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| Ref Type | Journal Article | ||||||||||||
| PMID | (38602417) | ||||||||||||
| Authors | Garmezy B, Borad MJ, Bahleda R, Perez CA, Chen LT, Kato S, Oh DY, Severson P, Tam BY, Quah CS, Harding JJ | ||||||||||||
| Title | A Phase I Study of KIN-3248, an Irreversible Small-molecule Pan-FGFR Inhibitor, in Patients with Advanced FGFR2/3-driven Solid Tumors. | ||||||||||||
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| Abstract Text | Despite efficacy of approved FGFR inhibitors, emergence of polyclonal secondary mutations in the FGFR kinase domain leads to acquired resistance. KIN-3248 is a selective, irreversible, orally bioavailable, small-molecule inhibitor of FGFR1-4 that blocks both primary oncogenic and secondary kinase domain resistance FGFR alterations.A first-in-human, phase I study of KIN-3248 was conducted in patients with advanced solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822). The primary objective was determination of MTD/recommended phase II dose (RP2D). Secondary and exploratory objectives included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular response by circulating tumor DNA (ctDNA) clearance.Fifty-four patients received doses ranging from 5 to 50 mg orally daily across six cohorts. Intrahepatic cholangiocarcinoma (48.1%), gastric (9.3%), and urothelial (7.4%) were the most common tumors. Tumors harbored FGFR2 (68.5%) or FGFR3 (31.5%) alterations-23 (42.6%) received prior FGFR inhibitors. One dose-limiting toxicity (hypersensitivity) occurred in cohort 1 (5 mg). Treatment-related, adverse events included hyperphosphatemia, diarrhea, and stomatitis. The MTD/RP2D was not established. Exposure was dose proportional and concordant with hyperphosphatemia. Five partial responses were observed; 4 in FGFR inhibitor naïve and 1 in FGFR pretreated patients. Pretreatment ctDNA profiling confirmed FGFR2/3 alterations in 63.3% of cases and clearance at cycle 2 associated with radiographic response.The trial was terminated early for commercial considerations; therefore, RP2D was not established. Preliminary clinical data suggest that KIN-3248 is a safe, oral FGFR1-4 inhibitor with favorable pharmacokinetic parameters, though further dose escalation was required to nominate the MTD/RP2D.KIN-3248 was a rationally designed, next generation selective FGFR inhibitor, that was effective in interfering with both FGFR wild-type and mutant signaling. Clinical data indicate that KIN-3248 is safe with a signal of antitumor activity. Translational science support the mechanism of action in that serum phosphate was proportional with exposure, paired biopsies suggested phospho-ERK inhibition (a downstream target of FGFR2/3), and ctDNA clearance may act as a RECIST response surrogate. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| FGFR2 act mut | Advanced Solid Tumor | predicted - sensitive | KIN-3248 | Phase I | Actionable | In a Phase I trial, KIN-3248 treatment demonstrated safety and preliminary activity in patients with advanced solid tumors harboring alterations in FGFR2 or FGFR3, resulting in an objective response rate of 9.25% (5/54, 5 partial responses) and disease control rate of 46% (25/54), with stable disease in 20 patients (PMID: 38602417; NCT05242822). | 38602417 |
| FGFR2 fusion | gastroesophageal junction adenocarcinoma | predicted - sensitive | KIN-3248 | Phase I | Actionable | In a Phase I trial, KIN-3248 treatment demonstrated safety and preliminary activity in patients with advanced solid tumors harboring alterations in FGFR2 or FGFR3, with an objective response rate of 9.25% (5/54, 5 partial responses (PR)), including 2 PRs in patients with gastroesophageal jucntion cancer harboring a FGFR2 fusion (PMID: 38602417; NCT05242822). | 38602417 |
| FGFR3 act mut | Advanced Solid Tumor | predicted - sensitive | KIN-3248 | Phase I | Actionable | In a Phase I trial, KIN-3248 treatment demonstrated safety and preliminary activity in patients with advanced solid tumors harboring alterations in FGFR2 or FGFR3, resulting in an objective response rate of 9.25% (5/54, 5 partial responses) and disease control rate of 46% (25/54), with stable disease in 20 patients (PMID: 38602417; NCT05242822). | 38602417 |