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Brief Report: Intestinal Lymphangiectasia With Selpercatinib and Pralsetinib Treatment
Rubio-Perez J1, Daher S1, Lin St2
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Background:
Selective RET inhibitors (SRIs) have durable activity in RET fusion-positive lung cancers. Insidious side effects may emerge with long-term use. This is the first systematic analysis of intestinal lymphangiectasia (IL), an underrecognized disorder characterized by dilated intestinal lacteals and potential lymph leakage, in this population.
Methods:
Patients with RET-altered lung cancers treated with selpercatinib or pralsetinib were eligible for this retrospective analysis. IL was classified as possible (radiologic findings), probable (radiologic and clinical findings), and definite (radiologic, clinical, and endoscopic or pathologic findings).
Results:
Of 113 patients, 33 (29%) had IL-associated radiologic findings. Cumulative incidence at 1, 3, and 5 years was 11% (95% confidence interval [CI], 6%-18%), 27% (95% CI, 19%-36%), and 31% (95% CI: 22%-41%), respectively. Prior immune checkpoint inhibitor exposure was associated with IL risk (hazard ratio, 3.02; 95% CI: 1.53-5.96; p = 0.001). Among patients with IL-associated findings, IL was classified as possible, probable, and definite in 25%, 60%, and 15%, respectively. Median time from SRI initiation to radiologic findings (involving the ileum and duodenum in 67% and 24% of patients with IL, respectively) was 15 months. Radiologic findings were associated with additional clinical findings (e.g., gastrointestinal symptoms, hypoalbuminemia, hypocalcemia, third spacing) in 76% of patients. All patients with assessable endoscopic biopsies had mild lacteal dilatation. IL improved radiologically and clinically in 64% of patients after SRI dose reduction or discontinuation.
Conclusion:
Drug-induced IL occurs with selpercatinib or pralsetinib treatment. The frequency increases with longer drug exposure. Serial monitoring is essential and when necessary, dose modification. Most cases do not lead to treatment discontinuation.
Insights
Selective RET inhibitors (SRIs) can cause intestinal lymphangiectasia (IL) in lung cancer patients. Early detection and dose modification are key, as most cases improve without stopping treatment.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- Selective RET inhibitors (SRIs) demonstrate durable efficacy in RET fusion-positive lung cancers.
- Long-term SRI use may lead to underrecognized side effects like intestinal lymphangiectasia (IL).
- IL is characterized by dilated intestinal lacteals and potential lymph leakage.
Purpose of the Study:
- To systematically analyze the incidence and characteristics of drug-induced intestinal lymphangiectasia (IL) in patients with RET-altered lung cancers treated with SRIs.
- To identify risk factors and clinical manifestations associated with IL in this patient population.
- To evaluate the impact of dose modification or discontinuation on IL outcomes.
Main Methods:
- Retrospective analysis of 113 patients with RET-altered lung cancers treated with selpercatinib or pralsetinib.
- Classification of IL into possible, probable, and definite based on radiologic, clinical, and endoscopic/pathologic findings.
- Assessment of cumulative incidence, time to diagnosis, associated clinical findings, and treatment outcomes.
Main Results:
- 29% of patients exhibited IL-associated radiologic findings, with a 5-year cumulative incidence of 31%.
- Prior immune checkpoint inhibitor exposure was significantly associated with increased IL risk (HR 3.02, p=0.001).
- IL manifested with diverse clinical symptoms and improved in 64% of cases following SRI dose reduction or discontinuation.
Conclusions:
- Drug-induced intestinal lymphangiectasia is an emerging complication of selpercatinib and pralsetinib treatment.
- The incidence of IL increases with longer exposure to SRIs, necessitating serial monitoring.
- While IL can be managed with dose modification, it rarely requires complete treatment cessation.
