CONTRADICTING EVIDENCE: The patient was enrolled into LIBRETTO-321 on the basis of detection of a KIF5B-RET fusion….After the initiation of first-line therapy with selpercatinib, the best overall response by IRC was partial response (PR)....The best intracranial response was a PR, which was also observed from week 4 until week 88 (Figs 2A-2D). There were no grade ≥3 AEs or dose modifications because of AEs. As of March 2022, the patient remains on treatment with a total treatment duration of 24.0 months.

We present here a case of TKI resistance in a patient with KIF5B-RET fusion advanced NSCLC. Following progression on cabozantinib, he was started on selpercatinib. At the time of initial diagnosis molecular profiling revealed a KIF5B-RET fusion...he initiated cabozantinib, remained on therapy for 4 months with subsequent progression at multiple sites. He was treated with selpercatinib for 23 months before oligometastatic progression. Molecular analysis via cell-free DNA again revealed KIF5B-RET fusion without any alterations known to cause TKI resistance.

Evidence of disease progression with a new adrenal lesion was seen on a subsequent scan 7.5 months after the selpercatinib treatment...Concurrently, plasma genotyping revealed the re-emergence of KIF5B-RET and RET-RPP38 at an AF of 4.59% and 2.30%, respectively. The original TP53 P190T was again detected at an AF of 12.2%. A high level of MET amplification (copy number ∼17), not previously present, was identified from plasma genotyping at the time of progression ( Fig. 2)...Given her symptomatic recurrence, no tumor re-biopsy was performed at the time of selpercatinib progression.