Results of the phase II CodeBreaK 100 trial established the efficacy and safety of sotorasib in patients with previously treated KRAS p.G12C-mutant locally advanced or metastatic non-small cell lung cancer (NSCLC). Results of a post-hoc exploratory analysis now show that sotorasib also has systemic durable anticancer activity in patients with NSCLC and stable brain metastases (BM), with a similar disease control rate in patients with and without BM. Moreover, intracranial complete responses were observed with sotorasib, with continued intracranial stabilization in most patients with evaluable BM.
Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. Based on the results of the phase II CodeBreaK100 trial, sotorasib received FDA approval for the treatment of adult patients with previously treated KRAS p.G12C-mutant locally advanced or metastatic non-small cell lung cancer (NSCLC). In this trial, sotorasib was found to be associated with an objective response rate (ORR) of 37%, a median progression-free survival (PFS) of 6.8 months and a median overall survival (OS) of 12.5 months. Interestingly, this clinical activity was accompanied by a favourable safety profile with mostly low-grade treatment-related adverse events. As brain metastases (BM) are a common finding in patients with NSCLC (30-50%) it would be interesting to gain more insights into the intracranial activity of sotorasib. While patients with active BM were excluded from the CodeBreaK100 trial, the study did include a subset of patients with stable, asymptomatic BM. During the 2021 World Conference on Lung Cancer, results were presented on the activity of sotorasib in patients with NSCLC and stable BM, including a descriptive evaluation of intracranial outcomes using specific response assessment criteria for BM (RANO BM)
CodeBreaK 100 study design
In CodeBreaK 100, patients with locally advanced or metastatic NSCLC harbouring a KRAS p.G12C mutation who progressed on prior standard therapies were treated with 960 mg sotorasib orally once daily until disease progression. The primary endpoint of the trial was overall response rate (ORR), with duration of response (DoR), disease control rate (DCR), PFS, OS and safety as secondary objectives. The evaluation of the sotorasib response in target and non-target stable BM was a post-hoc exploratory endpoint of the study. In total, the study included 40 patients with BM at baseline and 134 patients without these lesions. Overall, patient and disease characteristics were fairly similar between patients with and without BM, with the exception of a higher proportion of patients with only one metastatic site in the cohort of patients without BM (45% vs. 25% in patients with BM).
Per RECIST 1.1, sotorasib was associated with a DCR of 77.5% in patients with NSCLC and BM as compared to 84.1% in patients without BM. The median PFS was reported at 5.3 and 6.7 months, for patients with and without BM, respectively. The corresponding median OS was 8.3 and 13.6 months respectively. Overall, 8/40 patients (20%) with BM and 26/134 (19%) without BM reported grade 3 treatment-related adverse events (TRAEs). No patients with BM and 2/134 (1.5%) without BM reported grade 4 TRAEs (no fatal TRAEs occurred). Among patients with BM, a median tumour reduction of 27% was reported as compared to 40% in the cohort of patients without BM. Per central RANO BM review, 16/174 (9.2%) patients had baseline and ≥1 on-treatment evaluable scans. In total, 9 patients had 1 lesion; 2 had 4 lesions and 5 had ≥ 5 lesions. Overall, intracranial disease control was achieved in 14/16 patients (88%) with evaluable BM.
Sotorasib demonstrated systemic durable anticancer activity in patients with NSCLC with stable BM previously treated with radiation or surgery. The disease control rate was similar for patients with and without BM at 77.5% vs. 84.1%, respectively. Interestingly, intracranial complete responses were observed with sotorasib, with continued intracranial stabilization in the majority of patients with evaluable BM. Additional investigations are underway to also evaluate sotorasib in patients with active untreated BM (CodeBreaK101).
Ramalingam S et al. Efficacy of Sotorasib in KRAS p.G12C-Mutated NSCLC with Stable Brain Metastases: A Post-Hoc Analysis of CodeBreaK 100. Presented at the 2021 World Conference on Lung Cancer; Abstract P52.03.