Emergence of ALK Fusion Following RET TKI Therapy in NSCLC: Evidence of Bypass Resistance

Rearranged during transfection (RET) gene fusions develop in 1-2% of non-small cell lung cancer (NSCLC) cases, providing a promising target for novel cancer therapies, including RET tyrosine kinase inhibitors (RET-TKIs). Two RET-selective tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, have proven effective and tolerable in improving clinical outcomes in patients with RET fusion-positive lung cancer. However, multiple mechanisms of resistance to targeted RET therapies have been reported, most of which occur independently of RET in genes such as BRAF, EGFR, KRAS, or MET, highlighting the importance of identifying potential targets for new treatments. Anaplastic lymphoma kinase (ALK) fusions, with EML4-ALK being the most prevalent, are seen in approximately 5-7% of patients with NSCLC and have been reported to develop either de novo or as a resistance mechanism to EGFR-targeted therapy. While RET and ALK fusions are both known to be implicated in NSCLC, and in one case, secondary RET fusion occurred in response to ALK-TKIs, there have been no reported instances to date of ALK fusion developing as a mechanism of resistance to RET-targeted therapy.

We present a unique case of an acquired EML4-ALK fusion developing as a mechanism of resistance to RET-TKI therapy, which, to our knowledge, is the first instance of this co-mutation evolving secondary to RET fusion. This patient was diagnosed with stage IV NSCLC with a baseline KIF5B-RET gene fusion, and she was treated with the RET-TKI selpercatinib for ten months with eventual progressive disease (PD) and emergence of a secondary EML4-ALK fusion upon repeat genetic testing. She was subsequently treated with a combination of selpercatinib and brigatinib therapy for two months, during which she demonstrated clinical and radiographic response, before she eventually died from comorbidities while in hospice care.

This case presents a previously unseen mechanism of resistance to RET fusion with an emergent ALK fusion, and describes the clinical outcomes of second-line brigatinib treatment after PD on selpercatinib. These findings demonstrate the clinical benefit of repeat genomic testing in patients with NSCLC to guide targeted molecular treatments, and additionally contribute to the current understanding of acquired resistance mechanisms to RET-TKIs and associated patient outcomes.