Non–Small Cell Lung Cancer: Optimizing the Identification of KRAS G12C Mutations

Shared insight on best practices in non–small cell lung cancer management to utilize molecular testing and identify patients harboring KRAS G12C mutations.


Joshua K. Sabari, MD: KRAS mutations are quite common. KRAS broadly about 30% of our patients with non-small cell lung cancer. KRAS G12C makes up maybe about 12% of my population. We see this more commonly in those who have smoked in the past. It's interesting in patients who are younger female, and never smokers, it's uncommon to identify a KRAS G12C mutation. For example, in east Asia, in China, we may see a lower rate of KRAS G12C alterations than we may see here in the United States. It's important to understand your patient population. But Martin, how do you identify these alterations in clinic? What types of testing are we doing?

Martin Dietrich, MD, PhD: It's relatively easy to identify genetic alteration if we do the test. What we are really seeing is a paradigm shift that you mentioned already, Joshua, the classical patient population that we screened for oncogenic drivers are often geographically very distinct from the KRAS G12C populations, typically more rural, more men, older patients, smokers. Those were the searches for EGFR and ALK have typically been more disappointing. We must refocus on agnostic testing for every patient with non-small cell lung cancer. At the very least, with adenocarcinoma histology. But in my opinion, many of these mutations and many of the emerging biomarkers transcending histologies for actionable mutation. My impression is that we will move into an agnostic testing and not only in terms of histologies but also soon in terms of stage. We're seeing targeted therapies and immunotherapies moving into an earlier line setting from stage one essentially onward. We have approvals now for targeted therapies and in the adjuvant setting, certainly, approaches here for immunotherapies as well if properly matched genomically. And then, the neoadjuvant setting again, we need it from the very get go. The very first step in all decision making here, truly the molecular characterization. We have to reinvigorate the spirits that smokers are now a special area of interest, because they have a unique set of mutations. Not only KRAS, but BRAF, CMET and others that may be helpful for improving outcomes. What KRAS signifies is a biology that is more perturbed. And then, the backgrounds that we're seeing in EGFR and ALK, we have more secondary mutations, we have probably a high inflammatory background. And the, yeah, I want to say the targeted options for these patients probably a little bit more challenging, which in turn, signifies that there is an overlap with responses to immunotherapies which used to be mutually exclusive. But the first step regardless of our systemic therapy approaches this to get a molecular panel that includes all targetable mutations, not a good way of looking at histology or even the demographics of a patient and decide what mutations is going to be present. We will have to take the agnostic results as they come in. And in terms of testing, I think, we've seen a plateau of molecular testing on tissue. And for many reasons, I believe we're running into a tissue availability turnaround time issue.The true proper sequence of having results available at the time of diagnosis followed by a treatment decision often times interfered with many different mechanisms. And I believe liquid biopsy has been able to fill in very nicely for a number of these mutations in our space. And KRAS with the single point mutations that are very easily detectable on even the small snippets of circulating DNA with liquid biopsy is the prime example where the sensitivity in a stage IV setting is close to 100%. This is a fantastic opportunity to complement this. And I would predict that 2 years from now, it would be standard of care for every patient to have a tissue and a liquid biopsy obtained or requested at the same time of diagnosis and move forward with that. It is not yet done ubiquitously we've seen unfortunately, between the expectations of the guidelines and the real-world implementation, some gaps. But we're moving in the right direction. And certainly, a lot of progress has been made and the more targets we have, the higher the incentive will be for this.

Joshua K. Sabari, MD: You make such excellent points. If we were having this discussion, Martin, 10 or even 5 years ago, we were selecting patients based on pretest probability to obtain NGS. Younger patient, never smoker, predominantly female patient population. But you mentioned MET exon 14 skip alteration, BRAF V600E and now, KRAS G12C. These alterations are commonly identified in patients who have smoked. It's no longer OK to use our clinical judgement or pretest probability. We need to sequence all the patients. And I agree with you. I sequence both my adenocarcinoma as well as my squamous population. I agree that the squam population, we identify drivers in a low rate. But we're still identifying drivers at a 1-2% rate in that patient population. In 2022, if you want to give your patient a best possible therapy, it's critical to do broad panel NGS in the front line setting. And again, I couldn't agree more. I do both plasma and tissue concurrently in the upfront setting.

Transcript edited for clarity.

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