Treatment Strategies for NSCLC With Concomitant KRAS and p53 Mutations

Transcript:

Melissa Johnson, MD: [Dr Johnson], what about P53? How do you think about that in your practice with and without some of these other mutations?

Joshua Sabari, MD: P53 is quite common. As you know, it’s the guardian of the genome; it fixes the abnormality. I tell patients, when you have a P53 alteration or multiple P53 alterations, the cancer is just a little bit more aggressive, in my opinion. That analysis by Charu Aggarwal, [MD, MPH]: She looked at STK11, KEAP1, and P53 alterations, and she reported that for P53 in the wild subtype, it was about 48%, and in the mutant subtype, about 37%. We know that this patient population does not do as well. I can’t tell you that I have great data for KRAS and P53 alone; those patients don’t respond as well. That’s a patient whom I may continue to treat in the standard KEYNOTE-189 paradigm. It’s really the STK11 and KEAP1 alterations in combination with KRAS or in combination with KRAS and P53. Those are the patients who, in my opinion, may benefit from a CTLA4 inhibitor. Dr Johnson, you might imagine a patient with KRAS, STK11, KEAP1, and P53. How is that patient going to do in your clinical practice? Those are the ones we cry over.

Melissa Johnson, MD: That’s right. I tend to see that the P53-KRAS doublet patients may do a little better, by contrast, but the KRAS-STK11 or KRAS-KEAP1 doublets, those may do a little worse. The triplet KRAS-STK11- P53—it starts to really feel like metastatic cancer that has multiple mutations. For those patients, I wonder, beyond immunotherapy and chemotherapy, how we might treat them. There are strategies using glutaminase inhibitors that are rapidly approaching the clinic in phase 1 trials. These are patients who need innovative solutions beyond chemoimmunotherapy. This will keep us doing clinical research to try to figure it out. [Dr Sabari], anything that we didn’t hit that you wanted to bring up?

Joshua Sabari, MD: No. I think we hit most of the salient points here. The key takeaways for me are that KRAS is common—30% of our patients in clinical practice. Historically, KRAS patients do well with immunotherapy, but now we need to dive deeper. We must look at some of the coalterations with STK11 and KEAP1. And as you mentioned, those are the patients who do not do well. In my clinical practice, those are the patients for whom I’m considering the addition of a CTLA4 inhibitor. I agree with you, that we definitely need more data and we need better therapeutic strategies for our patients in this setting.

Melissa Johnson, MD: Thanks for joining me, Dr Sabari, in this rich and informative discussion this afternoon. Thank you to the viewing audience. We hope you found this discussion valuable in the treatment of your patients with non–small cell lung cancer. Join us next time.

Transcript edited for clarity.