immunotherapy and drug combinations including cabozantinib and nivolumab.
Dr Rebecca Case-Upton BSc (Hons), PhD
Kidney Cancer UK, Medical Publications
*You may find our Glossary of Terms useful when reading this article
Good news: Cabozantinib and Nivolumab recommended for use in Scotland
Kidney Cancer Scotland and Kidney Cancer UK welcome the news that the Scottish Medical Consortium (SMC) has recommended both nivolumab and cabozantinib for use within the NHS in Scotland. This follows a period of uncertainty when the SMC initially refused to recommend nivolumab; the drug was recommended for use in England and Wales in November 2016. We hope that the National Institute for Health and Care Excellence (NICE) will follow the SMC in recommending cabozantinib in England and Wales, a decision which is due to be published in August 2017. A lengthy consultation period is currently taking place. Both Kidney Cancer Scotland and Kidney Cancer UK are continually campaigning to reduce the ‘postcode lottery’ effect across the UK and feel that promising and effective drugs should be available for everyone.
What is nivolumab?
Nivolumab acts in a different way to other current targeted therapy treatments for kidney cancer, which either aim to kill tumour cells or stop tumour cell growth. Nivolumab is an anti-PD-1 (programmed death-1) monoclonal antibody which acts by blocking the receptor PD-1 on T-cells (part of the immune system), which reinvigorates the T-cells and allows them to attack the cancer cells. T-cells are often inactivated by a substance that cancer cells produce, which activates the PD-1 receptor on T-cells. Activating the PD-1 receptor causes the T-cell to become inactive so it doesn’t do its job and attack cancer cells. Nivolumab acts as an immune-modulator and stops the PD-1 receptor from being activated which in turn boosts the body’s own ability to attack cancer cells.
The PD-1 blockade is thought to specifically reinvigorate immune cells that are able to target cancer. It does not generally activate the entire immune system and this could help to reduce the side effects of the drug.
What is cabozantinib?
Cabozantinib is a new tyrosine kinase inhibitor for the treatment of advanced kidney cancer that is being appraised by NICE following successful clinical trial results. Cabozantinib acts in a similar way to the other TKI’s but has been shown to target c-MET and VEGFR2 tyrosine kinases.
The results of the cabozantinib phase III METEOR clinical trial look promising. Cabozantinib increased the overall survival of people with advanced kidney cancer to an average of 20.1 months compared to 12.1 months with everolimus. The period of time before the disease progressed (progression free survival) was 7.4 months with cabozantinib compared to 2.7 months with everolimus. 1
Combinations of drugs and the future of immunotherapy and TKI’s
Thankfully, both the SMC and NICE decided to recommend Nivolumab as the first immunotherapy checkpoint inhibitor to be made available on the NHS for Kidney Cancer. This is good news not only because it increases the number of drugs available and that the drugs look effective but also it has opened the door for many more clinical trials. Other immunotherapies might be recommended in the future and many more combinations of TKI’s and immunotherapies will be explored. The number of clinical trials using nivolumab in combination with different drugs has expanded significantly in the past few years. Examples of such trials are detailed below:
- We previously reported promising preliminary results from the clinical trial checkmate 214, which is comparing a nivolumab/ipilimumab combination to sunitinb, the results for this are expected in 2019. It is a phase 3 trial which is taking place in many locations across the world including the UK; it is still active but has finished recruiting. Ipilimumab (Yervoy) is a monoclonal antibody that acts by activating the immune system so it can attack cancer cells. It works in a similar way to nivolumab but targets CTLA-4 receptors on T-cells, which are also involved in an inhibitory mechanism of the immune system. Targeting both receptors together appears at this early stage to have an increased effect on reducing the inhibition of the immune system. https://clinicaltrials.gov/ct2/show/NCT02231749.
- A similar trial in America is comparing nivolumab to ‘nivolumab and ipilimumab’ and to ‘nivolumab and bevacizumab’. Bevacizumab is a monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). VEGF-A is a chemical signal that stimulates the growth of a tumours blood vessel supply. https://clinicaltrials.gov/ct2/show/NCT02210117?term=renal+cell+carcinoma+nivolumab&rank=17
- In America, South America and Germany the trial Checkmate 9ER is studying the use of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib compared to sunitinib in previously untreated advanced or metastatic Renal Cell Carcinoma. This is a phase 3 trial and is estimated to be completed in 2022. https://clinicaltrials.gov/ct2/show/study/NCT03141177?term=renal+cell+carcinoma+nivolumab&show_locs=Y#locn
- In America and Canada a checkmate 016 trial is currently comparing the life extending effect of combinations of nivolumab with sunitinib, pazopanib, or ipilimumab in patients with metastatic kidney cancer. The trial is currently active and is estimated to be completed in June 2018. https://clinicaltrials.gov/ct2/show/NCT01472081?term=renal+cell+carcinoma+nivolumab&rank=7
Nivolumab combinations: early phase trials
I have detailed a few of the larger trials with established drugs above but there are also many early phase trials happening, often in America in collaboration with Bristol Myers Squibb (BMS). The chart below details the variety of drugs nivolumab is combined with. Early phase 1 or 2 trials are initially used to see if the drugs are likely to be effective and aim to discover the safety of the drugs and their effective dose. Very often these trials do not yield positive clinical results but at this stage it is good to see that so many combinations are being explored.
|Nivolumab in combination with||Country of trial||Type of drug|
|HBI-8000||China||Drug that alters the way DNA is wound around histone. Decreased expression of proteins involved in cell differentiation, cell cycle arrest, tumour immunity, angiogenesis, drug resistance, and apoptotic elimination of damaged cells, all of which contribute to the development and progression of cancer.|
|X4P-001||USA||CXCR4 inhibitor. Involved in immune cell trafficking, may increase the influx of T-cells that can be further activated by nivolumab.|
|axitinib||USA||Tyrosine kinase inhibitor, inhibits ‘tumour supporting’ blood vessel formation.|
|Interleukin-2||USA||Cytokine that stimulates the immune system.|
|USA||Tyrosine kinases inhibitor including RET, CHR4q12, CBL, Trk, and DDR receptor families.|
|CB-839||USA||Glutaminase inhibitor. CB-839 could potentially have an impact on the treatment of cancer by first starving the tumour cell, and second facilitating the activation of T-cells in the nutrient-deprived tumour microenvironment.|
|Tivozanib||France||Tivozanib is a novel and potent vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR TKI).|
|Ibrutinib||USA||Ibrutinib may stop the growth of tumour cells by blocking some of the enzymes needed for cell growth|
|NKTR-214||USA||Cytokine that targets CD122 on T-cells (immune cells), acting to expand the number of these cells and promote their anti-tumour effects.|
|Valilumab||USA||Anti CD27. Targets the CD27 on immune cells, promoting their anti-tumour effects.|
|FPA008||USA||Cabiralizumab (FPA008) blocks the binding of both CSF1 and IL-34 to CSF1R, thereby inhibiting the activity and survival of the macrophages and monocytes (immune cells). These Tumour-associated macrophages (TAMs) are elevated in many tumours and are thought to be involved in suppressing the immune response against tumours.|
As you can see there are numerous clinical trials which are just starting using nivolumab in combination with a variety of different targets. Hopefully these trials will discover interesting and translate to useful drug combinations in the clinic.
The use of nivolumab is also being explored in different situations as well:
- The ‘ADAPTeR’ trial in the UK (Royal Marsden, London) is looking at the use of nivolumab as a preoperative treatment. This trial is currently recruiting and is due to finish in May 2018. https://clinicaltrials.gov/ct2/show/NCT02446860?term=renal+cell+carcinoma+nivolumab&rank=13
- In America a phase 1 clinical trial is being run to find out if nivolumab can be of use in non-metastatic disease.
- There are also a variety of clinical trials looking at stereotactic radiotherapy in combination with nivolumab.
The majority of these clinical trials are taking place in America but we will keep you updated on any trials that occur in the UK and Scotland. Kidney Cancer UK is currently in negotiations with a trial committee in the UK, with the aim to help support patients who may take part in a multiple immunotherapy combination trial they are planning. When this is finalised we will be able to give you more details on this trial. If you wish to donate to us in order to help us support research in this area please contact us on 01223 870008.
Clinical trials are continually being established and we will do our best to keep you updated. However if you wish to do your own research into this area, most clinical trials can be found on www.clinicaltrials.gov. ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. We found that using the search term ‘renal cell carcinoma’ came up with many good results and we used ‘nivolumab renal cell carcinoma’ to find the trials in this article.
The future of immunotherapy and the use of drug combinations in advanced kidney cancer is certainly expanding rapidly and in a variety of directions. Although clinical trials can take many years to complete we look forward to updating you on hopefully positive results and improvements in the life extending ability of these drugs. Kidney Cancer Scotland and Kidney Cancer UK are very happy that the SMC has decided to recommend the use of both cabozantinib and nivolumab. These drugs are paving the way for a future of using immunotherapies and multiple drug combinations for advanced kidney cancer.
- Choueiri et al, 2015. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373:1814-1823