Targeting KRAS Mutations in Advanced NSCLC - Episode 10

Practical Considerations for AMG 510 in KRAS-Mutant NSCLC

Benjamin P. Levy, MD: David, we’re participating in some studies in the future with this drug. I have not had direct experience with it personally, but I will soon. I don’t know what your take is on this data as well as any anecdotal experience you have with the drug.

David R. Gandara, MD: I agree with all your comments. It is a well-tolerated drug. It’s interesting that for chemotherapy, phase 1 trials always use a design where we go for the MTD, the maximum tolerated dose, based on dose-limiting toxicities, which figures the more you can give, the better. For targeted therapies, different companies have used different approaches. Some still use MTD, and others want to get a biologically effective dose, and they may do that based on surrogate markers, biopsies, blood tests, etc.

Here’s a drug where they escalated log fashion, many-fold, and they never got to the MTD. They said, “Well, it was pretty well tolerated, so we’re just going to give the highest dose.” I don’t disagree with that. But as you said, even much lower doses of the drug were effective in some patients. There’s a lot about this drug we don’t know. Because there have been multiple presentations, I have not seen the comutation status with this drug in this study. In other words, what about patients with TP53 plus this mutation, or STK11? What impact did that have? The other thing about the drug—and there was a separate abstract at the ASCO [American Society of Clinical Oncology Annual] Meeting, was using the same drug in patients with the same mutation but in colorectal cancer.

Benjamin P. Levy, MD: Yes, I was going to ask you about that.

David R. Gandara, MD: One of 25 patients had a response. That makes me think that comutation status is important. It’s not that the patients with colorectal cancer had a different KRAS mutation; they had the same mutation. But undoubtedly, based on prevalence data, we know that TP53 and STK11 are not of the same prevalence in colorectal cancer. I’m thinking the traveling partners do make a difference, but it’s too premature to say that. We’ll come back to this when we talk about some of the competitors where there may be more efficacy data in colorectal cancer.

Benjamin P. Levy, MD: It ran counter to me. We’re talking about these tissue-agnostic, genotype-directed studies with NTRK fusions and RET fusions, in which we’re seeing similar response rates no matter what the tissue of origin is. This was a little different. The data are just too early to know, but it seems that there’s such a difference if you have a KRAS G12C lung cancer and get treated with this drug versus a KRAS G12C colorectal cancer and get treated with this drug. I’ve never heard of the coalteration hypothesis, but it’s 1 that could have a lot of traction here.

David R. Gandara, MD: I just want to mention that earlier, I said KRAS mutation in colorectal cancer versus KRAS mutation in lung cancer is very different in terms of prediction of response to EGFR monoclonal antibodies such as cetuximab.

Benjamin P. Levy, MD: Yes.

David R. Gandara, MD: This isn’t the first time we’ve heard this story about KRAS being a different beast in the 2 different malignancies. Where does this drug, this AMG 510, stand in terms of the approval process?

Benjamin P. Levy, MD: Correct me if I’m wrong, but it has a breakthrough designation or a fast-track designation. The difference between that lingo is whether it’s an unmet need or if there are therapies that exist already. But I think this will move quickly. We are participating in some of the combination trials, but I hope with a fast-track designation, this will reach the clinic sooner rather than later. We’re in April 2020, and I hope by the end of the year—if not early first quarter of 2021—we’ve got this drug in our armamentarium to give patients. I don’t know what your thoughts are. I’m ambitious in my thoughts on how long it will take. What do you think?

David R. Gandara, MD: I agree with you.

Transcript edited for clarity.