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The safety, tolerability, and preliminary efficacy of the irreversible, small molecule pan-FGFR inhibitor KIN-3248 is under investigation in adult patients with advanced tumors harboring FGFR2 and/or FGFR3 gene alterations, as part of the phase 1 KN-4802 trial.
The safety, tolerability, and preliminary efficacy of the irreversible, small molecule pan-FGFR inhibitor KIN-3248 is under investigation in adult patients with advanced tumors harboring FGFR2 and/or FGFR3 gene alterations, as part of the phase 1 KN-4802 trial (NCT05242822).1
KIN-3248 was developed to address primary FGFR2 and FGFR3 alterations, as well as gatekeeper, molecular brake, activation loop mutations, and others that are expected to drive acquired resistance to FGFR-targeted therapies that are currently available. The agent has demonstrated activity spanning a wide range of mutations that drive primary disease and acquired resistance to other FGFR inhibitors, according to preclinical data.
“With the dosing of the first patient in our phase 1 trial of KIN-3248, we are excited to further advance the development of this next-generation therapy, which we believe is unique among FGFR inhibitors and has the potential to offer a new targeted therapy option for cancer patients with FGFR-altered tumors,” Richard Williams, MBBS, PhD, chief medical officer of Kinnate Biopharma, Inc., stated in a press release.
The multicenter, open-label, 2-part, phase 1 trial is anticipated to enroll approximately 120 patients with advanced-stage solid tumors and known FGFR2 and/or FGFR3 alterations, who have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and acceptable organ function.2
If patients have known clinically active or progressive brain metastases from non-brain tumors; a history of or current abnormal calcium-phosphorous homeostasis, ectopic mineralization or calcification, or corneal or retinal disorder/keratopathy; select gastrointestinal tract disease; or active, uncontrolled bacterial, fungal, or viral infection, they were excluded.
In the dose-escalation portion of the trial, referred to as part A, investigators will identify the recommended dose and schedule of KIN-3248 for further exploration in this population. The dose-expansion phase of the trial, referred to as part B, will examine the safety and efficacy of the agent at the recommended dose and schedule in patients with cancers driven by FGFR2 and/or FGFR3 alterations who were either naïve to, or pretreated with, FGFR inhibitors; this portion of the research will include patients with intrahepatic cholangiocarcinoma and those with urothelial carcinoma.
Approximately 10% to 20% of patients with cholangiocarcinoma harbor FGFR2 alterations.3 To date, 2 agents have been approved by the FDA for use in those whose tumors harbor FGFR2 gene fusions or rearrangements: pemigatinib, which was approved in April 2020 based on interim data from the phase 2 FIGHT-202 trial (NCT02924376),4 and infigratinib, which was approved in May 2021 based on findings from a phase 2 trial (NCT02150967).5
Secondary on-target FGFR2 resistance mutations have been found to occur in more than half of patients with cholangiocarcinoma who received approved FGFR inhibitors at the time of disease progression. KIN-3248 has been shown to have strong potency against wild-type FGFR1, FGFR2, and FGFR3. Unlike the FGFR inhibitors that have regulatory approval, this agent was noted to retain nanomolar biochemical activity against resistance mutations in FGFR2 and FGFR3.
Moreover, in cholangiocarcinoma cell lines that were engineered to express primary FGFR2 fusions and secondary resistance mutations, the agent proved to be active. In vivo, when administered to cancer cell lines or patient-derived mouse xenograft models, KIN-3248 was noted to be efficacious with acceptable tolerability. Across mouse models that harbored several mutations like M528I, M539L, and N550K molecular brake mutations, the agent resulted in tumor regressions that ranged from 68% to 116%.
When compared with other approved FGFR inhibitors, the agent showcased superior activity against distinct kinase domain mutations. Moreover, the in-vivo tumor reductions that were reported with the agent were found to be linked with strong inhibition of FGFR2 signaling.
“Successfully treating intrahepatic cholangiocarcinoma and urothelial cancer patients with FGFR2 and/or FGFR3 gene alteration–driven cancers remains a significant unmet need in cancer care,” Benjamin Garmezy, MD, assistant director of Genitourinary Research at Sarah Cannon Research Institute, Tennessee Oncology, added in the press release. “KIN-3248 brings a unique approach to potentially address the shortcomings of existing therapies in specific patient populations with primary FGFR2 and/or FGFR3 oncogenic alterations, including those patients with gatekeeper, molecular brake, and activation loop mutations.”