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Clinical Trial
. 2024 Apr 30;4(4):1165-1173.
doi: 10.1158/2767-9764.CRC-24-0137.

A Phase I Study of KIN-3248, an Irreversible Small-molecule Pan-FGFR Inhibitor, in Patients with Advanced FGFR2/3-driven Solid Tumors

Benjamin Garmezy  1 , Mitesh J Borad  2 , Rastilav Bahleda  3 , Cesar A Perez  4 , Li-Tzong Chen  5 , Shumei Kato  6 , Do-Youn Oh  7 , Paul Severson  8 , Betty Y Tam  9 , Cheng S Quah  8 , James J Harding  10
Affiliations
Clinical Trial

A Phase I Study of KIN-3248, an Irreversible Small-molecule Pan-FGFR Inhibitor, in Patients with Advanced FGFR2/3-driven Solid Tumors

Benjamin Garmezy et al. Cancer Res Commun. .

Abstract

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusion: 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.

Significance: 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.

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Figures

FIGURE 1
FIGURE 1
KIN3248 mean concentrations (mean ± SD) in patients following oral daily administration of KIN-3248 during cycle 1 day 1 and day 2.
FIGURE 2
FIGURE 2
Serum phosphate by KIN-3248 C1D1 exposure. Baseline and on-treatment serum phosphate were measured locally in all 54 participants. A, Scatter plot of serum phosphate (mg/dL) after approximately 1 week on KIN-3248 by KIN-3248 C1D1 exposure (AUC0–24). Significant correlation between KIN-3248 exposure and serum phosphate level after approximately 1 week of treatment (nominal C1D8: actual study days 6, 7, 8 or 9). Linear fit with SE. Pearson R = 0.55, P = 1.7e-5. B, Scatter plot of initial change in serum phosphate by KIN-3248 C1D1 exposure (AUC0–24). Significant correlation between C1D1 KIN-3248 exposure and the initial change (∼1 week) in serum phosphate (PhosC1D8 – PhosC1D1). Pearson R = 0.62, P = 7.1e-7. One participant was missing the C1D1 phosphate measurement, so the screening measurement was used as the baseline value for that participant.
FIGURE 3
FIGURE 3
Antitumor activity. A, Best percent change in target lesions by KIN-3248 starting dose level. Bars are color-coded by the gene (FGFR2 or FGFR3) that was altered according to the molecular report provided for study eligibility evaluation (local testing). Bars are labeled with the best overall response for each evaluable participant. X-axis is labeled with the tumor type of each participant, with the labels color-coded (black or red) to show which participants have been previously treated (*) with one or more FGFR inhibitors. Participants with documented on-target acquired resistance mutations, either by local testing or central ctDNA analysis, are indicated with distinct symbols. B, Twenty-six patients were evaluable for efficacy and were tested by central ctDNA analysis. Box and whisker plot of change in mean variant allele frequency of ctDNA after first cycle of KIN-3248 treatment by best overall response. C, Scatter plot of change in mean variant allele frequency of ctDNA after first cycle of KIN-3248 treatment by best % change in target lesions. X-axis direction is reversed. Linear fit with SE. Pearson R = 0.45, P = 0.021.
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