Targeting KRAS Mutations: A Novel Approach in Advanced NSCLC - Episode 2

KRAS Mutations in Solid Tumors

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Alexander Drilon, MD: RAS is an important proto-oncogene. In fact, there are 3 different types: KRAS, HRAS, and NRAS. For lung cancer in particular, we’ve known that KRAS hot spot mutations have existed since the late 1990s, and this was prior to the discovery of EGFR, ALK, RET, ROS, etc. We know that KRAS, in terms of its normal biology, functions as a sensor that integrates external stimuli in the wild-type state and then transduces those stimuli to the inside of the cell, thereby mediating processes such as cell growth and migration.

We also know that KRAS, in particular, can cycle between 2 different states: the on state, or the active confirmation, and the off state, or inactive confirmation. That cycling is mediated in part by binding to molecules such as GTP when the protein shuffles between these different states.

Paul Bunn, MD: There are certain molecular alterations that drive cancer, and our belief is that those molecular alterations occur at the very earliest onset of the disease. Therefore, essentially, all the cancer cells have the same molecular alteration.

Of those molecular alterations, the most frequent ones are KRAS, and these are thought to be driver oncogenes, where all the cells have those particular KRAS mutations. Therefore, they are potentially susceptible to treatment aimed at those particular alterations.

For every molecular alteration, there may be 1 or more than 1 molecular alteration that’s a driver. For example, EGFR and most common molecular alterations are deletion 19 and a coin mutation that’s now L858R, but there are other molecular alterations in the EGFR family. In a similar way, there is more than 1 KRAS mutation that can drive the tumor. The most common is what we call KRAS G12C, but there are also KRAS G12B and other KRAS G12 mutations. Then there are KRAS mutations in other places, such as Q61. But the most common are G12C. The first specific KRAS treatments that have been devised thus far are for KRAS G12C.

Some lung cancers, even the most common, have this glycine substitution at G12C, and if one does any specific KRAS mutation analysis or any next-generation sequencing analysis, one will find which KRAS mutation they are, and whether a G12C is present or not. Again, this is really important because just like an EGFR, it may be that there are different drugs for different mutations. In KRAS, as far as we know, the prognosis is fairly similar across different KRAS mutations, but the treatments may be completely different.

For KRAS, it may be that for KRAS G12B will have different drugs from what we will have for G12C. In fact, it’s highly unlikely. But if you have a KRAS G12C mutation, all the cells will have that, and 1 treatment will likely be effective. Maybe that will be combinations in the future for that resistance. We don’t know how resistance is going to occur, but it’s highly likely that a specific treatment won’t kill all the cells, even though all the cells have that alteration.

Jonathan Riess, MD, MS: In terms of the frequency of KRAS mutations and, in particular, KRAS G12C, where there are a lot of exciting direct inhibitors in development, KRAS mutations constitute about 25% of all solid tumors on average. That’s the same in lung adenocarcinoma. About half of those mutations, about 13%, have the KRAS G12C amino acid substitution. To put that in context of newly diagnosed non–small cell lung cancer, there are about 228,000 new diagnoses of lung cancer per year estimated in the United States, the majority of those with metastatic disease. We’re looking at tens of thousands of patients per year who can be impacted by these direct KRAS inhibitor treatments. In terms of looking at that piece of pie of oncogene-driven subsets of non–small cell lung cancer, it’s probably the largest piece of pie that we could target. It’s exciting that we now have KRAS inhibitors in development in clinical trials to address this large unmet need.

In terms of KRAS mutations and other solid tumor types, the KRAS mutations constitute about a quarter of all mutations across solid tumors. It’s frequently encountered in multiple cancer subtypes, such as colorectal cancer, pancreatic cancer, and others. The frequency between G12C and other KRAS amino acid substitutions and that proportion varies by tumor type. But KRAS mutations are encountered commonly throughout a broad spectrum of solid tumors.

Transcript Edited for Clarity