It’s good to start with the rationale behind the trial since TONIC is really an exploratory trial and is based on preclinical data. What we know from breast cancer is that in breast tumours there are only a few immune cells while if you talk about immunotherapy you would like to have many immune cells surrounding your cancer cells. The question is how can we heat up a cold tumour, so making a cold tumour hot? If you look at the literature on preclinical research you see that using radiation or certain chemotherapies can be in the benefit of your immune system. So it has been shown, for example, that chemotherapy you can increase your androgen presentation or you can increase immunogenic cell death. So our main question is whether we can use those treatments, so standard chemotherapy or radiation, to enhance the effect of immunotherapy in triple negative breast cancer patients.
I understand that the TONIC trial came with an adaptive design, can you tell us more about that construction?
Yes. Adaptive design basically means that while the trial is ongoing you adapt your design. Either some trials can be expanded, our trial will be downsized. So we started with five small groups of treatments, five cohorts, and depending on the results that we gain we will downsize the number of arms. So we really would like to continue with the arms with the most promising results.
That makes sense. What were the five arms that you outlined?
The five arms are as follows: in the first arm patients start with radiation, three times 8Gy in a period of two weeks and then nivolumab was given until disease progression. In the second cohort patients started with low dose doxorubicin, very low dose, administered weekly, 15mg for two weeks and then immunotherapy was administered. In the third cohort we gave low dose cyclophosphamide, simply a tablet a day, for two weeks. The fourth cohort two times cisplatin, relatively low dose, and the number five cohort was the control group, so immunotherapy only.
How did it go?
So far we have randomised 55 patients and for 50 cases we can have a read-out on efficacy. The response rate for all groups together was 25% and that’s, if you compare to other immune therapy trials in triple negative breast cancer, relatively high. So you would expect a response rate between 5-10% for this group and we go up to 25%. That is, of course, small numbers and the trial is not finished yet but it could be due that we first started out with an immune induction treatment. But then the question comes in is it simply immune induction that can downsize your tumour or is it really the immunogenic effect. That’s still a question we are working on in the lab.
What are the planned endpoints and follow-up for this trial?
The endpoints are the standard endpoints that are used for metastatic triple negative breast cancer, so response rate and survival. But since we really would like to study what the radiation and chemotherapy does bring to the table the trial is mainly based on translational endpoints. So a biopsy before radiation and a biopsy after radiation and the question is can you really increase the amount of immune cells. For example, CD8 cells, do they go up after this immune induction treatment?
When can we hope to start hearing more about the outcomes from the trial?
A good question. We are now finalising the stage I and that will take a couple more months and in the meantime we analyse the biopsies. So hopefully by the end of next year we will have more answers to the most important questions.