in the body of women during pregnancy.
However, tumors in renal cell carcinoma have been shown to express high levels of PD-L1, effectively protecting against an immune system attack. By using a specific antibody called avelumab, researchers and clinicians can disrupt the interaction and promote the immune system to fight cancer. In combination, they can use antiangiogenic drugs, such as axitinib, which stop tumors from growing their own blood vessels. These complimentary approaches show promise, but must be evaluated for safety and toxicity through detailed clinical trials.
Investigating combination therapy with avelumab and axitinib
One of these recent studies focused on determining the antitumor activity and safety profile of a combination therapy of avelumab and axitinib. The work was conducted by a collaborative group of researchers and medical doctors based in the UK, USA, Japan and Italy and was sponsored by the pharmaceutical companies Pfizer and Merck. The results were published in the journal Lancet Oncology.
The study was conducted in 2 phases: A dose-finding phase and a dose-expansion phase. In dose-finding phase, different increasing doses of the combination therapy were given to participants to find the maximum tolerated toxicity. In the dose-expansion phase, a greater number of subjects were included with different types and stages of renal cell carcinoma to acquire additional information.
The study was designed to attempt to answer two questions:
- What kind of toxicity would be observed with the combination therapy
- Would it be effective in fighting against tumor growth?
The researchers looked to evaluate these questions within the first four weeks of treatment.
The overall results established a maximum tolerated dose that showed that those levels represented a manageable safety profile. In order to evaluate this, they looked for adverse events that ranged from mild to severe. These included indicators such as anemia, high blood pressure and abnormal increases in the expression of certain proteins. Six patients passed away before the end of the trial, and the investigators determined that five cases were related to disease progression but one was related to a condition induced by the treatment. Of all the participants, 58% displayed adverse events of some kind.
The effectiveness of avelumab and axitinib in combination therapy showed promising results. Among the participants, 58% had objective responses, with some kind of shrinkage in the size of their tumors. Two common medical imaging techniques, Magnetic Resonance Imaging (MRI) and Computed Tomography (CT), were used to make these assessments.
The researchers also measured the expression of PD-L1 in the tumor microenvironment for all participants, and the study found a positive correlation between levels of that expression and objective response to the combination therapy. This suggests that quantifying PD-L1 expression levels in patients could be used as a factor to determine whether combination therapy is appropriate for future patients.
One limitation of this study was the lack of a parallel monotherapy group (a set of patients given only avelumab or axitinib), to compare to the combination group. The authors also noted that longer follow-up times will be needed to fully assess the antitumor activity of the drugs in combination.
Written by Adriano Vissa, PhD
Reference: Choueiri TK, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advance clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial