osimertinib + selpercatinib

Osimertinib + selpercatinib is a combination therapy that targets two distinct oncogenic drivers in NSCLC. This combination is specifically used to overcome resistance to osimertinib in EGFR-mutant lung cancer patients who have acquired RET fusions as a resistance mechanism. Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that targets EGFR mutations, while selpercatinib is a selective RET kinase inhibitor that targets RET fusions. The combination has shown promising efficacy in clinical trials and compassionate use programs, with response rates of approximately 50% and disease control rates of 83% in patients with EGFR-mutant and RET fusion-positive lung cancers who experienced prior progression on osimertinib[1][2]. The most common dosage regimen is osimertinib 80 mg daily combined with selpercatinib 80 mg twice daily[1]. The combination has demonstrated clinical benefit with a median treatment duration of 7.9 months, with some patients experiencing responses lasting over 25 months[2]. Resistance mechanisms to this combination therapy can be complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target mechanisms (EML4-ALK/STRN-ALK, KRAS G12S, BRAF V600E), as well as RET fusion loss or polyclonal mechanisms[1]. The combination is generally well-tolerated with manageable side effects, including fatigue, hypertension, xerostomia, increased creatinine, and dermatitis acneiform[7].