Incidence of Brain Metastases and Intracranial Activity of Sotorasib in Patients with NSCLC with G12C Mutation of the KRAS Oncogene

Study Population

A total of 899 patients with metastatic NSCLC with KRAS mutation (of which 392 had the G12C mutation) were enrolled in the study between September 2013 and December 2021. A total of 35.1% of the patients had synchronous brain metastases (i.e., detected within 3 months of the primary diagnosis). There was no significant difference in the incidence of brain metastases between patients with KRAS^G12C (37.2%) and KRAS^non-G12C (33.5%; p = 0.26).

The primary outcome was overall survival (OS). Patients with KRAS^G12C mutation and untreated brain metastases who were taking sotorasib were selected to evaluate its intracranial activity.

Key Findings

Overall survival was significantly longer in patients with metastatic NSCLC without brain metastases (16.0 vs. 13.2 months; p = 0.017). A similar trend (but not statistically significant) was observed in the subgroup with KRAS^G12C mutation (19.0 vs. 16.1 months; p = 0.063).

When comparing NSCLC with KRAS^G12C mutation in patients with synchronous brain metastases and those without, there was no significant difference in the proportional score of the programmed death-ligand receptor (PD-L1; median 40 vs. 20%; p = 0.222) or in tumor mutational burden (TMB; median 9.89 vs. 10.65 mutations/Mb; p = 0.324). In a small number of patients with NSCLC and brain metastases, a new BRCA2 mutation was found (n = 9/95 vs. 1/142; odds ratio [OR] occurrence 0.07; 95% confidence interval [CI] 0.01−0.51; q = 0.021).

A total of 6 patients with NSCLC and KRAS^G12C mutation and untreated brain metastases who started using sotorasib were identified to assess its intracranial activity. With an average follow-up period of 8.8 months (95% CI 7.8 − N/E), the median OS was not reached (95% CI 8.7 − N/E). Below are the case studies of 2 patients with an intracranial response to this treatment.

Selected Cases

Case Study 1

A 75-year-old female patient (with a history of tobacco use) with metastatic lung adenocarcinoma with KRAS^G12C mutation and disease progression after chemotherapy (last line vinorelbine) and treatment with an immune checkpoint inhibitor was found on brain MRI to have multiple supra- and infratentorial lesions (largest 10 × 6 mm in the right lateral cerebellum). On brain MRI 6 weeks after starting treatment with sotorasib at a dose of 960 mg per os once daily, partial regression of all lesions was demonstrated. Treatment continued for 8.8 months from its initiation with minimal side effects.

Case Study 2

A 72-year-old male patient (with a history of tobacco use) with metastatic (liver, skeletal, and brain involvement) NSCLC with KRAS^G12C mutation had new and progressing known lesions (largest 12 mm in the right gyrus precentralis) detected on brain MRI after first-line chemoimmunotherapy. After starting sotorasib, partial regression of the lesions was noted on brain MRI after 5 weeks (and 2 months of therapy). Due to subsequent progression of the largest lesion, the patient underwent stereotactic radiosurgery. Treatment with sotorasib continued for 8 months from its initiation, with good tolerance except for elevated liver parameters.

Conclusion

This retrospective series of cases of metastatic NSCLC with KRAS^G12C mutation and untreated brain metastases provided preliminary evidence of the intracranial activity of sotorasib. In the future, prospective clinical studies with a larger number of participants will be needed.

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Source: Lamberti G., Aizer A., Ricciuti B. et al. Incidence of brain metastases and preliminary evidence of intracranial activity with sotorasib in patients with KRAS^G12C-mutant non-small-cell lung cancer. JCO Precis Oncol 2023; 7: e2200621, doi: 10.1200/PO.22.00621.