Precision Medicine: Key Updates for Treatment of NSCLC - Episode 8

KRAS Testing in Non¬–Small Cell Lung Cancer

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Benjamin Levy, MD: Let’s move on. I’ll make sure to get those to you, Josh. There is now testing for KRAS G12C, a genotype thought to be undruggable. We’re wrestling with so many challenges with KRAS-mutant lung cancer, including its potential smoking association and worst outcomes. There are KRAS mutations with TP53 and KRAS mutations with STK11 mutations that may sort out efficacy, or lack thereof, with immunotherapy. We’ve had a lot of movement in the KRAS G12Cspace as a druggable target for TKIs [tyrosine kinase inhibitors]. Josh, maybe you can go over the drugs that are available, starting with an AMG 510 and what this has done for your clinical practice in terms of looking at these patients and going back to understand what type of KRAS mutations they may have.

Joshua Bauml, MD: This is really fascinating. One of the reasons why KRAS mutation, despite being 1 of the most common molecular alterations seen in adenocarcinoma, was not previously been thought to be druggable is because its natural ligand has such a high affinity. To design a drug that can bind competitively with it is just impossible without having substantial toxicity. The reason KRAS G12C seems to be different is that the particular mutation creates a back door on KRAS. We call it an allosteric binding site. A drug can bind elsewhere and prevent the activity of the kinase. There are 2 drugs that we’ve seen data on in this space. The first is AMG-510, and the efficacy was impressive. The response rate as of its presentation last year in non–small cell lung cancer was 48%. Interestingly, these types of mutations can also occur in colorectal cancer, and there is no response there. That’s interesting.

Benjamin Levy, MD: Can you explain that to me?

Joshua Bauml, MD: If I could, I would be in a much bigger window. I’d get a blue ribbon. I’m working on getting the blue ribbon and the gold star.

Benjamin Levy, MD: OK.

Joshua Bauml, MD: There’s some heterogeneity in terms of the biology, but I don’t think anyone knows. That’s the truth. One of the interesting aspects of AMG 510 is that it is really well tolerated. We’ve participated in this trial. I’ve had patients on it. The drug was very well tolerated. There were no grade 4 or higher adverse events in the trial. The rate of grade 3 adverse events was 8.8%, and that’s really impressive.

There’s another drug that there have recently been published data on, MRTX849. Similarly, its response rate was about 50% in lung cancer. They did see some responses in colorectal cancer: 25%. Again, it is a really well-tolerated drug. This is exciting. But the key variable moving forward is that while these response rates are exciting, they’re not osimertinib-alectinib-level exciting. What are we missing on this is biology. The next step will likely be to conduct combination studies evaluating both of these agents, as well as others in the marketplace.

Benjamin Levy, MD: Yes, we’re participating in some of these studies combining it with immunotherapy, given that some KRAS mutations may be more sensitive to immunotherapy approaches than others. Understanding synergy with immunotherapy and TKIs and whether it can be done safely is going to be critical. Becca, what are your thoughts on these data and how you move forward? What do you generally do in your practice with KRAS G12C, as it stands now?

Rebecca Heist, MD: I agree with both of you. It’s fabulous to have drugs that have this level of activity and that are generally well tolerated. As much as I can, I put people with G12C on a clinical trial of 1 of these G12C inhibitors. As you were alluding to, a combination strategy is going to be moving forward in trials. In addition to combinations with immuno-oncology, there are combinations with EGFR and combinations with SHP2. Over the next year or 2, those data are going to read out and we’ll have a sense of whether there are combinations that will work best, in terms of synergy, for effectively blocking and prolonging the duration of the response as much as possible. This is a real game changer in lung cancer because of the sheer number of patients who have KRAS G12C.

Benjamin Levy, MD: Yes, it’s a frequent mutation and a druggable mutation with a drug that’s well tolerated. Lyuda, what is your final parting shot on KRAS before we move on to fusions?

Lyudmila Bazhenova, MD: I have nothing to add to what everyone else said, except maybe “testing, testing, testing.” To me, this is 1 of the mutations that now needs to be tested because you can probably find a site next to you that has either 1 of the 2 that Josh discussed, or a couple of others that are in development already.

Benjamin Levy, MD: Yes, we’re about to bring on this trial, and it’s for patients who are treatment refractory. I’ve had to go back and find out, because I couldn’t remember at the time. It didn’t matter to me what type of KRAS they had because it was 12 or 18 months ago. We’re having to go back retrospectively to look at which type of KRAS they have to see if they’re candidates for the study. The story has evolved very quickly. It’s very interesting.

Transcript Edited for Clarity