New RAF-targeted therapeutic shows early promise against tumours with BRAF and RAS mutations
Dr Jayesh Desai - Royal Melbourne Hospital, Melbourne, Australia
We’ve conducted a phase Ia trial, it’s a first in human trial, with a new compound known as BGB283. BGB283 is essentially a RAF-dimer inhibitor so it targets both BRAF mutations, V600E mutations that are well known, as well as potentially non-V600 mutations. It hopefully will serve by being a RAF-dimer inhibitor as a downstream pathway inhibitor for RAS mutations.
The other effect that this compound has as well is that it is an EGFR inhibitor as well. This may be of particular interest and relevance in colorectal cancer with BRAF mutations where we know that EGFR is thought to be the key escape pathway that occurs with first generation BRAF inhibition.
What did you find?
So far in this trial in which we treated 31 patients in escalating doses, so a typical phase Ia study, quite a heterogeneous group of patients encompassing different tumour types. However, all patients were molecularly pre-selected for having either a RAF or BRAF mutation. In terms of clinical data, in terms of efficacy, we have seen some on-target responses including a patient with a BRAF V600E melanoma as well as a patient with a thyroid cancer with a BRAF V600E mutation. Both patients have had prolonged responses, the melanoma patient in fact has had a complete response. Interestingly, we also have seen some activity in RAS mutant tumours, a patient with a KRAS mutant endometrial cancer has had a partial response that was sustained for about a year and a half. We also had another patient with an endometrial cancer who has been on study for about a year and a half who has had a minor response, so not quite a partial response. In addition there has been a patient with non-small cell lung cancer with a KRAS mutation who has had a non-confirmed partial response but this patient is also still on study and has been on study for over a year. We also have seen stable disease in other patients with both RAS mutations, BRAF V600E mutations and also some patients with non-V600E mutations as well.
What was your method of treatment?
In this trial we’ve just used BGB283 as a single agent, the objective of the trial was to define the maximum tolerated dose and to assess early safety and also to assess pharmacokinetics as well. What we’re able to show is that we have a maximum tolerated dose that has been defined as 40mg/day given on a daily basis. The recommended phase II dose is 30mg/day and this is based on the cleanest safety profile at that dose and also efficacy that we’ve seen at that dose level as well. So that has now moved into a large phase Ib trial which is ongoing. In this trial we have ten different arms which represent tumour types and molecular subtypes covering both RAS and BRAF mutations to hopefully give us a clearer sense of whether we will see activity in particular tumour types that are driven via those particular pathways.
What is the long term impact?
In terms of thinking of what the long-term impact with this drug may be the key actually is to better understand RAS and RAF biology in particular tumour types. Already it’s quite clear that RAS mutations can have a different effect depending on what cancer type they actually exist in. So tumour context is particularly important and it’s quite clear that where you have RAS mutations that exist in a tumour type where the signalling may not, in fact, occur clearly downstream that targeting a downstream pathway may not, in fact, lead to much benefit. There are certainly some tumour types where the expectation is that that signalling pathway will be more linear and downstream and therefore if you can effectively target downstream you’re more likely to see activity. I suspect that that is what we are likely to see so the phase Ib study will be important in giving us some early hints on whether we will see efficacy in particular tumour types and perhaps may not see efficacy in others. Time will tell.
Clearly one approach here is in being able to try and target particular pathways. The other key point to make, which you have brought up in relation to the use of genomics and other tools, is to get a better understanding of the signalling networks that may occur. So, as I’ve said, if RAS does signal in a fairly linear manner downstream in some tumour types we may expect to see activity. But clearly there will be some tumours in which that does not occur. Being able to understand that, understand the context of that, is going to be particularly important and that is something that we’ll need to continue to try and explore further.
What about toxicity?
Clearly one of the key endpoints of this phase Ia study was to look at tolerability. BGB283 was well tolerated overall. The maximum tolerated dose was 40mg/day, the dose limiting toxicities at 40mg and above were thrombocytopenia. What we found, though, was at a lower dose, at the recommended phase II dose at 30mg/day this was less of an issue and we certainly believe that we can take the drug forward. In terms of longer term tolerability there are a number of patients in this trial that have received drug for at least six months and, in fact, a number have received drug for at least twelve months. It does look like we can deliver the drug safely and in a tolerable way over a longer period of time but, again, time will tell as we conduct further studies with larger populations of patients.
What is your take home message?
For my perspective this trial has been completed successfully. Certainly this is an agent that appears to have on target effects, it’s well tolerated. We have a recommended phase II dose to take forward. The expanded phase Ib study will give us some insights into what tumour types we might expect to see activity in and then understanding the context in an individual patient is going to be critically important. So we will know that by selectively targeting particular kinases we may ultimately see a beneficial effect.