Successful and On-going Long-Term Disease Control (>24 Months) with Gilteritinib in an ALK+ NSCLC Patient with Brain Metastasis Who Has Progressed on Multiple ALK TKIs. A Case Report and Review of Literature on Gilteritnib

Sai-Hong Ignatius Ou,1,2 Cathleen June Park,1,2 Zhaohui Liao Arter,1,2 Misako Nagasaka1,2 1Department of Medicine, University of California Irvine School of Medicine, Orange, CA, 92868, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, 92868, USACorrespondence: Sai-Hong Ignatius Ou, University of California Irvine School of Medicine, 200 South Manchester Ave, Suite 400, Orange, CA, 92868, USA, Email [email protected]: Despite the approval to date of 3 generations of ALK tyrosine kinase inhibitors (TKIs) and the clinical development of a 4th-generation ALK TKI, neladalkib (NVL-655), patients still eventually progress on sequential treatment of various generations of ALK TKIs. Patients with advanced ALK+ NSCLC can survive many years with sequential use of various generations of ALK TKIs but will eventually exhaust all approved available ALK TKIs. Further options for these patients besides clinical trial could include the repurposing of approved multi-targeted TKIs for other oncologic indications. Gilteritinib, a multi-targeted FLT3 (and AXL, ALK, ROS1) TKI, is approved as monotherapy at 120 mg once daily for FLT3+ refractory/relapsed acute myelogenous leukemia (AML).Case Description: Patient is currently an 82-year-old African-American female never-smoker who was diagnosed with stage 4 NSCLC at age 62. Almost 7.5 years after initial diagnosis and after disease progression on multiple chemotherapy regimens, her tumor was found to harbor an EML4-ALK v1 fusion. Since then, she has been treated with multiple ALK TKIs including crizotinib, alectinib, brigatinib, and lorlatinib sequentially (from age 75 to 80) but requiring dose reduction and interruption of lorlatinib due to neurocognitive toxicity from previous stereotactic brain radiation and resection and eventual discontinuation of lorlatinib. Repeat plasma genotyping after discontinuation of lorlatinib revelaed EML4-ALK v1 without known off-targeted resistances. With written consent from patient and family, she was started on gilteritinib 80 mg once daily with a quick dose increase to 120 mg and achieved stable disease with rapid clearance of ALK fusion from plasma, stability of the CNS metastasis, as well as a decrease in CEA and size of the left upper lesion. Patient is alive today and doing well without CNS effects while on full-dose gilteritinib.Conclusion: This is the first patient case report with > 24 months on-going follow-up demonstrating that gilteritinib could be repurposed as a potent and tolerable ALK inhibitor based on previously reported pre-clinical activity and with potential CNS activity. A Phase 2 trial of gilteritnib in alectinib- or lorlatinib-refractory ALK+ NSCLC is being planned (NCT07140016).Plain Language Summary: Key findingsGilteritinib could be repurposed as a potent and tolerable ALK TKI with CNS activity.What is known and what is newPreclinically, gilteritinib has been demonstrated to possess potent ALK inhibitory activity with an IC50 similar to lorlatin (Figure 1) and can overcome certain acquired ALK mutations. Gilteritinib has also demonstrated activity in AML harboring an RANBP2-ALK fusion. This case report extends this pre-clinical observation to successfully treating one patient with advanced ALK+ NSCLC with progression on all three generations of ALK TKI and not eligible for clinical trial with neladalkib, demonstrating safety of full-dose gilteritinib 120 mg once daily with intracranial activity without CNS adverse events, unlike what this patient experienced with lorlatinib even at a very low dose.What is the implication, and what should change now?Gilteritinib could be repurposed as a potent and tolerable ALK TKI in the refractory/relapsed setting against several single acquired ALK resistance mutations (but not ALK G1202R gate-keepr mutation) without off-target resistance mechanisms. Given its safety, tolerability, and similar IC50 to lorlatinib (IC50 = 0.78nM [gilteritinib]; IC50 = 1.2nM [lorlatinib]), gilteritinib should be investigated in earlier settings in the treatment of advanced ALK+ NSCLC. Currently, there is a Phase 1– 2 clinical trial of gilteritinib in ALK+ NSCLC ongoing at the University of Michigan (NCT06225427) and Astellas Pharma Inc, which owns gilteritinib, is planning phase 2 trial of gilteritinib in alectinib- and lorlatinib-refractory ALK+ NSCLC patients (NCT07140016).Keywords: gilteritinib, lorlatinib, ALK fusion, non-small cell lung cancer