Dr Joshua Sabari on Burden, Treatment Options for Patients With KRAS-Mutated NSCLC

KRAS mutations as a whole make up about 30% of cases of non–small cell lung cancer, most commonly in older patients, smokers, or those who have a history of former smoking, said Joshua Sabari, MD, a thoracic medical oncologist, Perlmutter Cancer Center, NYU Langone Health.

What mutations are considered actionable when we're talking about advanced non–small cell lung cancer and how common are these mutations?

The most common actionable driver alterations in lung cancer include EGFR, which we see in about 20% of patients. That includes exon 19 deletion and L858R, the activating mutations, as well as the uncommon or EGFR exon 20 insertion mutations, which makes up about 1% to 2%. The next most common alteration that we see is KRAS G12C. KRAS G12C occurs in about 10% to 12% of patients with non–small cell lung cancers, now actionable in the second line. We next see ALK fusions occurring in about 3% to 5% of patients with non–small cell. We then get into less common alterations, MET exon 14, about 3% to 5% of patients. And then ROS1, RET, BRAF V600E about maybe 1% or 2% of the patient population, HER2 exon 20 insertion mutations about 1%. And then the NTRK fusion, which is quite rare, about 0.025% of the population. But as a whole, if you take all of these alterations, it accounts for more than 50% of patients with non–small cell lung cancer enriched in adenocarcinoma, and we can match patients to targeted therapy with improvement in their survival.

What is the clinical burden of KRAS mutations in non–small cell lung cancer? What patient population is associated with this mutation?

KRAS mutations as a whole make up about 30% of patients with non–small cell lung cancer, most commonly seen in older patients, smokers, or have a history of former smoking in the past. And it's interesting that when you compare this mutation, KRAS, to the other driver alterations we mentioned, like EGFR, those are more commonly seen in younger, healthier patients, never smokers. So patients with KRAS alterations tend to be older, former smokers, and have more comorbidities, particularly cardiac or cardiovascular disease, compared with that younger patient population we mentioned. KRAS G12C is a unique subtype of KRAS mutations and makes up about 10% to 12% of this population.

How are KRAS mutations detected in this disease? What testing methods are used and maybe what are some of those barriers associated with testing?

So broad molecular testing is critical in the diagnosis and treatment of a patient with stage IV lung cancer. We generally use broad panel next-generation sequencing of both DNA and RNA to identify KRAS mutations, as well as the other mutations we discussed. We can also use plasma-based assays, next-generation sequencing assays to identify these somatic alterations in the blood.

What treatment options are available for patients with KRAS mutated non–small cell lung cancer? And briefly, what are some of those factors you consider when you're selecting a course of treatment for these patients?

Currently, there are no FDA-approved frontline agents for KRAS G12C, so the standard of care in a patient with KRAS G12C mutation is either chemotherapy plus immunotherapy or immunotherapy alone, depending on the PD-L1 expression or programmed death ligand-1. In the second-line setting, there is an accelerated approval for sotorasib at 960 milligrams oral daily for patients with KRAS G12C mutations. And we just saw the confirmatory phase 3 study presented at ESMO comparing sotorasib to docetaxel; sotorasib with about a response rate of about 25%-28% vs docetaxel, about 10%. It's interesting that despite these being targeted therapies, we still have a long way to go. So an improvement in progression-free survival, albeit very small. And we did not see a survival benefit because the study did allow for crossover.

How do you anticipate the treatment of KRAS mutations will evolve over time? What are you excited for here in the near future?

So, it's interesting. KRAS mutations are oftentimes overlooked by oncologists because it's not commonly seen in that population. We had mentioned the young, never smokers; these are patients who we commonly think of EGFR and ALK and other common driver alterations. And also, there are no FDA-approved agents in the front line. So oftentimes when a patient is ready for the second-line therapy, oncologists may not remember or recall that the patient has KRAS G12C mutation. I think this is a large population, it's a large unmet need for our patients. There are many novel KRAS inhibitors being developed at the moment targeting the cystine. So these are covalent inhibitors of KRAS G12C as well as noncovalent inhibitors thinking more broadly immunotherapeutics or potential RAS on type molecules. So it's a quite exciting time for patients with KRAS [mutation]. This has been an undruggable target for 30-plus years, and we're finally starting to see some early activity from some of these agents.

What are you working on in non–small cell lung cancer that you might be excited to share with us?

So there's lots of opportunities in non–small cell lung cancer to always improve outcomes for patients. My primary focus now is in KRAS G12C mutant lung cancer, particularly looking at developing targeted therapies with CNS [central nervous system] activity or intracranial activity. We know that brain metastases are quite common in patients with G12C mutations, upwards of 40% of patients are retrospectively identified. So it's important for these agents to have brain activity. One of the agents that has shown to have some brain activity that is not yet FDA approved is adagrasib or MRTX849, [which has] response rates in the phase 2 study of about 43% systemically with an intracranial response of about 32%. I think further studies are needed to better understand this activity in the brain, but one important unmet need for our patients with KRAS G12C is this concept of active and untreated CNS metastases. Another area of interest of mine is in the acquired resistance setting. So we know that these medicines work, however, patients rapidly develop acquired resistance mutations because the MAP kinase pathway is quite complex. So understanding the resistance is going to be very helpful at developing the next-generation inhibitors. Thinking about combinations potentially moving forward will be very, very important.

Are there any closing thoughts you'd like to add regarding KRAS going forward?

I think KRAS G12C is a significant number of patients that are seen in the clinic, 10% to 12%. And if you go to different areas in the country with a heavier smoking population, it might be upwards of 14% to 15%. And in a patient population that is a lighter or never-smoker population like East Asia or China, you're seeing rates in the 3% to 4% range. I think understanding your patient population, but more importantly, testing broadly. So molecular profiling all of your patients because KRAS G12C is an important mutation to identify. But again, it's important to understand all alterations in our patients, not just the one alteration that you are thinking about that day.