Understanding the Nature of a KRAS G12C Mutation in NSCLC

Expert oncologists Martin Dietrich, MD, PhD, and Joshua Sabari, MD, elucidate the emergence of KRAS G12C as a molecular marker in the setting of non–small cell lung cancer.


Joshua K. Sabari, MD: Hello and welcome to Approaches to the Treatment of non-small cell lung cancer harboring KRAS G12C Mutations. My name is Dr Joshua Sabari, I'm a thoracic medical oncologist at NYU Langone Health Perlmutter cancer center in New York. And I'm excited to have with me today Dr Martin Dietrich who's a thoracic medical oncologist at Florida Cancer Specialists & Research Institute. Welcome, Dr Dietrich. Why don't you jump in and start to open the discussion on where we are in targeted therapy non-small cell lung cancer particularly in the KRAS G12C space. It’s been many years in the making here, maybe walk us through what's happened over the last 30 years. And, unfortunately, not much.

Martin Dietrich, MD, PhD: Thank you, Josh, it's good to be here with you. And I'm looking forward to a good discussion. I'm excited about the things that have redefined non-small cell lung cancer. From the first additions of targeted therapies 20 years ago until today, really, subdivided lung cancer into so many specific algorithms of treatment defined by their genetic and immunophenotypic properties that it's changed upside down from chemotherapy-based approaches to targeted therapy for virtually every patient. This has been a great deal of progress. At the heart and center of it, for us, is obviously the molecular definition. The molecular characterization of disease, I believe, this is one of the most important steps for us. And probably the first, I want to say, rate limiting step for patients to be- to find on a molecular basis. And we've obviously refined not only the width of our targets but also the technology to do that. And obviously, now moving from single gene test into next generation sequencing and liquid based approaches to complement our classical tissue-based approaches help us define the individual subtypes. And, yeah, EGFR started our subtyping of lung cancer. But many additional types have been added including KRAS G12C which was always a big price to catch and not only in lung cancer but in many other sub types of other diseases as well. And I'm excited that we have the therapeutic options for this subtype, at least, in part available to our patients as well at this point.

Joshua K. Sabari, MD: Yes, it's interesting, EGFR, ALK, some of the other driver alterations, Martin, as you mentioned, we’ve come a long way in what we have for multiple therapeutics now, FDA approved, in those settings. Patients are living 3, 4 years on average, with this disease. Why has KRAS not been the same? Why is this a different driver alteration?

Martin Dietrich, MD, PhD: KRAS shares several unique properties. First, it's a very small molecule. It's a central switch with a great impact. But it differs in the biology from other oncogenic drivers by the absence of a tyrosine kinase. And by tyrosine kinase pockets and ATP-like binding structures, we did always have a very defined target in our molecular subtypes. KRAS never carried one of those. And the affinity of the substrate of GTP to KRAS is incredibly highest, it's not only a structural challenge but also an affinity challenge. And it required a refinement of our technologies to be able to establish targeted therapies that are able to inhibit KRAS specifically. We've only seen the beginning in this. But unfortunately, with some impact for our patients in that subtype.

Joshua K. Sabari, MD: Yes, before start talking about some of the therapeutics, I agree, I couldn't agree more. 30+ years of negative trials in the KRAS space. Why is KRAS G12C, that cysteine residue, why is that special? And what are some of the biology been about, how we're now able to target that specific residue? And when we talk about these drugs the next few minutes, I want to focus on KRAS G12C. What we're going to talk about may not apply, right, to other KRAS alterations here.

Martin Dietrich, MD, PhD: Yes. And we've just been starting to open clinical trials for other KRAS subtypes, G12D's the next big frontier and G5V and others we're looking at targeting. But the cysteine residue was a target with a small indentation on the protein that we were able to bind, lock in, and covalently bind for permanent inhibition. This was an enormous progress. If you think about a chain of amino acids, and with one amino acid change, both have shifting in size as well as it shifts in charge on the surface, the challenge couldn't have been greater. And the term “undruggable” applied here rightfully so. And it was probably coined towards KRAS for the longest time. We're very excited about having this opportunity now. This is helpful in permanently trapping KRAS. We're obviously facing a challenge of turnover of target reproduction and regeneration of KRAS molecules on the surface. We're not only looking at the depth of inhibition but also at a longitudinal inhibition that is important when KRAS is signaling. And it's such a central switch that all the attempts to target the surrounding downstream targets in the KRAS pathways have failed. They really never provided any additional positive results, so I think it was in the sum of results of downstream targeted inhibitions that you really needed to target the core driver here, which was KRAS. And for almost 2 years now and an option for our treatment.

Transcript edited for clarity.

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