Adagrasib Demonstrates Intracranial Activity in KRAS G12C+ NSCLC

Treatment with adagrasib (Krazati) elicited enduring responses and intracranial activity in patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC) and untreated central nervous system (CNS) metastases, according to data from the phase 1b portion of the KRYSTAL-1 trial (NCT03785249) published in the Journal of Clinical Oncology.¹

The confirmed intracranial objective response rate (ORR) was 42.0% (95% CI, 20.3%-66.5%), which included complete responses in 3 patients and partial responses in 5. Additionally, the intracranial disease control rate (DCR) was 90%. The median progression-free survival (PFS) was 5.4 months, and the 6-month and 12-month PFS rates, respectively, were 42.3% and 33.9%.

The most common any-grade CNS-specific TRAES included dysgeusia, dizziness, ataxia, aphasia, confused state, encephalopathy, headache, and insomnia.

Patients had a median time to response of 2.1 months, and the median intracranial duration of response (DOR) was 12.7 months, with 2 patients experiencing an ongoing response after receiving treatment for more than 10 months. Investigators reported CNS failure in 37% of patients, and 2 patients had CNS progression only. Per modified Response Assessment in Neuro-Oncology Brain Metastases (mRANO-BM) criteria, the confirmed intracranial ORR and DCR rates, respectively, were 35% and 85% among 20 evaluable patients.

Based on systemic review, the ORR was 30%, the median DOR was 5.6 months, and the median PFS was 5.3 months. Investigators noted a concordance rate of 79% between systemic and intracranial disease control. Moreover, the median overall survival (OS) was 11.4 months, and the 12-month OS rate was 41.1%.

“Patients with brain metastases from KRAS-mutant lung cancer face a poor prognosis,” lead study author Marcelo Negrao, MD, assistant professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a press release on data from the trial.² “The data indicate adagrasib may offer patients a good chance of seeing response in the brain without needing additional therapy, such as radiation.”

In the phase 1b portion of the KRYSTAL-1 trial, patients received 600 mg of adagrasib orally twice a day.

The primary end points of the study were establishing the safety and intracranial efficacy of adagrasib. Reporting adverse effects (AEs), laboratory abnormalities, dose interruptions, and treatment discontinuations constituted the study safety assessments. CNS efficacy assessments per blinded independent central review involved use of modified CNS RECIST v1.1 and mRANO-BM criteria.

Patients with KRAS G12C-mutated NSCLC and neurologically stable, asymptomatic, untreated CNS metastases were eligible for enrollment on the trial. Having an ECOG performance status of 0 or 1 was also required to enroll.

Of 25 patients, 19 were considered to be evaluable for intracranial activity, including 14 with target lesions and 5 with nontarget lesions only. The median follow-up was 13.7 months (95% CI, 8.5-not evaluable), and the median patient age was 66 years (range, 47-89).

Most patients receiving adagrasib monotherapy were female (52%), White (84%), had an ECOG performance status of 1 (72%), and were previous smokers (68%). Additionally, most received 1 prior line of therapy (60%) and previous treatment with checkpoint inhibitor therapy (80%).

Overall, 100% of patients experienced any treatment-related AE (TRAE), and 40% experienced a grade 3 TRAE. The most common any-grade TRAEs included nausea (88%), diarrhea (76%), vomiting (60%), increased alanine aminotransferase (40%), increased aspartate aminotransferase (40%), and fatigue (32%). There was 1 grade 4 event of neutropenia.

Dose modifications, reductions, and interruptions due to TRAEs, respectively, occurred among 60%, 32%, and 56% of patients. Additionally, 1 patient discontinued treatment due to grade 3 acute pancreatitis, and another discontinued treatment due to grade 2 fatigue.

The most common any-grade CNS-specific TRAES included dysgeusia (24%), dizziness (20%), ataxia (8%), aphasia (4%), confused state (4%), encephalopathy (4%), headache (4%), and insomnia (4%). There were 4 grade 3 CNS-specific TRAEs, including dizziness in 3 patients and encephalopathy in 1.

“Adagrasib is the first KRAS G12C inhibitor to prospectively demonstrate intracranial activity in patients with KRAS G12C-mutated NSCLC and untreated brain metastases. These findings support continued clinical development of adagrasib and of its combinations for patients with KRAS G12C-mutated NSCLC,” Negrao concluded.

References

1. Negrao MV, Spira AI, Heist RS, et al. Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial With KRASG12C–mutated non–small-cell lung cancer who have untreated CNS metastases. J Clin Oncol. Published online June 16, 2023. doi:10.1200/JCO.23.00046
2. Adagrasib effective for patients with KRAS G12C-mutant lung cancer and untreated brain metastases. News release. The University of Texas MD Anderson Cancer Center. June 16, 2023. Accessed June 21, 2023. https://shorturl.at/inD07