A phase 2, open-label, single-arm study of lirafugratinib in patients with previously treated, unresectable, locally advanced, or metastatic solid tumors (excluding cholangiocarcinoma) with <i>FGFR2</i> fusion or rearrangement.

TPS4251 Background: Tissue agnostic cancer therapies offer the potential to markedly change the treatment landscape by targeting oncogenic drivers rather than the tumor’s site of origin. Lirafugratinib is the first highly selective, irreversible inhibitor designed to target oncogenic fibroblast growth factor receptor ( FGFR)2 driver alterations and resistance mutations. In the phase 1/2 ReFocus Trial (RLY-4008-101; NCT04526106),46 subjects (Group 3) with non-cholangiocarcinoma solid tumors harboring FGFR2 fusion/rearrangements (f/r) received lirafugratinib 70 mg once daily. The ORR was 33.3% (95% CI 19.6 - 49.5). However, this sample size was insufficient to support regulatory approval of lirafugratinib for a tissue agnostic indication. Methods: The ELE-4008-202, phase 2, open-label, single-arm study (NCT07359820) is designed to further evaluate the efficacy and safety of lirafugratinib 70 mg in 20-30 subjects across 20 sites with FGFR2 f/r, previously treated, unresectable, locally advanced or metastatic, non-CCA solid tumors who have not received prior FGFR inhibitor therapy. The primary endpoint is objective response rate (ORR) by independent review committee (IRC) per RECIST v1.1; key secondary endpoints include duration of response (DOR) by IRC, investigator-assessed efficacy endpoints, safety, pharmacokinetic (PK) parameters, and quality of life (QoL) per EORTC QLQ-C30. Efficacy will also be evaluated for ORR, DOR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), time to response (TTR), time to progression (TTP) per investigator. Time to discontinuation (TTD) will also be assessed. Exploratory endpoints will include FGFR2 genotype per tissue assessment or liquid biopsy vs ORR and levels of other biomarkers in relationship to clinical activity. An interim analysis of the pooled efficacy dataset from ELE-4008-202 and Group 3 of RLY-4008-101 will be conducted once approximately 65 evaluable subjects with non-CCA tumors have been enrolled across ≥7 tumor types (≥5 subjects per tumor type). Enrollment of a tumor type may be capped once it has reached approximately 20% of the total subjects in the pooled data from the two studies. With 65 subjects, observing at least 21 subjects with a complete response (CR) or partial response (PR) (ORR ≥32%), will result in a 95% CI (lower bound &gt;20%) with the probability of observing ≥21 responders assuming a true ORR of 40% is approximately 92%. The results of this analysis will determine whether the pooled evaluable data from RLY-4008-101 and ELE-4008-202 meet regulatory requirements to support a tissue-agnostic indication for FGFR2 f/r non-CCA solid tumors. Clinical trial information: NCT07359820 .