Promising Response with Sotorasib in a Patient with KRAS G12C–Mutated Lung Cancer and Brain Metastases

KRAS mutations are one of the most common mutations in non–small-cell lung cancer (NSCLC) and are found in approximately 20% to 35% of all patients. Only recently has an effective targeted therapy against KRAS-mutated NSCLC been found. The CodeBreaK100 phase 2 clinical trial examined sotorasib, a KRAS G12C inhibitor. Sotorasib is a small molecule that works by binding to KRAS G12C and trapping it in an inactive state, rendering it ineffective at oncogenic signaling. Based on the positive results of the CodeBreaK100 trials, the US Food and Drug Administration approved its use in May 2021 for the treatment of patients with advanced or metastatic KRAS G12C NSCLC who have been treated with ≥1 lines of systemic therapy. The phase 2 study found that the objective response rate was 37%, the disease control rate was 80.6%, and the median duration of response was 11.1 months for these patients. Although patients with active untreated brain metastases were excluded, patients with evidence of metastatic brain disease were included in the study.

In the November 2022 article published on behalf of the International Association for the Study of Lung Cancer, the case of a 61-year-old man who had progressively worse headaches was presented. At first the headaches were assumed to be due to a left occipital hematoma, but after surgical tumor resection he was found to have active brain metastases due to adenocarcinoma with a primary lung origin in the right upper lobe (RUL). Next-generation sequencing of paratracheal node biopsy found KRAS G12C, TP53 V157F, and ARID2 E101 mutations. Postoperatively the patient was given stereotactic radiosurgery to the cranial resection cavity, and he was started on pembrolizumab 200 mg every 3 weeks. He developed thyroiditis that progressed to grade 2 hypothyroidism, which was treated with thyroid replacement therapy. After 4 cycles of pembrolizumab his RUL mass was stable. The fifth treatment cycle was delayed due to weakness and fatigue for what was thought to be grade 3 hypothyroidism requiring hospitalization. The thyroid replacement dose was increased, and the patient was discharged from the hospital with supportive care.

Within a week the patient was readmitted to the hospital with severe disorientation and profound weakness. Magnetic resonance imaging (MRI) of the brain revealed disease progression with leptomeningeal disease and multiple brain metastases. Corticosteroids were given and the patient’s family elected for hospice care and a trial of 960 mg of sotorasib daily. Brain radiation was discontinued. After 2 weeks of treatment with sotorasib, the patient had marked improvement in strength and mental status. A repeat brain MRI at 1 month of treatment showed that most lesions had resolved or were significantly smaller. Chest computed tomography showed a reduction in the RUL mass and lymph nodes. Approximately 2 months after sotorasib treatment, the patient developed grade 2 transaminitis, which eventually led to permanent discontinuation despite dose reduction and steroid treatment. Brain MRI 1 month after discontinuation showed ongoing intracranial response. Third-line therapy of carboplatin, pemetrexed, and bevacizumab was initiated 6 weeks after sotorasib discontinuation, and the patient remained on this treatment at the time of article submission.

Source: Yeh J, Marks JA, Alzeer AH, et al. Remarkable intracranial response to sotorasib in a patient with KRAS^G12C-mutated lung adenocarcinoma and untreated brain metastases: a case report. JTO Clin Res Rep. 2022;3(12):100428.