Video
Is There a Role for IO Therapy in NSCLC With Independent KRAS, STK11, or KEAP1 Mutations?
Author(s):
Expert oncologists Melissa Johnson, MD, and Joshua Sabari, MD, discuss the occurrence of individual KRAS, STK11, or KEAP1 mutations in patients with non–small cell lung cancer and if there is a role for immunotherapy in the treatment of these patients.
Transcript:
Melissa Johnson, MD: Hello and welcome to this OncLive Peer Exchange®…I’m Melissa Johnson, director of the lung cancer research program for Sarah Cannon [Research Institute in Nashville] and a medical oncologist with Tennessee Oncology, OneOncology. I’m joined by my fellow expert and friend, Dr Josh Sabari. I’ll let him introduce himself.
Joshua Sabari, MD: Thank you, Dr Johnson, for having me. I’m Josh Sabari, I’m a thoracic medical oncologist at NYU Langone Health Perlmutter Cancer Center [in New York]. I’m looking forward to discussion today.
Melissa Johnson, MD: Today we’ll discuss updates on the roles of immunotherapy in patients with non–small cell lung cancer and KRAS, STK11, KEAP1, and P53 [mutations] in light of the recent FDA approval, and we’ll discuss the data and context of its impact on clinical practice. Let’s jump right in. Is there a role for immunotherapy in patients with concomitant [mutations]? These are mutations that we have been aware of, and we’ve been seeing these on NGS [next generation sequencing] reports for a while now. Before we jump into the data, why don’t you talk to us about what goes through your head when you see patients with these mutations, and does it change your practice?
Joshua Sabari, MD: First off, we all want our patients to respond to therapy. We want to make sure there’s no driver alteration that is actionable with a targeted therapy. The next thing we look at when those patients don’t have an actionable mutation is the PD-L1 expression. We’re generally using a PD1-PD-L1 inhibitor alone, and then PD-L1-low or negative, that’s when we consider adding more therapy in order to help our patients respond as well as subdurability. More recently we’re seeing that genomic alterations or coalterations have become important in understanding whether patients may respond to immunotherapy. The KRAS space has exploded. Dr Johnson, you’ve been involved in the development of a lot of the KRAS inhibitors, what percent of your population do you think has a KRAS mutation in the upfront setting?
Melissa Johnson, MD: Good question. We estimate that KRAS mutations happen in about 30% of lung cancer, and in particular, we’re used to looking for KRAS G12C mutations. That happens in about 30% of the KRAS mutations, so…that is a good number to have in your head because that’s about the number of patients with STK11 mutations that we see in practice and KEAP1 probably half of that….KRAS is a mutation that we see a lot; STK11 and KEAP1 maybe less often. We have some interesting results over the past few years looking retrospectively at STK11 and KEAP1. Do you want to go through some of that data?
Joshua Sabari, MD: Sure, it’s interesting. The KRAS mutation population—and I love your math there, 30% of 30% so 13%, I will never forget that—is generally the heavier smokers. Those are patients who generally do better with immunotherapy. When you look at retrospective series for KRAS overall or KRAS mutation alone versus KRAS wild type, that’s the patient population who benefits from immunotherapy. What’s interesting is that you look at some of the coalterations, as you mentioned in STK11, which is more common obviously than KEAP1, that’s the patient population who does not do well and seems to need more than just immunotherapy or maybe immunotherapy, meaning a PD1-PD-L1 inhibitor plus chemotherapy. Dr Skoulidis’s group at [The University of Texas MD Anderson Cancer Center in Houston] have done multipleretrospective series showing that that patient population, despite PD-L1 expression or regardless of PD-L1 expression, seems to underperform. I’m curious why may that be, are there any data? I think it’s still early here, but why may that be?
Melissa Johnson, MD: I don’t know that we know, but I am tempted to explain it as a way that the cancer is figuring out how to use different pathways to grow, not the KRAS mutant pathways that we’re used to identifying. STK11 mutations can signify alternate means of gluconeogenesis for the cancer cells, and maybe they’re not growing and dividing in the same way. Just to reinforce what you’ve said, I have a friend who was at a neighboring institution in your town who’s now gone to work for AstraZeneca, and I remember asking him, “What do you do when you see a patient who has an STK11 mutation?” He said, “I cry.” That underscores for me the problem. These STK11 mutations, they predict that patients are not going to do well with immune therapy. I’ll push it one step further and say in some combinations patients won’t do well with chemotherapy, either, and maybe not even with PD1 and chemotherapy. These are resistant to the immune mechanisms that we are trying so hard to up-regulate in our frontline patients.
Joshua Sabari, MD: It’s interesting. This patient population also seems to have a lower PD-L1 expression, particularly those with KEAP1 alterations.
Transcript edited for clarity.
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