AACR 2014

New antibody-drug conjugate shows early promise against all forms of melanoma

Dr Jeffrey Infante - Tennessee Oncology, Nashville, USA

Can you tell us more about your findings surrounding antibodies and melanoma?

This is a first in human trial looking at a new antibody-drug conjugate for melanoma. So it’s an antibody that targets ETBR, or endothelin-B receptor, and targeting the endothelin-B receptor by itself with an antibody is not predicted to cause anti-cancer benefit or it’s not going to cause the cancer cells to die. But the fact that this is preferentially expressed on over half the patients with melanoma, it creates a target potentially that we could use with an antibody-drug conjugate that carries chemo on the back of it that you could then infuse this antibody-drug conjugate into the blood. The way these antibody-drug conjugates are developed are that the tips of the antibody, they’re Y-shaped molecules, are coded specifically for, in this case, ETBR, for expression of that which should be preferentially expressed only on melanoma cells. The antibody-drug conjugate would travel through the blood, it has chemo on the back of it.

So the idea of these antibody-drug conjugates are that you’re attaching a very potent chemotherapy that normally couldn’t be given intravenously and these are actually very old drugs that have been around for 25-30 years but that are too toxic when they’re given regularly as an IV infusion. But if you tack it to the back of an antibody they remain inactive. The idea is that it will travel through the blood looking specifically for the receptor carrying the inactive chemo. Then once it binds to the receptor it has to get internalised. Once it gets internalised that complex will be broken down and that’s part of the biology of how the linker releases the chemo and then once it’s released off the antibody inside the cell it releases the active chemotherapy directly inside the cancer cell.

What about companion diagnostics?

When you’re thinking about developing antibody-drug conjugates, one of the most important parts of that is to develop a companion diagnostic so you can see or predict what patients are likely to have expression of the target that you’re trying to deliver the drug to. So in this case what we were trying to do is look at patients’ tumour specimens and stain them for ETBR and see if that would eventually correlate with the patients that were getting benefit. So the hypothesis would be that if you had a high expression of ETBR in your cancer then we could predict that you would be more likely because that’s what the drug is targeting and delivering more chemotherapy per se to those cells.

What about adverse effects?

This is an early clinical trial. We treated 28 patients across multiple dose levels and on 24 of the patients we have what we would call radiographic responses where you have scans before going on the study and scans at least at the first tumour assessment which is six weeks. We also have IHC data for the companion diagnostic on that and there’s a trend that if you are someone whose tumour expresses ETBR, overexpresses or has a higher rate of expression of ETBR, that those are the patients that are the ones that are most likely to gain the clinical benefit. But it’s early, the numbers are small. The study did do an expansion of 24 extra melanoma patients and we need to make sure that that is correct.

What’s the next step for this study after the expansion phase?

When we give the antibody drug conjugate we think that the primary toxicities are related to the chemo on the back of it, that some of the chemo eventually gets out into the bloodstream. Either it came off before it got into the cancer cell and became active or once it destroys the cancer cell it releases some of the active chemo into the bloodstream. So there are inherent toxicities to these, the most common issue that we deal with in the clinic is fatigue, in this trial it’s always grade 1/2, we did not have any grade 3/4 fatigue but fatigue is an issue for patients. That being said, we’ve had patients on for over two years at this point so it seems that there are some patients that it is a very good drug and it’s tolerable. Other toxicities include hair loss which could be due to the way the drug targets the skin or melanoma, but also because the parent chemo causes hair loss so we don’t really know for sure. Then other GI side effects like diarrhoea and nausea can happen and then, particularly for patients that are on for multiple cycles, neuropathy becomes an issue, so that’s numbness and tingling in the fingers and toes. That’s mainly due to the payload which has the chemo on the back of it and that’s a known toxicity of those class of drugs. So over time about 30% of our patients developed peripheral neuropathy. Most of the time, though, if you looked at all the side effects almost everything is grade 1/2, the grade 3 changes that we’ve seen were neuropathy or neutropenia but that can tend to be manageable in the clinic and doesn’t change the dosing.

Could this be useful for ocular melanoma?

One of the interesting parts of the study was that it included patients with cutaneous melanoma, which are the most common, but also allowed patients that had mucosal or ocular melanoma. There were three patients with mucosal melanoma and eight patients with ocular melanoma. We had clinical benefit which would be either a partial response or someone that stayed on study for six months and maybe had minor radiographic changes but not enough to meet the criteria of partial response but was able to stay on the treatment and hold their tumour at bay. We had evidence of that in both those subtypes of melanoma and that’s kind of an unmet need right now in oncology for both mucosal melanoma and ocular melanoma.

What’s the next step for this study after the expansion phase?

The results from the escalation look very encouraging. I think what we would say is it would be proof of concept, that we showed that we can give the drug safely. When we give the drug we can measure levels of it in the body and it’s behaving the way we expect it to and people can tolerate it and stay on it very long. Then we also had what would be most important is that patients that were doing well from it and their tumours were either shrinking or stable and could stay on it a long time. But it was only 28 patients and we treated patients across multiple dose levels. So now that we have the recommended dose there’s an expansion of 24 patients to try to confirm that the tolerability is as good as what we saw initially and also that we’re seeing the clinical activity. Then, based on that, we’ll make a decision whether to go further in all melanoma or cutaneous melanoma or ocular or mucosal melanoma.