Adagrasib for Non-small cell lung cancer intracranial metastases [Neurosurgery Wiki]

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====== Adagrasib for Non-small cell lung cancer intracranial metastases ======

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[[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 [[case]]s. The [[development]] of brain-penetrant [[KRAS G12C inhibitor]]s like [[adagrasib]] offers a major therapeutic [[advance]].

===== 🔍 Evidence for Intracranial Efficacy =====

==== 1. Preclinical Evidence ====

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

Brain exposure confirmed through [[pharmacokinetic assay]]s.

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

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

===== 2. Clinical Evidence =====

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.

===== 📊 Key Strengths =====

✅ 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.

===== 🧪 Ongoing 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 inhibitor]]s, and [[MEK inhibitor]]s are also underway.

===== 🧠 Conclusion =====

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.
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Co-existing [[genomic]] [[alteration]]s 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
((Migliarese C, Sadeh Y, Torrini C, Turna Demir F, Nayyar N, Yamazawa E, Ishikawa Y, Ijad N, Summers EJ, Elliott A, Rahbaek L, Saechao B, Hallin J, Brastianos PK, Wakimoto H. Combination therapy of adagrasib and abemaciclib in [[non-small cell lung cancer]] [[brain metastasis]] [[model]]s [[genomic]]ally characterized by [[KRAS-G12C]] and [[homozygous loss]] of [[CDKN2A]]. Acta Neuropathol Commun. 2025 May 2;13(1):88. doi: 10.1186/s40478-025-01993-2. PMID: 40317086.))
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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.