Targeting KRAS Mutations in Advanced NSCLC - Episode 3

History of KRAS Testing in Advanced NSCLC

May 27, 2020
Targeted Oncology

David R. Gandara, MD: I will date myself. Our topic today is KRAS mutation, and we were among the very first to identify and publish on the identification of KRAS mutation in blood in the year 2004, about 15 years ago.

Benjamin P. Levy, MD: Quite incredible.

David R. Gandara, MD: We saw that after treatment where the patient clinically responded, the mutation disappeared from blood, and then that KRAS mutation came back. Now we’ll turn our attention specifically to KRAS. Let’s move toward how we test for KRAS. This has changed quite a bit over the last few years. Ben, give us background on what KRAS was used for in the first place, and what we use it for now.

Benjamin P. Levy, MD: What a change in the testing algorithm and the importance of KRAS testing. I’ll take you back to 12 to 15 years ago, my introduction to lung cancer, and where we thought KRAS was relevant or not. KRAS is the most common mutation that we see in non–small cell lung cancer, and we were testing for it sometimes. For me, as we started in the early or mid-2000s, KRAS, as far as I can remember, more showed lack of predictability to some of the EGFR TKIs [tyrosine kinase inhibitors]. There was a running theme that patients who were KRAS mutated were EGFR TKI refractory, and this was when we were using EGFR TKIs for all patients, not just EGFR mutations. There were also emerging data that KRAS tended to reflect worse outcome for patients. But in terms of treatment selection, it really wasn’t driving any sort of chemotherapy selection, because that’s what we were using when I started. It guided when not to use EGFR-directed drugs. We’ve come so far, to think that we were using these EGFR TKIs in all-comers and looking at KRAS as some mutation that predicted lack of response or outcome with these drugs. We’ve come a long way, obviously.

KRAS is now a part of our comprehensive genomic profiling. I can certainly identify some caveats to that now that the new drugs are coming out. We test KRAS in everyone, and about a year ago, we realized that the subtype of KRAS mattered. Now we have some drugs that we’ll talk about that are specific to KRAS G12C. What’s that forced me to do is readdress these patients who have been on chemotherapy for long periods, where the molecular testing was done maybe a year ago. Yes, I remember they had a KRAS mutation, but I don’t remember what subtype they had. Now that we have these new therapies, I’ve had to look back to see what subtype of KRAS they have and mark in my notes that they do indeed have the right subtype that may make them eligible for a clinical trial.

This is the evolution of both KRAS testing and my interpretation of KRAS utility during my career. How about you, David?

David R. Gandara, MD: I agree with you. KRAS was initially felt to be a rule-out for EGFR-targeted therapy, as you stated. We were the first to say that patients with EGFR sensitizing mutations could have a concurrent KRAS mutation. We presented those data at ASCO [an American Society of Clinical Oncology annual meeting], and a questioner from a large city on the East Coast said, “Well, that’s impossible, you have a bad test.” Two years later, that same institution got up and presented their series, which showed that it could happen concurrently with other oncogenes and probably has a worse prognosis than EGFR by itself, just like TP53.

That being said, now that we have next-generation sequencing, whether it’s in tissue or in blood, you get KRAS. You don’t have to ask for it, it’s part of the package you get. As you mentioned, more and more, it’s meaningful. It’s meaningful because we now have some small-molecule inhibitors. But it is also quite meaningful in terms of immunotherapy, and we’ll come back to that later.

Transcript edited for clarity.