The main reason for doing this research was that the first generation BRAF inhibitors such as vemurafenib, dabrafenib or encorafenib are effective only in a limited number of BRAF alterations which are called BRAF V600 mutations. They are ineffective in other activating mutations of the BRAF. In addition, paradoxical activation of the MAP kinase pathway which frequently happens when you use first generation BRAF inhibitors is often a reason for therapeutic resistance. PLX8394 doesn’t actually have these disadvantages. The mechanism of action of PLX8394 makes it effective not only against BRAF V600 mutations which signals the so-called isomonomer but also actually has an effect on dimeric signalling through BRAF and therefore can be effective also in other BRAF alterations and also prevents deactivation of the MAP kinase pathway.
Was there any specific assay/testing kit used in this study and what was the methodology for this study?
This one was a fairly typical phase I study which used the dose escalation design to determine the recommended dose for the first clinical testing group, the recommended phase II dose if you will. I don’t think there was necessarily anything specific. What was interesting about this study was that initially when we used PLX8394 by itself the exposure levels, which means concentration in the blood, wasn’t actually as high as needed for optimal efficacy. So actually we had to take a step back and we actually ultimately added another drug which is called cobicistat. Cobicistat is not an anti-tumour drug but it’s actually a drug which interferes with the metabolism of PLX8394 and by slowing down the metabolism of PLX8394 it helped us actually to achieve higher concentration levels which ultimately resulted in better efficacy. That was one of the main things which distinguished that from most of the other early phase clinical studies.
What were the key results obtained from this study?
Initially we enrolled patients in a relatively unselected fashion but very soon we realised that this drug has only efficacy, as expected, or most efficacy in patients with BRAF mutations or other BRAF alterations which result in the BRAF activation. So, as we presented as a recent EORTC NCI AACR meeting, were actually data on 45 patients with a variety of BRAF alterations. 82% of these patients had a BRAF V600 mutation which is the one for which you can use also the first generation BRAF inhibitors but 18% actually had non-V600 BRAF alterations. Actually, our best patient in the study with the most response was actually a patient with BRAF fusion which would fall into the bucket of non-V600 BRAF alterations.
We have seen actually quite a lot of responses for early phase clinical development. We saw ten partial responses, which is about 22% in the dataset which I presented at the meeting. Also there were about ten patients which somewhat overlap with the responding patients, although not 100%, so there were ten patients who remained on the study for more than 34 months which is actually, again, for early phase clinical research it’s quite impressive. The typical time on therapy is usually just a few months in early phase clinical research.
We’ve seen responses across multiple cancer types, including cancers which are very hard to treat such as brain cancers, gliomas, in low grade serous ovarian cancer, in papillary thyroid cancer and small bowel colorectal cancer, anaplastic thyroid cancer and melanoma, as I just pointed out. Also, one thing which needs to be mentioned because PLX8394 doesn’t result in this paradoxical activation of the MAP kinase pathway as a consequence of BRAF blockade which is different to first generation BRAF inhibitors, it also actually has some favourable consequences for the safety profile. So first generation BRAF inhibitors can result in skin toxicity such as actinic keratosis or even cutaneous squamous cell cancer in rather a large percentage of patients which is somewhere between 10-20%. PLX8394 which doesn’t result in the paradoxical activation of the MAP kinase pathway does not actually have this unpleasant side effect.
In fact, the adverse event profile or safety profile of PLX8394 is actually very favourable. The severe toxicities were quite infrequent and the only significant AEs which we have seen were elevation of liver enzymes, of bilirubin, which however were present in less than 5% of patients. So that’s actually for targeted therapy also quite a favourable safety profile.
What impact can the results from this study have on the future of cancer treatment?
It’s clearly an effective drug which deserves to be explored further but at the same time we have to admit that this is a phase I dose escalation study so even though the results are promising there is a lot of work which needs to be done.
Some of the data which we analysed from the patients who have been enrolled so far suggests that the quality of response can be actually proportionally related to the dose, if you will. So because the medicine is actually quite well tolerated we would like to explore whether we can actually go even to a higher dose than we identified so far. The doses which we have been using up to now are clearly effective but, again, the question is if we go higher do we actually get more efficacy than we have even now.
So that will be the first step. Once we actually get beyond that, which probably won’t take too long, then we will be looking at further development in specific indications in patients with this BRAF V600 and non-V600 mutations.
