Managing Mutations in Non-Small Cell Lung Cancer - Episode 7

Treatment Options for KRAS-Mutated NSCLC

Alexander Spira, MD, PhD, FACP, and Joshua Sabari, MD, detail possible therapeutic options for KRAS-mutated NSCLC, focusing on adagrasib and treating brain metastases.

Alexander Spira, MD, PhD, FACP: Currently, there is an FDA-approved drug called sotorasib. This was approved last year, and it is an oral drug specifically for KRAS G12C-mutated non-small cell lung cancer. It is approved for the second line of treatment outside of a clinical trial setting. There are currently no FDA-approved drugs for all the other KRAS variants, and this KRAS variant makes up a significant amount, about 14% of lung cancer patients, which is huge. The current treatment paradigm for KRAS G12C-mutated lung patients, outside of a clinical trial, is standard frontline therapy, which is usually chemotherapy with immunotherapy in the frontline setting if a patient can get immunotherapy. These drugs are currently reserved for the second line of treatment, so after progression.

Adagrasib is an investigational KRAS G12C inhibitor. The updated results from the KRYSTAL-1 study, [which are being presented or will have been presented at ASCO {American Society of Clinical Oncology} this year], show response rates in the 40% range. This is an update to the earlier phase 1/1B study with a very reasonable duration of response and relatively good activity. This is going to add to our armamentarium in terms of treatment for second-line KRAS G12C-mutated non-small cell lung cancer. Major adverse events appear to be GI [gastrointestinal] in nature—diarrhea, nausea, requiring dose reduction—and [occur] in a significant number of patients, but [adagrasib is] overall very well tolerated.

Joshua Sabari, MD: 20%–40% of patients with KRAS G12C alterations will develop brain metastasis. If you look at the EGFR and ALK population, it may be higher than that. It's important to think about the CNS [central nervous system] as a reservoir site or a site of potential resistance or progression of disease. Obviously, if a patient presents de novo with CNS metastasis, it is important to think about some form of local therapy, eg, radiation, or systemic therapy that has intracranial activity. To date, we have information on treated brain metastasis patients on CodeBreak 100 for sotorasib, as well as for potential adagrasib. We don't have data yet on untreated brain metastasis. I look forward to presenting that data at ASCO to show the intracranial activity of adagrasib in a cohort of patients treated on the Phase 1B expansion. Again, these are patients with untreated de novo brain metastasis who were given this medication. We know preclinically that adagrasib has phenomenal CNS penetration. In a preclinical animal model, we saw very good CNS activity and CNS penetration in 2 patients on this Phase 1B that we published in Clinical Cancer Research. We saw very high concentrations of plasma adagrasib, or I should say CSF [cerebrospinal fluid] adagrasib, over plasma. We looked at the Kpuu [unbound partition coefficient], which is the ratio of CSF drug to plasma drug; the ratio was 0.47, which is equal or similar to what we've seen with other various CNS penetrant agents like osimertinib or alectinib. I'm looking forward to seeing and presenting this data publicly. It's important to understand that CNS remains an important reservoir site of disease for our patients, and this may be a common site of progression in our patients treated with drugs that don't have adequate CNS activity.

Alexander Spira, MD, PhD, FACP: Unfortunately, a lot of KRAS G12C-mutated lung cancer patients will have brain metastases at presentation. It appears to be higher, about [25% more] of patients than other KRAS mutations or wild type KRAS patients. There is some evidence currently suggesting that the KRAS inhibitors, especially adagrasib, has CNS penetration. My colleague, Dr. Sabari, presented data at ASCO this year, which showed that there is evidence of CNS penetration measured by CNS activity. The previous phase 1 studies, which were small studies, also showed evidence of activity. There are preclinical models to demonstrate this. There's currently an ongoing, larger cohort to put it in perspective, but there's clear evidence that these drugs do get into the brain, which is important.

This transcript has been edited for clarity.