Drs. Banerji and Pachter Talk About RAF/MEK Inhibitor in RAS Mutant Tumors

Udai Banerji, Professor of Molecular Cancer Pharmacology at The Institute of Cancer Research, London, and Honorary Consultant in Medical Oncology, MBBS, MD, DNB, PhD, FRCP at The Royal Marsden NHS Foundation Trust, London, and Jonathan Pachter, PhD, Chief Scientific Officer at Verastem, talk about a study published in Lancet Oncology that found VS-6766, a unique inhibitor of the RAF/MEK signaling pathway, from Verastem Oncology, with a specific dosing regimen of 4 mg twice weekly, is tolerable and shows antitumor activity in patients with RAS mutant tumors.

Dr. Banerji: This is a report for a first in-human study of a drug VS-6766. It’s an unusual drug because it inhibits MEK … but also functionally inhibits the signaling from RAF to MEK, which is not present in a lot of MEK inhibitors. And the other very interesting part of this trial was the fact that it’s given intermittently, only twice a week, so the mechanisms are very rarely or in fact to my knowledge have not been those in such an intermittent fashion before.

Probably the most important part of the trial is the fact that we have seen clinical responses, which have been durable in patients with KRAS mutation, but it’s a huge area of unmet need and we hope this is the beginning of a set of clinical trials that will benefit patients in the future.

DocWire News: What are the most common questions your colleagues ask you about this study?

Dr. Banerji: The first question people ask us is that what tumor types have you seen the responses in? All oncologists want to help their patients and that’s the first thing they ask. “Why haven’t we heard of this before?,” “What indications does this drug work?” Clinically, what we’ve seen so far is KRAS mutant cancers [are an] area that need … some good news about the certain drugs which inhibit specific types of KRAS mutations, G12C mutations, so there’s a lot of academic literature now emerging.

However, what is very interesting in this clinical trial is that we’ve seen response in KRAS mutations which are not G12C. That’s still a large number of patients. That’s the first aspect. The second aspect in the tumor types we’ve seen in this particular trial that we’ve reported, we saw responses in patients with KRAS mutant lung cancer. Again, in patients who have, we did not. We also saw responses of patients with gynecological cancers, which typically with RAS mutations are low-grade serous ovarian cancers, but also endometrial cancers or endometrial ovarian cancers.

In this study, we’ve even seen responses rather unusually in multiple myeloma, but again, with RAS mutations. In addition to these solid tumors and KRAS mutations, we’ve also seen response in a patient with an HRAS mutation, which is a rare mutation. However, again, there are no targeted clinical drugs against these.

DocWire News: Will this data affects clinicians today? And if so, how?

Dr. Banerji: With this drug it has been very important to get to a tolerable dose which can be used as a single agent and in combination in the future, so that was the main aim of this particular study; it’s a phase one study. Of course, [the] icing on the cake is lots of patients that respond to them are very, very happy about that. But it has set the backbone of combination studies and single-agent studies.

I think for doctors, we more widely will need further studies, which are phase two and hopefully one day phase three studies, which are currently planned. So I can ask [Dr. Pachter] to update you on what studies are planned, but currently we have a few studies which are still cementing what we’ve seen so far in combination. However, for larger phase studies, we’ll need to open before patients and doctors have access to this more freely.

Dr. Pachter: Some of the signals from them commenting on the single-agent study that was just reported in Lancet Oncology, and also the combination with our FAK inhibitor, clearly in both studies we’re seeing exciting activity in low-grade serious ovarian cancer, which tends to be a RAS driven subset of ovarian cancer, as well as lung cancer, especially with KRAS G12V mutation. So based on Dr. Banerji’s work, Verastem is starting registration directed trials. The intent is to start them this year, one in low-grade serious ovarian cancer, which we’ve discussed with the FDA, and also in KRAS G12V mutant lung cancer.

We’re very excited about these as potentially leading to registration of VS-6766 alone, and we’re also testing it in combination with our FAK inhibitor and then we’ll determine which is the regimen to go forward with. Very importantly, we’re using this intermittent dosing schedule that Dr. Banerji mentioned and we think it’s really important here for having both activity [and] tolerability. That’s really key in this field. In addition, just briefly, Dr. Banerji is starting cohorts in other KRAS-driven diseases, pancreatic cancer, KRAS mutant, to see what VS-6766 as well as the FAK inhibitor combination do in those diseases.

DocWire News: My last question here was, “What is the next step for this research?,” but we just dovetailed right into that, which worked out really well, so I’m just going to end with, if either of you have any last closing comments to make.

Dr. Pachter: In the RAS pathway field is the need for what’s called vertical inhibition. So if you picture RAS-RAF-MEK-ERK as the pathway, what people are finding is you need to block more than one of those targets at the same time for durable inhibition, for benefit for patients. What we believe is that 6766, by hitting RAF and MEK, is probably the only drug that we know of that can do that in one molecule.

That really enables a potential to be a backbone for therapies for the RAS-driven cancers, but also it opens up the door to other [therapies], and Dr. Banerji can talk about what he’s doing with an mTOR inhibitor, but we’re also looking potentially at other combinations as well for RAS-driven cancers, and our hope is that there could be different combinations for different cancers where VS-6766 is in the middle of all of that.

Dr. Banerji: Just to add to that, scientifically, MEK is a very important node itself, and as an activating mutation, so is KRAS, so there are multiple downstream pathways and upstream pathways if there are feedback loops.

Also, one of my areas of research being feedback loops in proteomic mechanisms or plastic mechanisms of resistance to mechanism that certainly the pediatry kind is pathway is an important one.

I think there are multiple places a drug could be used. Before the surface, in terms of other RAS mutant cancers, or even hematological malignancies like myelom. But you have to pursue these logically, so we’re doing one step at a time.

It’s for patient benefits. I’ll be happy of any form of further academic input and collaboration.

DocWire News: This was a really wonderful interview, and I think this will make a really nice video. So thank you all so much for your time.