Abstract PS4-06-14: Tinengotinib in advanced or metastatic HR+/HER2- and TNBC: efficacy and biomarker correlative analysis from a phase Ib/II study

Abstract Background: Patients (pts) with advanced/metastatic hormone receptor positive /human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (BC) often develop resistance to endocrine therapy and CDK4/6 inhibitors, while those with triple-negative BC (TNBC) usually lack effective targeted therapies after progression on chemotherapy or antibody drug conjugates. Tinengotinib, a novel multi-kinase inhibitor targeting FGFRs, VEGFRs, Aurora A/B, JAK1/2, and CSF1R, demonstrated preclinical activity in BC models, including those resistant to standard therapies. Here we present the final efficacy, safety and correlative biomarker data of tinengotinib monotherapy in pts with HR+/HER2- and TNBC from the Phase Ib/II trial TT420X1103 (NCT04742959). Methods: Eligible pts with HR+/HER2- BC or TNBC with no effective standard therapeutic treatment options were enrolled. TNBC pts included acquired TNBC (aTNBC) disease, defined as pts initially diagnosed with HR+/HER2- BC but found to be transformed to TNBC at study entry. Tinengotinib was given as monotherapy at 10 mg or 12 mg daily dose (QD) dose levels, or 6 mg twice daily (BID) dose level . Response was assessed per RECIST v1.1, and safety was evaluated per CTCAE v5.0. Biomarker sampling for circulating tumor DNA (ctDNA) analysis was completed at baseline, cycle 3 day 1 (C3D1), the time of response, the time of progression and end of treatment (EOT). Results: As of 20Feb2024, 21 pts with advanced/metastatic BC were treated with tinengotinib monotherapy at 10 mg QD (n=3), 12 mg QD (n=16), and 6 mg BID (n=2) dose levels. All pts were female; median age 58 years (IQR 48-63), ECOG PS 1 in 100% of pts, 18 (85.7%) of pts had Stage IV disease, and 18 (85.7%) of pts had ≥3 lines of prior systemic therapy.Of 20 efficacy evaluable pts, objective response rate (ORR) was 30% (n = 6), duration of response was 4.81 months (mos) (95% CI 3.15, 6.01) and disease control rate (DCR) was 75% (n=16). Treatment related adverse events (TRAEs) were reported in 20 (95.2%) pts, 10 (47.6%) pts had G3/4 TRAEs, and no G5 TRAEs were reported. Eighteen pts were evaluable for ctDNA analysis. Among the most frequent alterations (TP53, DNMT3A, APC, PIK3CA, FGFR2 and PTEN), the incidence of ROS1 mutations was higher in pts with partial response (PR) (p=0.03), as well as in pts with PFS>3.5 mos (p=0.02). Of these 18 pts, 8 had TNBC and 6 had aTNBC. It was observed that pts with aTNBC had a longer PFS vs TNBC pts (4.3 vs 2.6 months, p=0.011); ORR was 67% vs 0% and DCR was 100% vs 50%. The incidence of ROS1 and DNMT3A mutations was higher in aTNBC vs TNBC (p=0.015 and p=0.026, respectively). Analysis showed a reduction in variant allele frequency (VAF) of 7 pts from baseline to C3D1 (p<0.0001), indicating a molecular response with treatment. One pt with progressive disease showed increased VAF in mutations of PIK3CA, PTEN, TP53, and RAD51D from baseline to EOT; 3 pts with acquired resistance to the therapy detected new gene mutations (DNMT3A, NF1, CTNNA1, ERBB3, MLL2, CDKN2A and PDGFRB) at EOT. Conclusions: Tinengotinib exhibited promising clinical benefit and manageable safety profile for the treatment of HR+/HER2- BC or TNBC. The biomarker correlative analysis revealed that ROS1 mutations could be a potential predictive biomarker. Early reduction in ctDNA VAF may serve as a pharmacodynamic biomarker. Baseline genomic alterations in PIK3CA, PTEN, TP53, and RAD51D may contribute to primary resistance, while acquired resistance may be associated with emergence of mutations in pathways of RAS/MAPK, PI3K/AKT, RTK, MET, and cell cycle regulation. The improved clinical outcomes and enrichment of ROS1/DNMT3A mutations in aTNBC pts define this transformed subtype as a subgroup warranting further investigation. Citation Format: S. Piha-Paul, S. Lavasani, F. Dayyani, S. Goel, A. Tsimberidou, N. Ibrahim, C. Barcenas, A. Ilheme, J. Rodon, E. E. Dumbrava, K. Hennessy, P. Peng, C. Sun, H. Wang, R. Xu, J. Fan, F. Meric-Bernstam. Tinengotinib in advanced or metastatic HR+/HER2- and TNBC: efficacy and biomarker correlative analysis from a phase Ib/II study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-14.