dacomitinib + selpercatinib

The combination of dacomitinib and selpercatinib represents a targeted therapy approach for treating EGFR-mutant non-small cell lung cancer (NSCLC) with acquired CCDC6-RET fusion. This combination has shown promise in clinical cases where resistance to single-agent therapy has developed. ## Mechanism of Action Dacomitinib is a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) that targets EGFR mutations, particularly L858R. It works by blocking the activated EGFR kinase, preventing downstream signaling that drives cancer cell growth[3][4]. Selpercatinib is a highly selective RET inhibitor that competitively binds to the ATP-binding site of the RET kinase, preventing autophosphorylation and blocking oncogenic signaling through pathways such as JAK-STAT and MAP kinase[6][8][10]. It was specifically designed to inhibit both wild-type RET kinase (present in RET-fusion-driven cancers) and various RET mutations[6]. ## Clinical Application The combination therapy has been documented in case reports where patients with EGFR-mutant NSCLC developed resistance to dacomitinib through acquired CCDC6-RET fusion[1][2]. In one notable case, a 68-year-old man with EGFR L858R-positive lung adenocarcinoma who developed resistance to dacomitinib due to a CCDC6-RET fusion showed clinical improvement when treated with the combination of dacomitinib (30 mg daily) and selpercatinib (80 mg daily)[1][2]. ## Dosing Considerations The dosing strategy for this combination requires careful consideration due to potential side effects. In the documented case, the selpercatinib dose (80 mg daily) was chosen based on the patient's previous side effects from dacomitinib and the lack of established guidelines for their combined use[1]. The dacomitinib dose was reduced from the standard 45 mg to 30 mg, and eventually to 15 mg in some cases, due to side effects such as acneiform eruption, paronychia, and lower limb edema[1]. ## CNS Activity Both dacomitinib and selpercatinib have demonstrated significant central nervous system (CNS) activity, which is particularly important for patients with brain metastases or neurological complications[1][4]. Dacomitinib has shown intracranial objective response rates of 96.7%, comparable to osimertinib and higher than first-generation EGFR-TKIs[4]. ## Resistance Mechanisms MET amplification has been identified as a mechanism of acquired resistance in patients treated with selpercatinib alone[2]. This suggests that resistance patterns to the combination therapy may be complex and require ongoing monitoring. This combination represents an important treatment option, especially in regions where third-generation treatments like osimertinib may not be accessible due to economic constraints or regulatory reasons[1].