TRIBE; TKI therapy in RCC; Immune Biomarker Evaluation
Research type
Research Study
Full title
TRIBE; Tyrosine Kinase Inhibitor (TKI) therapy in Renal Cell Carcinoma: Immune Biomarker Evaluation
IRAS ID
227414
Contact name
Fiona Thistlethwaite
Contact email
Duration of Study in the UK
1 years, 8 months, 3 days
Research summary
Research Summary
Metastatic Renal Cell Carcinoma (mRCC) is frequently fatal within months or a low number of years. Several new drugs have been developed in recent years that are life extending and can help alleviate symptoms, but there is little information to guide physicians and patients as to which drugs are the best choice for any one patient and in what order to use them.
The immunotherapy checkpoint inhibitor drug nivolumab is the most commonly used drug when first line tyrosine kinase inhibitor (TKI) is no longer effective in mRCC. However, in the pivotal trial, the objective response rate to nivolumab in this setting was only 25%. There are no predictive biomarkers that can identify the patients with the best chance of responding to nivolumab in mRCC, nor is there any information about the effect of first line TKI therapy on patient’s likelihood of responding to second line immunotherapy with nivolumab.
Evaluating and correlating immune and molecular characteristics from blood and tumour, may identify biomarkers that predict for a response to immunotherapy, and differences between different primary TKI therapies that could influence tolerance and response to second line immunotherapies.
Patients who have progressed on first line TKIs and who are planned to commence immunotherapy with nivolumab will be recruited from NHS sites in England and tumour and blood samples will be analysed in an attempt to identify predictive biomarkers for immunotherapy and to understand the effect of TKI therapy on their immune profile. We estimate that the trial will run for two years in total.Summary of Results
Metastatic renal cell carcinoma (mRCC) is frequently fatal within months or a few years after diagnosis. Several life-prolonging drugs have been developed that can help alleviate symptoms, but treatment algorithms to arrive at which drugs and in what order are not yet defined. Two classes of treatment are used currently, the immunotherapy checkpoint inhibitor such as nivolumab and tyrosine kinase inhibitors (TKI) that stop growth factors important to mRCC proliferation.
In our study, we recruited patients with mRCC whose disease progressed on TKI treatment and received nivolumab as the further treatment line. One-fifth of the patients drew a clinical benefit from treatment with nivolumab. We collected and analysed blood and tumour samples from these patients to identify better methods to predict response to treatment. Using specific staining techniques, we were able to measure the amount of different immune cells in the samples either near or far from tumour cell areas. We found two types of immune cells called Tregs and Macrophages tend to aggregate near the tumour cell areas. These cells support the growth of cancer, i.e., pro-cancer immune cells. Moreover, the number of immune cells were higher in patients who benefited from nivolumab than in those who did not. Patients with a high count of anti-cancer immune cells and low pro-cancer immune cells were associated with better outcomes.
We explored if the order of the two classes of treatment would be different. We found that a minority of patients had superior outcomes with nivolumab when used after TKI. Meanwhile, the majority of patients had superior outcomes with TKI when used after nivolumab. These findings are consistent with other studies showing that it is better to use both the TKI and immunotherapy upfront rather than each alone. However, these observations suggest that patients who stopped responding to TKI can still benefit from TKI therapy if combined with nivolumab later on.REC name
North West - Greater Manchester East Research Ethics Committee
REC reference
17/NW/0541
Date of REC Opinion
3 Oct 2017
REC opinion
Favourable Opinion