Future Directions in Managing KRAS-Mutant Advanced NSCLC

David R. Gandara, MD: We should close by talking about a couple of the brand-new agents, which I don’t know that much about. Maybe you know more. But the last time I looked, there were 5 drugs directly targeting KRAS mutations, predominantly G12C. There are a lot of modulators that we’re looking at in clinical trials, like SHP2 inhibitors and so forth. What about the other ones that are direct inhibitors? The data are good preclinically, but less is known in the clinic.

Benjamin P. Levy, MD: I agree. I didn’t even know there were 5, so I’ve learned something. I know of 2 more, a Johnson & Johnson drug and another license plate therapy that, as you said, have performed quite well preclinically. The question will be, Are there real meaningful differences when we put these drugs into clinic? Do we need this many drugs? Do we need to look at how to combine these drugs with other agents that elicit meaningful responses? It’s interesting, and I don’t know where this will all fit. If they mirror the other genotype-directed therapies, hopefully these drugs will land in the first line, and then we can build on that by adding drugs or looking at drugs in resistance. Maybe it is like what we have learned in EGFR, that we combine some of these drugs that are coming down with chemotherapy and improve outcomes that way, or with immunotherapy. We have a lot of drugs that have come down.

We’ve got to expand beyond KRAS G12C. We need to tackle the other subtypes if possible, and come up with some combination strategies that are rooted in scientific rationale. I don’t know of any differences with these new agents that are coming out in terms of their preclinical efficacy or whether they will make any difference compared with one another when it gets to the clinic.

David R. Gandara, MD: Luckily, there is a lot of research being done. At the AACR [American Association for Cancer Research Annual] Meeting, the KRAS dream team presented on non–small cell lung cancer. The preclinical data in particular were quite intriguing. Of course, I can’t tell you any of the results. There’s a lot going on, and hopefully it will lead to more understanding and even better use of these drugs or alternative strategies.

Benjamin P. Levy, MD: There have been such extraordinary advances in the field. I got into this field and had always learned KRAS is undruggable. It’s undruggable; we can’t do it. Here we are now, really at the forefront of some very exciting times for our patients in selecting therapies based on their genotype. Do you have any final parting shots, David, before we wrap up?

David R. Gandara, MD: One of my favorite quotations is, “Not all mutations are created equal,” and that’s true for the KRAS mutations. Lastly, we’ve built up from 1 to 2 to 4 to 8 oncogenes that we need to test for up front. Pretty soon we will have number 9, and that is to test KRAS specifically looking for G12C.

Benjamin P. Levy, MD: I love it. We are starting to hit the tip of the iceberg. It’s a very exciting time. This has been extremely informative. Thank you, Dr Gandara, for this insightful discussion. Thank you to our audience for watching this Targeted Oncology™ presentation on precision medicine. We hope you found this discussion to be useful and informative.

Transcript edited for clarity.