Background: A TKI involved in cell proliferation, migration and differentiation. RET chromosomal rearrangements, the product of intact tyrosine kinase domain of RET protein fusing with a portion of another gene, were first identified in lung adenocarcinoma in 2012. These fusions result in constitutive activation of RET, which promotes cancer cell growth, proliferation and survival. RET fusions have been identified in 1% to 2% of NSCLC and are exclusive of EGFR, ALK, KRAS and BRAF mutations.
- Clinical Features Associated: younger age, minimal/no smoking history, adenocarcinoma histology — the majority of patients have stage IV disease and have early lymph node metastasis and higher risk of brain metastasis.
Detection Methods: FISH, IHC, RT-PCR, NGS, liquid biopsy
Most Common Alterations:
- Fusion Partners: The most common and well characterized of RET fusion partners is KIF5B, accounting for approximately 70% of RET rearrangements followed by CCDC6 (10-25%) and NCOA4.
- Additional Fusion Partners Identified Include: CUX1, MYO5C, EPHA5, TRIM33, CLIP1, ERC1, PICALM, FRMD4A, RUFY2, KIAA1468, KIAA1217, ZNF477P, HTR4, and TRIM24.
- Acquired Resistance Mutations: The most common mutations identified post-TKI include RET V804 gatekeeper mutation, G810S/R/C, and S904F.
FDA-Approved Targeted Therapies:
- Selpercatinib (Retevmo, Eli Lilly):
- Highly selective ATP-competitive small-molecule RET inhibitor received approval by the FDA in 2020 for the treatment of advanced RET-rearranged NSCLC. Selpercatinib has been shown to have significant CNS penetration and low drug interactions. Approval was based on the phase 1/2 LIBRETTO-001 study of patients with advanced RET fusion-positive NSCLC. At time of approval, an ORR of 68% was found in previously treated patients with a median PFS of 18.4 months. An ORR of 85% was found in treatment-naive patients. Updated results of the LIBRETTO-001 study in 2019 showed an ORR in patients with CNS metastasis of 91%.
- Most Common Adverse Events: dry mouth, diarrhea, hypertension, elevated liver enzymes, fatigue, constipation, headache, nausea, elevated creatine levels, swelling of the hands and legs
- Pralsetinib (Gavreto; Blueprint Medicines, Genentech):
- Highly selective RET inhibitor was granted approval by the FDA in 2020 for adults with metastatic RET fusion-positive NSCLC. Pralsetinib has been shown effective in both patients with NSCLC with primaryRET fusions and mutations as well as acquired RET resistance mutations. Approval was based on the phase 1/2 ARROW multi-cohort trial of patients with RET-positive NSCLC. At the time of approval, an ORR of 57% was found for previously treated patients with 5.7% experiencing a complete response and 80% experiencing a response of 6 months or longer. An ORR of 70% was found in treatment-naive patients, with 11% experiencing a complete response and 58% experiencing a response of 6 months or longer. Additionally, an ORR of 55% was found in patients with measurable brain metastasis
- Most Common Adverse Events: fatigue, elevated liver enzymes, anemia, constipation, hypertension, low white blood cell count, diarrhea, elevated creatine, low neutrophil count, musculoskeletal pain
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