2023 Targeted Therapies of Lung Cancer Meeting (Poster)-P1.18. Phase II Trial of Regorafenib and Oral Methotrexate in Previously Treated Advanced KRAS Mutant Non-Small Cell Lung Cancer

P1.18. Phase II Trial of Regorafenib and Oral Methotrexate in Previously Treated Advanced KRAS Mutant Non-Small Cell Lung Cancer

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A phase II trial was conducted to evaluate the efficacy and safety of the combination of regorafenib, a multi-kinase inhibitor, and oral methotrexate in patients with previously treated advanced KRAS mutant non-small cell lung cancer (NSCLC). KRAS mutant NSCLC currently has limited targeted treatment options beyond KRAS G12C inhibitors. Computational modeling identified regorafenib and methotrexate as a potential therapeutic option due to their synergistic inhibition of multiple targets in KRAS mutant NSCLC. <br /><br />The trial enrolled 18 patients with metastatic or recurrent KRAS mutant nonsquamous NSCLC who had received at least one prior line of systemic therapy. Regorafenib was administered at a daily dose of 80-120 mg, while methotrexate was given twice weekly and dose escalated if tolerated. The primary endpoint of the trial was progression-free survival (PFS).<br /><br />The results showed that the combination treatment was limited due to toxicity, and thus the study did not meet its primary endpoint. The median PFS was 3.7 months, and the median overall survival (OS) was 10.4 months. Prolonged stable disease was observed in some patients. The unconfirmed objective response rate (ORR) was 16.7%, with three partial responses observed. The disease control rate (DCR) at 8 weeks was 66.7%.<br /><br />Treatment-emergent adverse events of grade 3 occurred in 14 patients, with dyspnea and hypophosphatemia being the most common. One dose-limiting toxicity (DLT) occurred, and one patient experienced a treatment-unrelated grade 5 aspiration.<br /><br />Although the combination treatment did not demonstrate significant efficacy in this trial, ongoing analysis of circulating tumor DNA (ctDNA) dynamics using the CAPP-seq method may provide further insights. <br /><br />In conclusion, the combination of regorafenib and oral methotrexate showed limited efficacy in patients with KRAS mutant NSCLC due to toxicity. More research is needed to explore alternative treatment options for this patient population.

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Jacqueline Aredo, Stanford Cancer Institute, United States

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Speaker Jacqueline Aredo, Stanford Cancer Institute, United States

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Keywords

phase II trial

efficacy

safety

combination

regorafenib

methotrexate

KRAS mutant NSCLC

toxicity

progression-free survival

alternative treatment options