Your Health, We Care
Release date: 2024-11-15 15:22:02 Recommended: 174
According to NCCN guidelines, for patients with KRASG12C-mutated non-small cell lung cancer (NSCLC), two drugs are currently approved for second-line therapy, particularly for patients with adenocarcinoma or squamous cell carcinoma: sotorasib (Lumakras) and adagrasib (Krazati). Approval for both drugs applies to patients on second-line and subsequent treatments.
Adagrasib is recommended as monotherapy for patients with metastatic disease who have previously received PD-L1 inhibitor plus or minus chemotherapy (sequentially or in combination). The drug is also indicated for patients with stable central nervous system (CNS) metastases. The treatment regimen is for patients to take 600 mg capsules twice a day on an empty stomach. The primary endpoint of treatment is overall response rate (ORR), and secondary endpoints include duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
In the patient population, the majority of patients have an ECOG performance status of 0 or 1, and most are former or current smokers. The histological type was mainly adenocarcinoma, and to a lesser extent squamous cell carcinoma (2.6%). The majority of patients had metastatic disease (11.2% had locally advanced disease). For some patients, adagrasib can even be used as their fifth-line treatment. Of those who received the drug, 12.1% received five or more lines of therapy, including those with bone, central nervous system, adrenal and hepatic metastases.
In this heavily treated patient population, adagrasib achieved an ORR of 42.9% as a single agent. One patient achieved a complete response, while the majority achieved a partial response (42.0%) and stable disease (36.6%). This is a good outcome for patients receiving third-line or higher line therapy. Disease was controlled in 79.5% of patients, with median PFS of 6.5 months and median OS of 12.6 months at data cut-off (median follow-up: PFS 12.9 months; OS 15.6 months).
KRASG12C mutations are associated with central nervous system metastases, with 27% to 40% of patients presenting or at some point in the course of the disease presenting with CNS metastases. Adagrashib has shown clinically significant cerebrospinal fluid permeability in a preclinical model with a cerebral plasma concentration of 0.47, comparable to many other TKIs approved for patients with CNS metastases, showing good CNS penetration. In a post-hoc assessment of the optimal intracranial response in these patients, it was found that 33.3% of patients had confirmed intracranial response. Patients with CNS metastases at baseline had a median duration of intracranial response of 11.2 months and a median intracranial PFS of 5.4 months. These data suggest that adagrasib may be an effective drug for patients with central nervous system metastases.
In addition, the study also observed about 25 patients with untreated central nervous system metastases who achieved very similar good responses after taking adagrasib. These patients are metastatic patients who have not received radiation therapy. Studies excluded patients with cerebellar or brainstem metastases or leptomeningeal disease, but most brain metastases were included and some good responses were observed.
However, adagrasib also has some significant side effects, such as gastrointestinal toxicity, with diarrhea occurring in about 70% of patients. Fatigue is also a common adverse event. In addition, 37% of patients developed any grade of hepatotoxicity, with 10% of patients experiencing grade 3 and 4 hepatotoxicity, which showed a fairly high risk of hepatotoxicity.
For treatment options for patients with brain metastases, is the use of the KRASG12C inhibitor adagrasib versus radiotherapy or other approaches more effective? Based on current data, Sotorasib and Adagracsib may be better options. In contrast, docetaxel does not have good central nervous system permeability and therefore may not be the best choice for the patient population with brain metastases.
