Renal Cell Cancer Treatment: The Old, the Almost Old, and the New

Clear cell renal cell cancer (ccRCC) is the predominant type of kidney cancer, accounting for 70% to 75% of all kidney cancers. Here, I outline the current treatment landscape for ccRCC, highlighting what’s new and what’s on the horizon.

Surgical removal of the cancerous kidney is most often the first treatment after diagnosis, especially if the tumors exceed 3- to 4 cm in size. Smaller tumors can instead be monitored for a time, because they often grow slowly, or they can be excised without removing the entire kidney. Even if distant metastases have not developed at the time of surgery, 30% to 40% percent of ccRCC patients will develop metastatic disease. No adjuvant (post-surgery) treatments have proven to be effective so far in preventing metastatic recurrences after surgery.

The clinical behavior of ccRCC after surgery can vary greatly, depending on the stage of resected cancer, as well as its pathological grade and other patient-specific factors. Risk categories are usually calculated and assigned to patients because they greatly affect the timing and choice of treatment after surgery. The presence of certain mutations (BAP1, PBRM1, and TP53) is also predictive of the disease course, and these should be taken into consideration in defining a patient’s risk category.

ccRCC is considered to be an immunogenic cancer, largely due to the high numbers of T cells—a type of immune system cell—often seen within tumors. Back in 1992, the U.S. Food and Drug Administration (FDA) approved high dose IL-2 (aldesleukin), an immune-stimulating small protein (cytokine), as a treatment for RCC, even though IL-2 treatment benefits only a minority of patients, and is extremely difficult for patients to tolerate. Another immune-stimulating agent, interferon-alpha, was also used to treat RCC, but like IL-2, it causes severe toxicity and has low response rates.

Most ccRCC tumors (up to 80%) have mutations in the tumor-suppressor gene VHL. This gene is mutated in a rare inherited syndrome called von Hippel-Lindau disease, and members of VHL families most often develop ccRCC. The pathogenic consequences of disabling mutations in VHL are many, but the most striking is perhaps the acquired ability of VHL-mutant tumor cells to promote and attract the growth of new blood vessels to the tumors (vascularization).

Treatments to inhibit vascularization

Chemotherapy is not effective in treating metastatic ccRCC. However, the fact that RCC tumors are highly vascularized has served as the basis for exploring specific drugs that may prevent the growth of blood vessels (angiogenesis). These drugs are known as anti-angiogenic, and they are tyrosine kinase inhibitors usually suppressing the activity of a number of receptors with tyrosine kinase activity. Vascular endothelial growth factor (VEGF) receptor, a protein necessary for the growth of new blood vessels, is one of the receptors targeted by anti-angiogenic drugs. Over the years, the FDA has approved several of these drugs as single agents, meaning that each can be used on its own to treat RCC: sunitinib (Sutent), sorafenib (Nexovar), pazopanib (Votirent), and, later, cabozantinib (Cabometyx).

The duration of a patient’s response to kinase inhibitors is limited because they eventually develop resistance to the drugs. Other drugs, like everolimus (Affinitor) and temsirolimus (Torisel) were approved by the FDA for patients who stopped responding to kinase inhibitors. Later, drugs specifically developed to inhibit vascularization became FDA-approved: axitinib (Inlyta) in 2012, and lenvatinib (Lenvima) in combination with everolimus in 2016.

Immune checkpoint drugs

Immune interventions—treatments that involve using a patient’s own immune system to treat cancer—became a focus of interest in RCC again with the development of immune checkpoint drugs. In this new field, the first FDA approval for ccRCC was granted to nivolumab (anti-PD-1) in 2015, specifically for treating patients who stopped responding to anti-angiogenic drugs. The approval was based on favorable comparison to sunitinib in clinical trials.

In April 2018, the FDA approved a combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4) for patients with previously untreated ccRCC of intermediate and high risk. Clinical trials comparing this combination to sunitinib, showed that the combo improved overall survival by 32%.

Combination treatment: immune checkpoint plus anti-angiogenic drugs.

Combining these two different treatments became an area of high interest just a few years ago, and the effort has now been rewarded by recent FDA approvals of two combinations as new, effective, first-line treatments for ccRCC. In April 2019, the FDA approved a combination of pembrolizumab (anti-PD-1) and axitinib (it improved overall survival by 47% compared to sunitinib), and avelumab (anti-PD-L1) plus axitinib was approved in May 2019 (survival data not yet mature).

Lenvatinib and pembrolizumab are likely in line for FDA approval based on strong clinical trial results seen so far. A trial with this combination has reported a 64% overall response rate and stable disease in 30% of patients—a disease-control rate of nearly 100%. Importantly, some patients receiving the new combo treatment in this trial had relapsed following previous treatment with an anti-PD-1 drug.

A large international trial called COSMIC-313 is currently exploring the combination of cabozantinib with both nivolumab and ipilimumab in previously untreated patients with intermediate and poor-risk RCC. Many other trials are also evaluating the efficacy of different combination treatments.

Now, with many options available for the first-line treatment, careful consideration should be given to the choice of the most relevant one to start with, and how to sequence treatments. The combination of immune checkpoint drugs and anti-angiogenic drugs is now a clear choice for patients who have no contra-indication for immune interventions because it provides both a significantly higher response rate and response duration compared to anti-angiogenic drugs as single agents. What to do next if a response is not seen, or is not durable, is still an open question.

New drugs to watch

CB-839 is a glutaminase inhibitor in clinical development for RCC because this cancer strongly depends on glutamine metabolism. In combination with cabozantinib, CB-839 conferred a 50% response rate and a 100% disease-control rate in pretreated patients in a clinical trial.

PT2977 is a drug that inhibits HIF2a, a protein activated by the loss of VHL and which mediates an increase in angiogenesis. This drug, as a single agent, has reported activity in 24% of heavily pretreated RCC patients. It is combined with cabozantinib in an ongoing trial.

Even though not a new entity, the cytokine IL-2 is not out of consideration. Several trials now offer it in combination with anti-PD-1 drugs, and a combination with pembrolizumab has already shown very good efficacy in a small trial, with 13 out of 18 patients responding (treatment with IL-2 requires hospitalization). There is a “milder” version of IL-2 designed to have fewer side effects, NKTR-214 (bempegaldesleukin), which is also in trials in combination with immune checkpoint drugs.

Another cytokine drug, pegilodecakin (modified IL-10, another immune cytokine), has reported efficacy in 40% of pretreated RCC patients when combined with an anti-PD-1 drug.

It is clear that a lot of progress has been made in the treatment of RCC, but a lot more is needed in terms of understanding of how to best sequence treatments, and define predictive markers of response.

Image Credit: Metastatic clear cell renal cell carcinoma in the bladder (Credit: Nephron)