SY28-4 Clinical development of RET inhibitors for RET fusion positive non-small cell lung cancer (NSCLC)

Abstract

RET gene rearrangements retaining the kinase domain are oncogenic drivers in NSCLC, papillary thyroid cancer, and multiple other cancers. In NSCLC, the most common RET fusion partners are KIF5B (most common) and CCDC6. The frequency of RET fusion positive NSCLC was reported 1-2% and, it was also 2% (182/8621, between Feb. 2013 and Oct. 2020) in the East Asian lung cancer genomic screening (LC-SCRUM-Asia). Base on the LC-SCRUM-Asia clinical genomic database, the patient characteristics were median age 61 (29-85) years, female 62%, never smoker 64% and adenocarcinoma 97%. Because RET fusion is thus an attractive therapeutic target in NSCLC, multikinase inhibitors with RET inhibitor activity, such as vandetanib and cabozantinib, have been evaluated in prospective clinical trials. A clinical study of vandetanib for RET fusion positive NSCLC (LURET study) was conducted in Japan and objective response rate (ORR) was 53% and median progression free survival was 4.7 months. However, as a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea and this resulted in only limited clinical efficacy. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors such as selpercatinib (LOXO-292) and pralsetinib (BLU-667) demonstrated improved efficacy and a more favorable toxicity profile. These drugs appear to have broad activity across tumors with activating RET alterations. In a phase I/II clinical trial of selpercatinib (LIBRETTO-001), ORR 64% in 105 previously treated RET fusion positive NSCLC and 85% in 39 previously untreated patients were observed. RET-selective inhibitors selpercatinib and pralsetinib demonstrated favorable antitumor activity and safety profiles in RET fusion positive advanced NSCLC, and both received approval by the US FDA for it. In addition, the mechanisms of resistance to selective RET inhibitors are currently investigated.