DNA damage response inhibition

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Published: 4 Jul 2017
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Dr Giorgio Massimini - Vice President, Head of Early Clinical Oncology, Merck, Darmstadt, Germany

Dr Massimini speaks with ecancer at WIN 2017 about novel drugs suitable as monotherapy or in combination to inhibit DNA repair pathways in tumours.

He highlights VX970 / M6620, a novel drug affecting the ATR kinase pathway of DNA repair, as well as M3814 which is currently in assessment combined with radiotherapy, and considers class-associated toxicities of DNA repair pathway inhibition.


It’s essentially a new target that is coming out from the Vertex pipeline. We acquired the pipeline in January as Merck and now we are working diligently with the Vertex colleagues to transfer the entire portfolio to our development. It’s definitely a very interesting target; it might have activity as a monotherapy, as a drug, VX970, which now is called M6620, so you have to use that number from now on just to complicate a bit matters. But, as I said, it can be active as a monotherapy in a selected tumour where the tumour is completely dependent from the ATR. Even more importantly, it is active in combination with chemotherapy and potentially radiotherapy and other types of therapy at this time.

We already have data that has been shown today indicating that in combination with chemo you can induce responses in patients that are resistant to chemotherapy as well as in selected tumours with defects that are sensitive to ATR. So for us it’s a very good asset that we are trying to push forward and we hope to be able to give it to patients pretty soon in order to help especially these late stage patients that are really in need of further treatment.

M3814 is a DNA PK inhibitor. It’s another part of the DNA repair system that is targeted in this case. We are developing in combination with radiotherapy and also with chemotherapy at present a drug in phase I showing a good tolerability profile and we are still dose escalating in terms of a combination with radiotherapy. We chose that particular approach and people keep forgetting that 50% of the cancer patients will receive radiotherapy and many of them will be cured by radiotherapy. If you are able to increase the cure rate of radiotherapy by including M3814 it will be a major advantage because it will increase the cure rate of patients and at least 25% of the patients that we see right now are metastatic so it will become metastatic at a certain point. If we reduce these numbers it will be a great bonus for them, for the patients, for us and for society.

Can you tell us about the biological background and the future for DNA repair as a target?

Biologically it’s extremely interesting because we always try to eat the DNA of the tumour. In fact, if you look back to most of the cytotoxics that we have used in the past they were either intercalating with the DNA like platinum or they were interacting with the DNA. What we have now is a better understanding of the DNA repair so we are moving from damaging the DNA to blocking the repair of the DNA which may be a more effective and less toxic way to get a similar result.

Is there a risk of toxicity if left untargeted?

That is still to be determined because this is not a single agent treatment unless you have a tumour that has a mutation that is specifically sensitive to this blockade. In this case we already have shown that the tolerability is acceptable and so far the number of patients are limited but nevertheless we haven’t seen anything dramatic in terms of side effects. In combination with chemotherapy it’s basically uncharted ground for the time being for DNA PK inhibition. For the ATR inhibition we already have some data and it seems tolerable.