AACR 2016

Entrectinib, a novel treatment for TRK fusions, shows early promise against a range of cancer types

Dr Alexander Drilon - Memorial Sloan Kettering Cancer Center, New York, USA

The results that I presented, they represent updated results from two separate phase I trials of a drug called entrectinib which is an inhibitor of three different gene groups but actually five proteins altogether – TrkA, B and C, Ros1 and Alk. We presented combined both safety data and efficacy data for entrectinib. For the safety data it’s a large experience now in 119 patients treated on both trials and we showed that the drug was safe and well tolerated. There are really only two bad toxicities which we call dose limiting toxicities but the majority of the side effects are really lower level in terms of their severity, so grade 1 or 2. The most common ones were tiredness, a change in taste and also pins and needles, either around the mouth or we call them paraesthesias. 

But probably the more exciting portion of the presentation was the efficacy data and, just to frame that, it was really in a subpopulation of patients, so 25 patients altogether, that had gene rearrangements or gene fusions of any of the five genes NTRK1, 2 and 3, Ros1 or Alk.  These are patients who had not gotten targeted therapy before, that’s an important point. If you look at the effectiveness of entrectinib in all 25 patients about 80% of patients had a radiological response or RECIST response to therapy. So impressive results but, more importantly, if you frame them within the context of each of the three different groups, patients whose cancers had NTRK fusions, even though there were only five of them that I presented at the conference, all five of them benefitted from therapy clinically. So they had disease shrinkage and response via RECIST or a volumetric analysis in many of them. So the patients that I treated also had accompanying improvements in quality of life. So that was 100% in a small population.

For Ros1 the response rate was about 86% and for Alk the response rate was 57%. So if you look to the experience with FDA approved targeted therapies for Alk or Ros1, just to compare the response rate, it’s in the ballpark of about 60-70%, so comparable results to what we already have available for patients for Alk and Ros. But certainly the fact that these Trk fusions were able to find in patients and they benefit substantially for therapy, that to me probably represents the most exciting subset that we reported on in this series.

Do you see entrectinib being used as a stand-alone treatment or in combination?

A stand-alone treatment, absolutely. So for NTRK there is nobody in the space that has an FDA or an approved drug with any regulatory agency. So entrectinib stands to be a first line front line therapy for patients with really any advanced solid tumour that harbours an NTRK fusion. For the Ros1 space, like I mentioned, it really works best in patients who are treatment naïve, so again first line, and if you ask me how that compares to crizotinib the drug is much more effective at penetrating the blood-brain barrier so it’s highly CNS penetrant. The thought is that crizotinib, while it can get into the brain, doesn’t get into the brain as effectively so this may be a good first line Ros1 option, especially for patients who either have existing brain metastases or who have a high propensity to have brain metastases.

Then the Alk space is crowded, in the US there are three FDA approved therapies for Alk now. This drug seems to work best for patients who are treatment naïve. So, to me, the space for entrectinib will probably be in non-lung cancer patients that have an Alk fusion. So that’s where I see the drug going.

Are there any trials involving entrectinib?

There are a few lessons that we can learn from this experience. One, I would really advocate that we test for these fusions, specifically the NTRK ones because we have demonstrated that you can not only find them in patients’ tumours but now we have drugs that are active against these fusions plus, they’re available now on clinical trials. So, to answer your question, entrectinib is currently being explored in a phase II trial called STARTRK-2 that’s taking that same population, Alk, Ros1, NTRK fusion but TKI treatment naïve. So if you find these events, this is a global multicentre study, and there’s a centre that’s close to you then I would absolutely send that patient because there’s a high likelihood that the patient would benefit from treatment. So that’s where the drug is being explored now.

How do you see immunotherapy and targeted therapies relationship changing in the coming future?

We’ve learned that these populations of patients that benefit from either immune therapy or targeted therapy, there’s not a very huge intersection. So people think of immune therapy as a very exciting way or manner of approaching cancer therapy but, just speaking from the lung cancer experience, it seems like patients who are poised to benefit from an immune checkpoint inhibitor are patients who have a very strong or heavy history of smoking or those with a different alteration called the KRAS mutation. On the other hand, patients who benefit most from targeted therapy – EGFR, Alk, Ros – these are patients who have, in general, never smoking or minimal former smoking type lung cancers. So this pulls everything together into what we call precision medicine. It’s trying to figure out not just the best targeted therapy but the best therapy in general, be that immune therapy, targeted therapy, for a patient based on their characteristics.

Do you have a closing statement?

I think most of it I’d said already, that these drugs are in development and that they can benefit patients. So I would make a plea for oncologists to test for these events, preferably with a broad platform. But also a challenge that we’re going to have to face eventually is that now we’re dealing with smaller and smaller slices of the pie and so, from a regulatory perspective, at some point we have to entertain the fact that we might have to look at whether or not a targeted therapy can be approved for a particular target independent of what cancer the patient has. And that absolutely has to happen when you get down to 0.5%, 0.3% events, assuming that the targeted therapeutic works across a broad variety of different tumours.