Transcript Related Guidelines

Targeting KRAS

Sandip P. Patel, MD · University of California at San Diego

Disclosures

September 21, 2021

Key Takeaways:

  • Kirsten RAt Sarcoma viral oncogene homologue (KRAS) mutations are common activating mutations found in various types of cancer 

  • The US Food and Drug Administration (FDA) has approved sotorasib, a KRAS G12C inhibitor, in the second-line treatment of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer

  • KRAS represents an important drug target, with a KRAS G12C inhibitor approved in non-small cell lung cancer and also currently being investigated in combination with other therapies

This transcript has been edited for clarity.

One of the areas of drug development that has been particularly promising for patients has been the development of inhibitors to KRAS, in particular, KRAS G12C.[1] This is a very specific mutation in a protein that historically has been thought to be undruggable.[2] Of course, now, we have one FDA-approved small molecule drug and one in the pipeline, which will likely be the floor, not the ceiling, of benefit that patients will receive as we try to better understand the ideal therapeutic combination.[3,4] One of the key aspects of KRAS G12C is the ability to be seen across multiple tumor types, so this is a mutation that is seen in non-small cell lung cancer, pancreatic cancer, and colorectal cancer.[1,2] We see different efficacy in different subgroups. 

The FDA approval for sotorasib, the KRAS G12C inhibitor, currently is in non-small cell lung cancer,[3] where the response rates are about 40% in patients who have previously received chemotherapy or chemoimmunotherapy.[5] One point to make about drugs like sotorasib, in particular, is that their absorption in the body is actually affected by the pH,[3] and so patients who are on acid suppressor pills should be told to separate those out from their ingestion of the targeted therapy in order to ensure adequate drug levels. 

Increasingly, as we look at the next best steps, we are going to see that combination therapy targeting KRAS G12C, in particular, will be important, and these are currently being tested in clinical trials.[6,7] I also think we're going to start to see small molecule inhibitors against other KRAS-specific isoforms, such as G12D, and in combination with other therapies as well. I think the future is bright for the targeting of KRAS. We need to take a step back and better understand the importance of molecular testing and to make a molecular diagnosis for these patients. It's not enough to test for one or two genes for the vast majority of patients, and in particular for patients with metastatic, non-squamous, non-small cell lung cancer where we'll soon probably have over a dozen targetable aberrations. The most efficient way is to test with next-generation sequencing, which can either be done on tissue or with a liquid biopsy in blood.[8,9] Increasingly, we're understanding that patients can benefit from these personalized approaches above and beyond just giving chemotherapy, which may not have any specific activity for a given patient. 

I think the testing aspect of KRAS is important and it can only really be done by DNA sequencing. It is important that panels contain this gene, but the other aspect is how we retain that information because the current approvals for sotorasib are the second-line space.[3] Making sure our electronic medical record documents the molecular profile, so that if the patient progresses after immunotherapy or chemoimmunotherapy, we remember that the patient's best therapy will be sotorasib or another KRAS-targeting agent in the second line is important. I think this is one of the key aspects to ensure that these test results are reflected in our care for these patients, and they are able to get access to these promising drugs. 

Another point about KRAS G12C in non-small lung cancer is it tends to be a mutation that is seen in former smokers.[10] So, now we have driver mutations for which we have targeted small molecules, both for patients who tend to have never-smoking disease, such as EGFR, ALK, ROS1, etc. But now, a mutation that can have a predilection for patients who have prior smoking history with KRAS G12C, it is important to test everyone, regardless of their smoking history, because we have effective agents for these therapies. 

KRAS G12C represents not only a scientific revelation in terms of drug design for targeting this pathway but also a new base for us to have combinatorial approaches to target KRAS G12C, as well as other KRAS isoforms.[2,6] I think the best is yet to come for these patients. So, this is the start, not the beginning of the KRAS story, but it's a very promising one. 

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