Dr Chad Tang - MD Anderson Cancer Center, Houston, USA

My study at AACR was a phase II single-arm study looking at a bit of a novel treatment paradigm in patients with low-volume, we call it oligometastatic, kidney cancer where we’re looking at radiation therapy without a standard of care systemic therapy to control the patients. In addition to the clinical results of this trial, we also had data on a very interesting circulating tumour DNA assay that we found to be prognostic for these patients.

What was the study design?

The study design was a single-arm phase II study in which patients with clear cell renal cell carcinoma with up to five sites of the disease received radiation to all active sites of disease. They then went on surveillance with standard of care imaging, usually a CT scan every three months, and at the time of progression if the progression was limited, meaning up to three sites, they then went around again and had another round of radiation therapy and they were maintained off systemic therapy.  In the event that the progression was not limited, meaning more than three sites, then patients were started on systemic therapy and they were off the active component of the trial.

The primary endpoint of the trial was systemic therapy free survival which we powered it to detect an improvement that was greater than two years, this is based on a historical control with surveillance alone.

What were the findings of this study?

The primary endpoint was met in this study. The systemic therapy free survival was 34 months with a confidence interval with the lower bounds being 28 months. This exceeded our prespecified threshold of success which was 24 months. So we ultimately think that the study was successful.

In addition, a secondary primary endpoint, the other primary endpoint I should say, of progression free survival, which was more exploratory, was also found to be 18 months which was highly promising. Furthermore, overall survival did not seem to be compromised in this patient cohort. The three-year overall survival was 87% and the toxicity rate was quite modest at about 6-7% grade 3 or higher toxicities.

In addition, with regards to our correlative analysis, the circulating tumour DNA was found to be detected in the majority of patients. This ctDNA was found to be prognostic, both at three months for systemic therapy free survival and at baseline. So at both timepoints we found that, at baseline and three months, that circulating tumour DNA was prognostic.

What is the importance of these results?

I think the importance is that the primary treatment for patients with metastatic kidney cancer, regardless of low volume, high volume, is doublet systemic therapy with a PD-1 inhibitor and ipilimumab or a tyrosine kinase inhibitor. These are effective treatments, they’ve really improved outcomes in kidney cancer, but they’re expensive financially, either to the patient or the healthcare system, and they have toxicity rates reported to be between 40-80%. Now, the reason why this is beneficial is that we found you can be off these drugs for at least three years with radiation therapy and other metastasis-directed therapy and that the costs are substantially less, by an order of magnitude, and the toxicities are also an order of magnitude less. So it’s an option for select patients with low-volume disease that you can get some high quality, relatively minimal healthcare exposure with radiation alone and there’s no evidence at this point that doing this strategy is going to make systemic therapy less effective later on.

Is there anything else you would like to add?

I think the other thing to add is that there are no good biomarkers in kidney cancer and what we found was circulating tumour DNA, which is a very promising biomarker in multiple histologies, which was always thought not to work in kidney cancer because kidney cancers can really be low shedding and relatively have less genetic mutations. We found that, it was with the second generation assay utilised by Myriad, that this was a promising assay to be able to detect the majority of patients with low-volume indolent disease and that this detection was prognostic of outcomes.

So we feel that that has implications not only for this setting with oligometastatic but also with other settings as well, those with more higher volume metastatic disease where we see the standard of care systemic therapy or those post-nephrectomy who are thinking about adjuvant systemic therapy