RET rearrangement as a mechanism of resistance to ALK-TKI in non-small cell lung cancer patient with EML4-ALK fusion: A case report

Patients with non-small cell lung cancer (NSCLC) and anaplastic lymphoma kinase (ALK) mutations have previously derived substantial benefits from ALK tyrosine kinase inhibitors (ALK-TKIs). However, resistance may develop in some patients. We present a case of co-mutation with anaplastic lymphoma kinase (ALK) and rearranged during transfection (RET)-rearranged NSCLC, representing a novel resistance mechanism to ALK-TKIs, in which the patient exhibited a favorable response to combination therapy with ensartinib and pralsetinib. Notably, the patient survived 12 months without experiencing adverse events, a rare occurrence in ALK-rearranged lung adenocarcinoma cases. This case provides further evidence for the existence of RET rearrangements in ALK-positive lung cancer and their potential treatment response to a combination of ALK inhibitors and pralsetinib. This case underscores that a dual-target therapy involving ALK inhibitors, specifically ensartinib and pralsetinib, could be a viable approach in cases of RETrearranged lung cancer with concurrent targetable ALK mutations. We propose the consideration of this dual-target approach, specifically employing ensartinib and pralsetinib, in managing RET-rearranged lung cancer coexisting with targetable ALK mutations. Given the potential efficacy of these treatments, it is imperative to proactively conduct molecular profiling tests in NSCLC patients upon the emergence of resistance.