Sotorasib in the Treatment of a Patient with NSCLC and DIC – A Case Report
Sotorasib is the first clinically used inhibitor of the KRAS oncogene with the G12C mutation. Its efficacy in the targeted treatment of non-small cell lung cancer (NSCLC) is still under research, but it is expected to bring significant benefits. The effect of sotorasib in a patient with a low baseline performance status (PS) and active brain metastases is presented in the following case report.
Case Description
A 62-year-old female patient, a smoker (7.5 pack-years), was diagnosed with lung adenocarcinoma in clinical stage IVB (T2N2M1c), with no targetable oncogenic mutation proven at the time of diagnosis.
First-line treatment was initiated with chemoimmunotherapy combining carboplatin, pemetrexed (500 mg/m2), and atezolizumab (1200 mg). This was followed by a 7-month remission period. Upon documented disease progression, second-line treatment with docetaxel (75 mg/m2) was administered. After 2 months of treatment, disease progression was again noted.
For the initiation of third-line treatment, the patient was admitted with proven brain metastases and thrombocytopenia. At this time, her PS was 3. Tests indicated disseminated intravascular coagulation (DIC) with a platelet count of 58,000/μl, fibrinogen level of 87 mg/dl, prothrombin index of 45%, and D-dimer level of 12.7 μg/ml.
Treatment with sotorasib was initiated as part of an ongoing clinical trial program. Two weeks after the start of treatment, the platelet count normalized within reference values, and the patient's overall condition improved – her PS reached a score of 1. After 2 months of treatment, imaging studies showed containment of metastases in the lungs and liver and the disappearance of brain metastases. No toxicity related to sotorasib was observed during treatment.
After 4 months, an increase in carcinoembryonic antigen (CEA) levels was noted, and a newly appeared tumorous mass in the liver was biopsied. It was verified as a TTF1-positive metastasis of lung adenocarcinoma. Next-generation sequencing (NGS) did not reveal any new targetable mutations, except for the already detected KRASG12C and TP53G154V tumor suppressor gene mutations (detected prior to the initiation of third-line treatment).
Discussion
Rapid responses to molecular-targeted therapy for NSCLC have been reported in the literature, but the above case report represents the first published instance of such a response with sotorasib in the treatment of lung cancer with the KRASG12C mutation. Although the achieved remission duration was shorter compared to other treatments, a very rapid and significant improvement in the patient's performance status was observed. It hence seems appropriate to evaluate the occurrence of the KRAS oncogene mutation in all patients with low performance status who are considered for further treatment. Alongside the KRASG12C mutation, other gene mutations (TP53, LRP1B, STK11, KEAP1, and CDKN2A) frequently co-occur. Some of these (TP53, STK11, and KEAP1) are associated with the effectiveness of sotorasib treatment and potential resistance development.
In the reported case, sotorasib treatment led to significant tumor mass reduction, though a resistant lesion appeared in the liver after some time. No additional relevant mutations were detected in this lesion. The resistance development mechanism has been described in relation to the enhanced ability of tumor cells to rapidly synthesize KRASG12C proteins following patient exposure to the KRASG12C inhibitor.
Notable adverse effects of sotorasib treatment include increased liver enzyme activity – alanine aminotransferase (ALT) and aspartate aminotransferase (AST). A decline in platelet count may also occur, although severe thrombocytopenia has not been observed in any monitored case, nor has sotorasib-associated DIC. In the presented case report, the drug was administered to a patient with laboratory-confirmed DIC, but no bleeding complications or symptomatic coagulopathy developed.
Sotorasib was previously considered effective in patients with stable brain metastases and now seems beneficial in patients with active metastases as well.
Conclusion
The published case of a 62-year-old woman describes the promising effect of sotorasib in the treatment of rapidly progressing NSCLC with the KRASG12C mutation and multiple metastases. After administration, there was a rapid improvement in performance status, quality of life, and tumor burden reduction. This short-term, but significant, improvement is noteworthy regarding subsequent treatment options.
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Source: Kunimasa K., Tamiya M., Inoue T. Rapid response to sotorasib of a patient with KRAS G12C-mutated lung cancer with cancer-associated disseminated intravascular coagulation: a case report. JTO Clin Res Rep 2022 Dec 6; 4 (1): 100442, doi: 10.1016/j.jtocrr.2022.100442.
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