Ras GTPase

Sure.

So the new drug is called Deroxanracib, and it is a pan-RAS inhibitor.

And what does that mean? RAS, or specifically KRAS, is a protein that is present in all pancreatic cancer, almost all pancreatic cancers.

And it's a gene that causes the cancer to grow.

I'm your host, Ayla Ellison.

Revolution Medicines recently made history with the approval of Deraxan Razib, its RAS inhibitor for advanced pancreatic cancer.

But RevMed is far from the only biotech trying to crack RAS.

In this week's episode of The Top Line, Fierce Biotech's Darren and Corvaya sits down with Veristem Oncology CEO Dan Patterson and Chief Scientific Officer Jonathan Pachter to talk about what the approval means for the field and how Veristem is working to push RAS inhibition even further.

Let's get into it.

Dan, John, thank you so much for joining me on The Top Line.

It's a big leap forward, probably the biggest advance in pancreatic cancer in 20 plus years.

I think what it means for the field more broadly, it's proven that this approach works.

So they're GTPase off-state inhibitors, where they lock the mechanism in the off-state to prevent signaling and oncogenesis.

You also then have RAS-on inhibitors, You also have pan-RAS-on inhibitors.

So an on inhibitor simply locks RAS in the on state, leading to similar sort of cell death and prevention of signaling in this patient population.

Remember, it's this constant sort of back and forth between the on and off state.

No, I agree with Solange on that.

I agree that by using a mutant selective inhibitor, you see less toxicity in general.

But you can imagine that if you have a sort of multiple or poly, you know, sort of heterogeneous resistance mechanism, you may want to consider a RAS-on inhibitor.

We also were involved in the Deroxon RACIB RMC6236 Phase 1, and we did see some activity post the earlier generation KRAS G12C inhibitors, specifically in escalation.

I mean, everybody knew, but sort of one of the pioneers of the research.

of the pancreatic research world specifically, but also obviously I think your interest is more focused on the idea of RAS and KRAS.

So I would love to just have you sort of introduce yourself broadly.

I kind of gave you a little heads up, but if you wanted to sort of let any listeners know sort of other facets about who you are on your work before we get started, I'd love to hear it.

Thank you.

I'm Frank McCormick.

I'm a professor at UCSF where I have a lab working on different aspects of RAS signaling, but I also oversee the RAS National Initiative at Frederick, Maryland, where I've been overseeing this big project to target KRAS since 2013 when we launched the project.

I've been trying to target RAS proteins or KRAS proteins in particular for a very long time.

His research focuses on designing approaches for early detection and studying novel therapeutics for pancreatic cancer.

He and his research team have been at the forefront of studying RAS inhibitors in the laboratory and in the clinic, so he is a great authority to help us understand where we are today with this development.

Welcome, Dr. Wolpin.

Well, thank you.

And the data from the clinical trial, which we'll talk some more about, really showed that it benefits patients both in terms of quality of life, but also how long they're able to live with their cancer.

So I think the first and foremost thing that this approval does is it provides now broad access to a medicine we have seen that is effective in patients with pancreatic cancer.

I think the second thing is it really shows the field, the importance of targeting RAS.

As you said at the beginning, that is a very important gene that drives pancreatic cancer.

various variants and mutations within a specific type of gene.

I'll dig into it further, but those are the two main things that really make this different from some of the other targeted therapies that have been investigated over the years is that it is almost doubling survival for patients and it is a multi-selective inhibitor, meaning that it's targeting various kinds of RAS mutations.

which I can describe a little further too.

Yeah, you'll have to because I think a lot of people ask a lot about that and it's going to get over the confusion.

But so it's not considered a chemotherapy then?

No, it is not a chemotherapy.

Serexon Rassive is an investigational targeted therapy that's actually a pill and it's designed to shut down RAS, which is a protein that acts like an accelerator for cancer cell growth.

So the way that we describe it is like a gas pedal being stuck to a

And indeed, her two positive tumors is a rare but a highly talkable marker subtype requiring specialized biomarker-driven treatment pathways.

We have learned that HER2 amplification or overexpression is present in 3% to 5% of metastatic or rectal cancer patients and that it's most frequently in left-sided and RAS and BRAF white act tumors in this setting.

There is a general recommendation to test all patients with chemorefractory metastatic colorectal cancer for R2-positive.

But if for a reason testing should be limited to a certain subclinic, group of patients, left-sided tumors, left-sided and RASB-RAF-VADER tumors can be then the target population and testing can be restricted to this population.

The prognostic

significance of HER2 positivity remains controversial.

What should be done in HER2 positive patients with the EGFR antibodies? If you look further into some of the data that have been published, important data leading to the approval of tucathinib in some parts of the world, in the US by the FDA, was based on the Mountaineer study.

The Mountaineer study was a study in which tucathinib was studied, but also the combination of tucathinib and trastuzumab.