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04-07-2023 | Non-small-cell lung cancer | News

Adagrasib shows intracranial efficacy in KRYSTAL-1 trial

Author: Shreeya Nanda


medwireNews: An analysis of the KRYSTAL-1 study indicates that adagrasib has intracranial activity in people with KRAS G12C-mutated non-small-cell lung cancer (NSCLC) and untreated central nervous system (CNS) metastases.

The researchers say in the Journal of Clinical Oncology that these are “the first prospective data for a KRASG12C inhibitor” in this patient subgroup.

They add: “These results provide proof-of-concept for adagrasib’s ability to penetrate the CNS and provide CNS activity,” and support “further investigation in this population.”

For the current analysis, the team focused on the 25 participants of the KRYSTAL-1 study with KRAS G12C-mutated NSCLC and neurologically stable, asymptomatic, untreated CNS metastases, all of whom received adagrasib at a dose of 600 mg twice daily.

Over a median follow-up of 13.7 months, treatment with adagrasib resulted in an intracranial objective response rate, as per the CNS RECIST v1.1 criteria, of 42% among the 19 evaluable patients. Responses lasted for a median of 12.7 months and three were complete, while five were partial. The intracranial disease control rate was 90%.

The median intracranial progression-free survival was 5.4 months and at the 12-month mark, 33.9% were alive and disease-free. Overall survival was a median of 11.4 months and the rate at 12 months was 41.1%.

“The safety and tolerability profile seen in this cohort […] was broadly consistent with previous reports from the KRYSTAL-1 trial,” say Marcelo Negrao (The University of Texas MD Anderson Cancer Center, Houston, USA) and colleagues.

Treatment-related adverse events (TRAEs) of grade 3 occurred in 40% of the 25 participants evaluable for safety, with the most common being vomiting (16%), nausea (12%), and dizziness (12%). There was one TRAE of grade 4 – a case of neutropenia – and none of grade 5.

A total of 60% of patients needed dose modifications – reduction or interruption or both – as a result of TRAEs, and two patients discontinued treatment, one due to grade 3 acute pancreatitis and the other due to grade 2 fatigue.

Negrao et al report that the majority of CNS-specific TRAEs, such as dysgeusia, ataxia, aphasia, headache, and insomnia, were of grade 1–2, with just four patients experiencing grade 3 events – three cases of dizziness and one of encephalopathy – and no events of grade 4 or 5.

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J Clin Oncol 2023; doi:10.1200/JCO.23.00046