• Adagrasib in KRYSTAL-12 has Broken the KRAS (G12C) Enigma Code in Non-Small Cell Lung Carcinoma
• Safety and Intracranial Activity of Adagrasib in Patients With KRAS(G12C)-Mutated Non-Small-Cell Lung Cancer and Untreated CNS Metastases in the KRYSTAL-1 Trial: A Case Series
• Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRAS(G12C)-Mutated Non-Small-Cell Lung Cancer Who Have Untreated CNS Metastases
• Evaluating the intracranial activity of adagrasib
• Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation
• Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer

Adagrasib (Krazati) is a selective, irreversible inhibitor of the KRAS G12C mutation. Intracranial metastases (brain metastases, BM) occur in up to 40% of Non-small cell lung cancer patients, and KRAS G12C is present in ~13% of Non-small cell lung cancer intracranial metastases cases. The development of brain-penetrant KRAS G12C inhibitors like adagrasib offers a major therapeutic advance.

Christian Migliarese et al. (2025) showed that adagrasib crosses the blood-brain barrier (BBB) in orthotopic brain metastasis mouse models.

Brain exposure confirmed through pharmacokinetic assays.

In adagrasib-resistant SW1573 cells, the combination with abemaciclib (a CDK4/6 inhibitor) induced apoptosis and extended survival.

Monotherapy with adagrasib prolonged survival in adagrasib-sensitive H2122 BM models.

Early-phase trials (e.g., KRYSTAL-1) reported intracranial responses:

Objective intracranial response rate (ORR): ~33–42%

Some patients with measurable brain metastases showed partial responses or stable disease.

CNS penetration confirmed by CSF concentration data in limited cohorts.

Well-tolerated at 600 mg BID, though GI side effects and QTc prolongation may occur.

✅ Selective targeting of KRAS G12C

✅ Oral administration

✅ BBB penetration

✅ Durable CNS activity

✅ Synergy with agents like CDK4/6 inhibitors in resistant clones

⚠️ Limitations

⚠️ Not all patients respond; resistance via bypass pathways (e.g., MET, EGFR) occurs.

⚠️ Limited efficacy in KRAS wild-type or non-G12C tumors.

⚠️ CNS toxicity, although manageable, must be monitored—particularly in combination regimens.

⚠️ Long-term CNS efficacy is still being investigated in larger, controlled trials.

Several trials are evaluating adagrasib for NSCLC with brain metastases:

KRYSTAL-1: Phase 1/2 study evaluating adagrasib as monotherapy or in combination.

KRYSTAL-10: Combining adagrasib with checkpoint inhibitors (e.g., pembrolizumab).

Trials incorporating abemaciclib, EGFR inhibitors, and MEK inhibitors are also underway.

Adagrasib represents a significant step forward in treating NSCLC with brain metastases harboring KRAS G12C mutations, especially due to its oral availability, brain penetration, and target selectivity. While promising, combination strategies and biomarker-guided patient selection will be critical to maximize its CNS efficacy and overcome resistance.

Co-existing genomic alterations such as homozygous deletion of CDKN2A/B may impact the utility of adagrasib. Migliarese et al., therefore, explored the combination therapy employing adagrasib and abemaciclib, a brain-penetrant CDK4/6 inhibitor, in NSCLC BM models driven by KRAS-G12C and CDKN2A loss. In both adagrasib-resistant SW1573 cells and adagrasib-responsive H2122 cells, the combination of adagrasib and abemaciclib was slightly synergistic in inhibiting cell viability in vitro through targeting the KRAS-ERK and CDK4/6-Rb signaling pathways. Combination treatment was necessary to activate caspase 3/7-mediated apoptosis in SW1573 cells, while adagrasib alone and in combination comparably elicited apoptosis in H2122 cells. In vivo, combination treatment with adagrasib (75 mg/kg) twice daily and abemaciclib (50 mg/kg) daily was associated with body weight loss (about 10%) in mice bearing orthotopic BM derived from SW1573 or H2122 cells, requiring a 50% dose reduction of adagrasib in some animals. Notably, combination treatment, but neither monotherapy, extended animal survival in the SW1573 model. On the other hand, adagrasib monotherapy and combination were similarly effective at prolonging survival, while abemaciclib monotherapy was ineffective in the H2122 model. Pharmacokinetic studies confirmed brain-penetrant properties of both agents and revealed drug-drug interactions as abemaciclib exposures in the plasma and brains were increased by the presence of adagrasib. Immunohistochemistry demonstrated on-target pharmacodynamic effects of both agents in BM in mice. The work thus supports that the combination therapy of adagrasib and abemaciclib can offer a therapeutic strategy in NSCLC BM genomically characterized by KRAS-G12C and CDKN2A loss ¹⁾

Migliarese et al. provide compelling preclinical evidence that co-targeting KRAS G12C and CDK4/6 pathways may overcome resistance to adagrasib in brain metastases from NSCLC with CDKN2A/B loss. The mechanistic rationale is sound, and the use of brain-penetrant drugs is a major strength. However, toxicity, modest synergy, and pharmacokinetic concerns limit immediate clinical enthusiasm.

📌 Clinical Implications The combination may be most useful in adagrasib-resistant, CDKN2A-deleted BM, but careful dose adjustment and monitoring will be essential.

Future trials must integrate immunotherapy arms and investigate biomarkers of response beyond KRAS/CDKN2A status.

There’s a need for phase I trials with adaptive dosing, especially in patients with CNS involvement.