Biological Therapy
Biological therapies are drugs made from natural substances from the body which are used to enhance the body’s immune system, kill cancer cells, or stop them from growing. Unlike certain other cancers, biological therapies for the treatment of renal cancer are not often used in combination with chemotherapy or radiotherapy; RCC is unusual in that these standard cancer treatments have little effect on renal tumours. Biological therapies include the following:
- Immunotherapies, which boost the body’s immune system, such as interleukin-2 (IL2) and interferon-α. Nivolumab, a monoclonal antibody which inhibits PD-1 receptors.
- Tyrosine kinase inhibitors (TKIs) are protein kinase inhibitors that interfere with the signalling pathway that controls tumour cell growth and angiogenesis. TKIs include sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), axitinib (Inlyta®) cabozantinib (cabometyx) and Tivozanib (Fotiva).
- Mammalian target of rapamycin (mTOR) inhibitors are also protein kinase inhibitors that inhibit cell growth and angiogenesis. mTOR inhibitors include temsirolimus (Torisel®) and everolimus (Afinitor®).
- Monoclonal antibodies interfere with the signalling pathway that helps tumours grow blood vessels. An example of a monoclonal antibody is Ipilimumab (Yervoy®).
Immunotherapies
Immunotherapies have had a resurgence in recent years with the development of a fully humanised monoclonal antibody directed against the human cell surface receptor PD-1 (programmed death-1) called nivolumab. Nivolumab binds to and blocks the activation of PD-1 via its ligands, PD-L1 and PD-L2, resulting in activation of T cells and cell-mediated immune responses against tumour cells. There are a number of clinical trials either ongoing or completed, which compare the effectiveness and safety of nivolumab with current targeted therapies.
The combination treatment of ipilimumab and nivolumab has been recommended by NICE for people with untreated advanced renal cell carcinoma that is at intermediate or high risk of getting worse, the results of a clinical trial (CheckMate 214) show that nivolumab with ipilimumab is more effective than sunitinib.[1]
Checkmate 914 is a trial looking at ipilimumab and nivolumab or nivolumab on its own to treat renal cell carcinoma. It is for people having surgery for kidney cancer who have a high risk of the cancer reoccurrence.[2]
Contact 03 is a trial is looking at adding a drug called atezolizumab to cabozantinib as a treatment for renal cell carcinoma. It is open to people with advanced cancer that is inoperable. [3]
The Caper trial is looking at a new combination of treatment for people with Clear cell renal cell carcinoma that has metastasised or if surgery to remove it is not possible. It is for people who have already had an immunotherapy. You might have an immunotherapy for kidney cancer that has spread. But sometimes it doesn’t work or stops working. So researchers are looking for ways to improve treatment. In this trial they are looking at a combination of 2 drugs called:
– Pembrolizumab; and
– cyclophosphamide
The aim of this trial is to find out if durvalumab on its own or in combination with tremelimumab can stop or delay kidney cancer coming back. The aim of this trial is to find out if durvalumab on its own or in combination with tremelimumab can stop or delay kidney cancer coming back. [4]
Rampart study
The aim of this trial is to find out if durvalumab on its own or in combination with tremelimumab can stop or delay kidney cancer coming back after surgery.
In this trial some people:
are actively monitored and don’t have either of the drugs in the study
– have durvalumab
– have durvalumab and tremelimumab [5]
The KEYNOTE – B61 study is looking at a new combination of treatment for kidney cancer that has metastasised.
It is for people with non-clear cell renal cell cancer and who have not received treatment before.
There is no standard treatment for people with nccRCC that has spread.
Doctors want to improve the treatment options for people with non-clear cell renal cell cancer that has spread. To do this they are looking at a new treatment combination of pembrolizumab and lenvatinib. [6]
In the Wire trial you will have treatment before surgery. The drugs they are looking at target different parts of cancer cells and can reduce the size of the cancer. You would normally have these drugs for longer than you will in this trial. So the researchers don’t think they will shrink the tumour. But they think it will give them important information about how they work on the cancer cells. This will help in testing these drugs in future clinical trials.
There are 3 drugs. Depending on when you join this trial you might get 1 of these drugs or a combination of them. The drugs are:
– cediranib
– olaparib
Cediranib is a cancer growth blocker called a tyrosine kinase inhibitor (TKI). It works by blocking the protein tyrosine kinase that cancer cells need to grow and multiply.
Durvalumab is an immunotherapy. It works by helping the body’s immune system fight cancer.
Olaparib is a targeted drug called a PARP inhibitor. PARP is a protein that helps damaged cells repair themselves. By blocking PARP cancer cells can’t repair themselves and so they die.
As a part of the trial you give samples of cancer tissue (biopsies ) and have scans done. [7]
Tyrosine Kinase Inhibitors (TKIs)
Researchers are investigating various combinations of systemic drugs and sequencing of treatments to find the most effective regimen for the treatment of renal cancer.
- The PISCES trial was a patient preference study, comparing sunitinib with pazopanib in terms of quality of life and side effects. The results of the study came out in favour of pazopanib, with 70% of patients preferring pazopanib to sunitinib due to better quality of life and feeling less tired. Only 22% preferred sunitinib and 8% had no preference.
- The PRINCIPAL study is the largest prospective, observational study of pazopanib in patients with advanced/metastatic RCC and the study results are consistent with prior clinical data of pazopanib and confirm the efficacy and favourable safety profile of pazopanib treatment for this patient population in the real‐world clinical setting.[8]
- The results of the Star study found that treatment breaks off from Sunitinib or Pazopanib were acceptable to patients and clinicians, and were not detrimental to overall survival or quality of life, and had significant cost savings.[9]
- Researchers on the Panther trial concluded that having pazopanib before surgery was safe and possible. It helped some people with intermediate risk factors and most of them were able to have surgery as planned.[10]
- The SORCE study results concluded that Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.[11]
- Another trial is looking at whether sorafenib has an effect on the growth of kidney tumours and cysts in people with von Hippel-Lindau syndrome.
- Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors.[12]
- One phase 3 study concluded that Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. [8]
- The A-Predict trial is investigating the safety and efficacy of treatment with axitinib in patients who have not had surgery.
- Lapatinib (Tyverb) is a licensed treatment for advanced breast cancer that targets the human epidermal growth factor receptors, ErbB1 (EGFR) and ErbB2 (HER2). Trials are ongoing to see if blocking these receptors can stop RCC cells from growing and dividing.
Mammalian Target of Rapamycin (mTOR) Inhibitors
A number of clinical trials are ongoing to compare current (everolimus and temsirolimus) and new mTOR inhibitors with TKIs and chemotherapy for the treatment of advanced RCC:
- The findings of the ASPEN trial showed that sunitinib significantly increased progression free survival for patients with RCC compared to everolimus.[13]
- The ROVER trial compared a mTOR inhibitor called GDC-0980 with everolimus for the treatment of advanced RCC. GDC-0980 is also a phosphoinositide 3 kinase (PI3K) inhibitor, which blocks the action of PI3K preventing cancer cell growth and angiogenesis. Everolimus was found to be a more effective treatment.[14]
- A potent, selective mTOR inhibitor, called AZD2014, was compared to everolimus for the treatment of metastatic RCC in the ZEBRA clinical trial, but was found to be inferior to everolimus.
- Results of the RAPTOR study in papillary mRCC demonstrated that everolimus provides some clinical benefit to this patient population and highlights the need for central pathological review of this rare tumour.[15]
- Currently there is a trial comparing a drug called MK-6482 with everolimus for kidney cancer. It is open to people with kidney cancer that has metastasised and cannot be removed with surgery. MK-6482 is a targeted drug that is a growth blocker. It works in a different way to everolimus to slow down the growth of cancers.
Researchers think that MK-6482 might be more advantageous than everolimus. [16]
Vaccines
Vaccines are a type of immunotherapy. Cancer vaccines are designed to try to stimulate the body’s own immune system to fight the cancer. However, because cancer originally develops from normal body cells, cancer cells are hard for the immune system to identify because the immune system does not recognise the cancer cells as foreign. Unlike vaccines for infectious diseases, cancer vaccines are not preventative and are given as a treatment to patients who already have the disease.
Cancer vaccines can be general and given to any renal cancer patient, or they can be specific for an individual patient. There are two types of vaccine being tested for renal cancer:
- Tumour cell vaccines are made from an individual patient’s renal cancer cells, which are removed from the tumour during surgery. Attaching a foreign protein, such as an inactive bacterial protein to the cells, deactivates the cancer cells. This also makes the cancer cells easier for the immune system to recognise.
- Dendritic cell vaccines encourage the immune system to attack cancer cells. The patient’s dendritic cells (white blood cells) are removed from the blood and primed with renal cancer cells before being injected back into the patient.
Research into vaccines for the treatment of renal cancer is in its infancy and cancer vaccines are only available in clinical trials. Research is ongoing to try to slow down or stop advanced renal cancer and as an adjuvant therapy after surgery to try to prevent recurrence and/or spread. Vaccines are also being studied in combination with other treatments, such as nephrectomy, other immunotherapies, TKIs, or chemotherapy:
- A clinical study found that the drug IMA901 did not improve overall survival when added to sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. The magnitude of immune responses needs to be improved before further development of IMA901 in this disease is indicated. [17]
- The ADAPT trial is investigating a personalised dendritic cell vaccine called ASG-003 for advanced RCC in combination with sunitinib, and comparing it to sunitinib alone. [18]
New Biological Therapies in Development
A number of biological therapies are currently in development for the treatment of advanced renal cancer. These include:
- The COSAK trial investigated 2 new TKIs; cediranib and saracatanib. The study showed that a combination of cediranib and saracatanib did not offer any benefits over cediranib alone. [19]
- A study looking to treat people with advanced TCC renal cell carcinoma with LY3143921 hydrate has shown some promise in laboratory research and animal studies. It is a type of drug called a Cdc7 inhibitor. Low levels of Cdc7 are usually found in normal cells, but there can be higher levels of Cdc7 in cancer cells. Researchers think that LY3143921 hydrate can block the action of Cdc7. This could stop the cancer cells from multiplying and cause them to die. As normal cells have lower levels of Cdc7, they might be less affected by the drug. So a person might have fewer side effects. [20]
- Belzutifan is a novel drug that has shown promising efficacy and tolerability in participants with VHL-associated ccRCC. Belzutifan is also in phase II and III clinical development for the treatment of renal cell carcinoma (RCC) that is not associated with VHL disease.[21]
In many countries with national health services, new cancer treatments are appraised for cost-benefit before they are recommended for reimbursement by the government. In the UK, the body that carries out such appraisals is NICE. Currently avelumab and axitinib, nivolumab and ipilimumab, cabozantinib, tivozantinib, sunitinib, pazopanib are recommended for first-line treatment by NICE, and lenvatanib and everolimus, cabozantinib, everolimus, nivolumab, axitinib for second-line treatment; NICE did not consider any other treatments as cost effective[16]. The Scottish Medicines Consortium (the equivalent to NICE for NHS Scotland) approved Pembrolizumab with axitinib for the first-line treatment of advanced kidney cancer, but is still not available in the rest of the UK. [13] And most recently, Nivolumab and Cabozantnib are now available to patients in Scotland for untreated advanced Kidney cancer. [14]
The challenge facing cancer researchers today, and pharmaceutical companies in particular, is the discovery and development of safe and effective renal cancer treatments, which offer value for money within the NHS. With spiralling drug development costs, the ever-increasing regulatory requirements imposed on pharmaceutical companies, and a government body that employs outdated and inappropriate methods for assessing the cost-benefit of cancer drugs, this is certainly a big challenge in the UK.
Chemotherapy
Chemotherapy is not very effective for the treatment of renal cancer, in particular RCC, and biological therapies have been shown to be more successful at treating advanced RCC. Chemotherapy is more often used to treat transitional cell carcinoma (cancer of the lining of the bladder, the pelvis of the kidney, or the ureter). However, cancer researchers are always developing new chemotherapies, which are tested for the treatment of renal cancer in clinical trials.
- Chemotherapy and biological therapy combinations (IL2, interferon-α and 5FU; sunitinib and GC chemotherapy) are being tested for the treatment of RCC.
- The Atlantis study is looking at ways to delay transitional cell carcinoma reoccurring after chemotherapy. The trial team are testing a number of different treatments. In this trial you have 1 of the following medications:
– cabozantinib or a placebo
– rucaparib or a placebo
– enzalutamide or a placebo
The overall aims of this trial are to find out:
If having additional treatment can increase the time before these cancers come back, if having more treatment can help people live longer, and what the side effects are.[2]
References
-
- Nivolumab with ipilimumab for untreated advanced renal cell carcinoma (2019) NICE technology appraisal guidance 581 https://www.nice.org.uk/Guidance/TA581 15th May 2019
- https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/clinical-trials-search?populate=Kidney%20cancer&f%5B0%5D=field_trial_status%3A4386
3.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459236/ Oncologist. 2019 Apr; 24(4): 491–497. Published online 2019 Mar 13. doi: 10.1634/theoncologist.2018-0787 -PRINCIPAL study
6. https://ascopubs.org/doi/abs/10.1200/JCO.20.01800 DOI: 10.1200/JCO.20.01800 Journal of Clinical Oncology 38, no. 34 (December 01, 2020) 4064-4075.Published online October 14, 2020 – SORCE study
-
- Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. doi: 10.1016/S1470-2045(14)70030-0. Epub 2014 Feb 17. PMID: 24556040; PMCID: PMC5719485. https://pubmed.ncbi.nlm.nih.gov/24556040
13. PMID: 33616314. https://pubmed.ncbi.nlm.nih.gov/33616314/
- Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. Eur J Cancer. 2016 Dec;69:226-235. doi: 10.1016/j.ejca.2016.08.004. Epub 2016 Sep 24. PMID: 27680407.https://pubmed.ncbi.nlm.nih.gov/27680407/
- IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 https://pubmed.ncbi.nlm.nih.gov/27720136/
12. Study Finds Apitolisib Less Effective Than Everolimus in Metastatic Renal Cell Carcinoma https://ascopost.com/News/36421
SEPTEMBER 7, 2020 (KSCN 2020)
- Nice Guidelines
Kidney cancer research, Cancer Research UK: http://www.cancerresearchuk.org/about-cancer/type/kidney-cancer/treatment/whats-new-in-kidney-cancer-research. Accessed March 2016.