You’ve been looking at patients with clear cell renal carcinoma, what were you trying to do? What were you trying to investigate right here?

We know from what has previously been shown and for medications that are presently approved for advanced clear cell kidney cancer that these tumours are highly sensitive to antiangiogenic therapy. We know that the biology of clear cell type renal cell cancer largely depends on tumour angiogenesis. The agents that are presently approved and target tumour blood vessel growth all do so by inhibiting one molecular pathway signalling through the vascular endothelial growth factor, VEGF. On this trial we are adding a second agent that blocks vascular growth through a different pathway, the ALK1 pathway, which is a pathway that is important for blood vessel growth in a later stage, stability maturation of blood vessels once induced by VEGF. So we are targeting the same problem from two different angles.

So could you tell me what you did in the study?

In this study which is composed of two parts we paired axitinib, an approved targeted agent that blocks VEGF receptor 2, with a novel compound called dalantercept which is a fusion protein that traps the ligands to a protein called ALK1. These two agents are both antiangiogenic drugs but they block neovasculature in tumour cells in two different stages of angiogenesis. In the first part of the study we combined these two study medications at different dose levels to determine safety and identify the optimal dose. In the second study part, which recently opened to accrual, we are now comparing the standard medication, axitinib, plus the investigational agent dalantercept to standard agent axitinib plus placebo to tease out what exactly the benefit is of adding that second agent to standard therapy.

Dalantercept is different from the other antiangiogenics, isn’t it?

Yes. It’s very important to note that all of the five agents that are presently approved for the treatment of metastatic kidney cancer that block angiogenesis do so by targeting VEGF, the vascular endothelial growth factor. Dalantercept, the investigational agent that we’re testing on this trial, blocks angiogenesis in a later stage through a different pathway, the so-called ALK1 pathway, the activin-like receptor 1 kinase pathway.

So what did you do in the study that you’re now reporting?

The piece that we are reporting is the dose escalating phase I portion of the study, the first part of the study where we are, for the first time, combining axitinib, which is an approved VEGF tyrosine kinase inhibitor, with dalantercept, the new ALK1 directed angiogenesis inhibitor. We are testing this combination or we have tested this combination at three different dose levels and we have defined the safe dose level to move forward into the second piece of the trial which is now ongoing and randomises patients between axitinib plus placebo versus axitinib plus dalantercept.

So you are into phase II, have you got a signal on efficacy?

Correct. So we have a signal on safety, which was the main purpose of part 1 but of course we also have an early efficacy signal which turns out to be very promising. We do see higher response rates than what we might expect from historical controls and the median progression free survival with the combination, which is early data at this point, for a limited number of patients is very promising.

What could be the advantages of targeting the ALK1 pathway as well as the VEGF pathways?

The advantage is a more complete interruption of tumour angiogenesis. We think that we can prevent the development of treatment resistance, at least to an extent, and there are preclinical models that suggest that adding ALK1 inhibitors to VEGF inhibitors is more effective than just using either of the two alone in RCC models.

Of course at the moment you can’t try the ALK1 inhibition alone, you need to do it in combination with the trusted therapy.

I think it’s likely more effective to do it in combination so that was the strategy from the get-go. Would it have been possible to do a monotherapy trial? Possibly, but the whole point behind doing the study is to improve upon the current standard and the belief is that to improve upon the current standard we need combination therapies. Combinations that have been tested in the past have been far too toxic and I think the great benefit to this trial, as we’ve learned in part one, is that these medications pair very well together.

So could you run me through the toxicities? It’s a question of managing them and are they manageable.

What’s very important is that the toxicity profile for each of these two agents alone are non-overlapping. So the toxicities that are typically dose limiting for VEGF targeted agents such as hand-foot syndrome, hypertension, proteinuria, were not observed on the phase I single agent study for dalantercept that was done in other tumours. The toxicity profile for dalantercept, and that is something we again saw in this trial here, includes anaemia and fluid retention events. Those were dose dependent but all low grade in incidence, grade 1, grade 2.

You’re getting a signal on efficacy, how big a signal?

The signal that we’re getting is difficult to interpret given the number of patients that we have. The overall response rates across all patients treated on part 1, that includes the ones treated at the lowest dose levels, is 25%. It’s important to note that most of the patients on this study are heavily pre-treated, so 60% of the study population had two or more prior lines of therapy. So if you use that information and put the response rates into perspective with other trials that we have seen, for instance the [?? 6:01] trial which is a phase III trial in the third line setting where the response rate for sorafenib or dovitinib was less than 5%, then the responses north of 20% that we are seeing now are certainly very encouraging.

So what does this mean to busy cancer doctors today?

What this means is that this study is now available across thirty centres already, actively accruing, and will be active at about fifty centres, that’s the goal. It also means that it is a study that I think is of high interest to our patients. Every single patient going on this randomised placebo-controlled trial will receive standard axitinib, no-one is going to receive less than the standard of care. 50% of patients going onto part 2 of this trial in addition to their standard axitinib will receive dalantercept and the signal that we’re getting from part 1 is that there’s a good chance they will derive additional benefit from the combination.

So do you see a promising future for extending antiangiogenesis?

I would say that we’re certainly very excited about part 2 of this study because we have been positively surprised by part 1. I’m a firm believer in using RCC biology as guidance to what we do in drug development. We know that over 90% of cancers in the clear cell RCC spectrum are dependent on angiogenesis through loss of VHL so I think for this disease this combination is highly relevant.