A recent study estimated that there were 431,000 new cases of renal cell carcinoma (RCC – kidney cancer) and an estimated 179,000 deaths in 2020 worldwide. In non-metastatic settings (i.e., where the cancer is localised in the kidney and has not spread beyond) more than 90% of patients survive at least 5 years. However, in patients with metastatic RCC (where the cancer has spread to other parts of the body) the outcome is poorer.

RCC can be categorised into 2 main groups – clear cell RCC, which accounts for 75-80% of all cases, and non-clear cell RCC (nccRCC), which can be further subdivided into smaller groups based on the differences in histology, for example cell shape and cellular alterations. Around 5% of nccRCC cases have a genetic disposition and, like in Birt-Hogg-Dubé syndrome (BHD), these tumours are commonly multiple and bilateral and have an earlier age of onset compared to nccRCC not associated with a genetic condition. In general, kidney cancer associated with BHD is normally slow growing and rarely metastasises. This blog post will focus on the features and treatment of nccRCC. However, it does not discuss oncocytoma or hybrid RCC, 2 of the most common types of BHD-associated kidney cancer.

Types of nccRCC

• Papillary RCC – the most frequent type of nccRCC and 2^nd most common type of kidney cancer. Several genetic mutations are associated with papillary nccRCC, but this type is not normally associated with BHD.
• Chromophobe RCC – the next most frequent type of nccRCC and one of the most common types associated with BHD. Chromophobe RCC is also associated with a number of other rare genetic syndromes including tuberous sclerosis and Cowden syndrome.
• Other types of nccRCC include collecting duct RCC, MiT family translocation RCC and renal medullary carcinoma. None of these have been previously associated with BHD and are all very rare, aggressive forms with poor prognoses.

Although the treatments for advanced clear cell RCC have significantly evolved, little progress has been made in metastatic nccRCC due to the low incidence rates and the clinical and molecular diversity of this cancer, resulting in limited numbers of therapies available. Over the past decade, researchers have produced the cancer genome atlas, an in-depth molecular understanding of key cancer-causing alterations in different cancers. Importantly, this includes some types of RCC including clear cell, chromophobe and papillary and has revealed specific spectrums of molecular features for each type to improve the therapeutic management.

A recent paper by Marchetti et al., describes the most important signalling pathways involved in different nccRCC subtypes and includes an overview of ongoing/recently published clinical trials involving nccRCC patients (1).

nccRCC signalling pathways

There are 3 main pathways that are important in driving tumourigenesis (cancer formation) in nccRCC.

1. VEGF axis pathway

This pathway is involved in angiogenesis (the formation of new blood vessels). This is an important pathway in driving the growth of tumours which need a good network of blood vessels to provide oxygen and essential nutrients. There are several existing anticancer drugs that target this pathway to slow the growth of tumours.

2. Mesenchymal-Epithelial Transition (MET) pathway

This pathway is associated with tumour growth, metastasis and malignant cell infiltration (spread of the cancer). This pathway is particularly important in papillary RCC in which the MET gene is often mutated. A number of MET-directed inhibitory cancer drugs have been developed and some, such as cabozantinib target both the MET and VEGF pathways.

3. mTOR pathway

We have recently discussed the mTOR pathway and its role in BHD-related kidney cancer. Although there are several mTOR inhibitors available which are used in other clinical settings, they have not shown to be effective in the setting of BHD.

Immunotherapies

Generally, RCCs are characterised by a dysfunctional immune cell infiltrate leading to immune suppression in the tumour microenvironment allowing growth of the tumour. This makes it targetable by immunotherapy drugs that work against the major proteins that mediate the immune suppressive environment in the tumour microenvironment. These major proteins are called PD-1, PD-L1 and CTLA-4.

Although the use of immunotherapies in clear cell RCC was assessed in 2015, it has only recently been studied in the context of nccRCC and there are now several recently published and ongoing clinical trials (see our clinical trials page for more information on how clinical trials work).

• The recent KEYNOTE-427 phase II clinical trial looked at the efficacy and safety of the immunotherapy pembrolizumab (a PD-1 inhibitor) as a monotherapy in advanced nccRCC (types papillary, chromophobe and unclassified). The study showed promising clinical activity however the response rates were higher for papillary and unclassified RCC than chromophobe.
• Another phase II clinical trial tested nivolumab (another PD-1 inhibitor) in combination with cabozantinib in 2 cohorts of patients. The first had papillary, MiT family translocation or unclassified RCC and the second had chromophobe RCC. Like the KEYNOTE-427 trial, this showed promising clinical efficacy in the first cohort but there was no response in the second cohort of chromophobe RCC patients.
• Several other trials assessing immunotherapies or combination immunotherapies are underway and are showing promising preliminary results.

The International Kidney Cancer Coalition have a very user-friendly clinical trials search tool that gives up-to-date information on current clinical trials.

Various novel strategies for the treatment of nccRCC are also emerging and are under investigation (2). These include combination therapy of the PD-1 inhibitor camrelizumab and cytokine-induced killer cells. These are immune cells that can recognise and specifically kill cancer cells. The field of individualised DNA plasmid cancer vaccines is also progressing and are used to induce an anti-tumour immune response.

Summary

nccRCC is very diverse and complex but we are constantly improving our knowledge and understanding of these cancers and therefore increasing the number of therapeutic options. However, there is still lots of research to be done including the identification of biomarkers for the prediction of progression and response to treatment for nccRCC. Recruitment of sufficient numbers of patients to clinical trials for nccRCC is still an issue due to the rarity and diversity of this group of cancers. Innovation in clinical trial design will be key to the success of future clinical trials in this context.

One of the most striking observations from this review was the lack of response to immunotherapies in chromophobe RCC. As this is one of the most common types of kidney cancer in BHD patients, it is particularly important to us as a charity that further work can be performed to understand why this is the case. This knowledge is greatly needed to open up the therapeutic potential of these immunotherapy drugs which made huge advances in the treatment of other cancers.

References

1.        Marchetti A, Rosellini M, Mollica V, Rizzo A, Tassinari E, Nuvola G, et al. Molecular Sciences The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory? 2021 [cited 2021 Sep 10]; Available from: https://doi.org/10.3390/ijms22126237

2.        M S, F M, G A, V M, A C, A L-B, et al. Designing novel immunocombinations in metastatic renal cell carcinoma. Immunotherapy [Internet]. 2020 Dec 1 [cited 2021 Sep 10];12(17):1257–68. Available from: https://pubmed.ncbi.nlm.nih.gov/32998603/