Express precise treatment of cholangiocarcinoma, preliminary clinical results of highly specific FGFR2 inhibitors are positive

▎Editor of WuXi AppTec's content team recently, Relay Therapeutics announced that its highly specific FGFR2 oral inhibitor RLY-4008 has achieved positive mid-term in its phase 1 clinical trial in patients with FGFR2 variant cholangiocarcinoma and a variety of other solid tumors.
Data
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FGFR2 is a receptor tyrosine kinase that often mutates in certain cancers
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However, small molecules that inhibit the activity of FGFR2 usually also inhibit the activity of FGFR1 and other FGFR family members.
This off-target effect brings many toxic and side effects in clinical applications
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Relay's proprietary technology platform developed a specific FGFR2 inhibitor RLY-4008 through detailed analysis of the dynamic balance of protein conformation
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Preclinical studies have shown that RLY-4008 exhibits FGFR2-dependent anti-cancer activity in cancer cell lines.
While shrinking tumors, it has minimal impact on other targets (including other proteins in the FGFR family), and has good anti-off-target properties
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In addition, RLY-4008 shows potent activity against known drug-resistant mutations in cells and in vivo preclinical models
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▲RLY-4008 has a very high FGFR2 specificity (picture source: Relay Company's official website) As of September 9, 48 of the 49 patients enrolled in the trial had primary FGFR2 mutations
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Most patients are cholangiocarcinoma patients and have received multiple treatments including pan-FGFR inhibitors (FGFRi), and some patients carry FGFR2 resistance mutations
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The key results of the interim data are as follows: RLY-4008 has good activity in cholangiocarcinoma patients who have not been treated with FGFR inhibitors.
Three of the six patients achieved partial remission, and the tumor shrank by 56% to 83%
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70% of patients with acquired resistance mutations (n=10) showed radiological tumor shrinkage and complete clearance of circulating tumor DNA (ctDNA), indicating that RLY-4008 is expected to treat or prevent acquired resistance
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Early signs of activity were observed outside of FGFR2 fusion-positive cholangiocarcinoma, tumors shrank in 6 patients, and 3 of them achieved confirmed partial remission
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Among all patients undergoing treatment, about 80% of patients achieved radiological tumor shrinkage
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RLY-4008 is generally well tolerated in 49 treated patients and has not been shown to be limited by hyperphosphatemia (associated with inhibition of FGFR1 activity) and diarrhea (associated with inhibition of FGFR4 activity) off-target toxicity
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Most of the adverse events after treatment are low-level adverse events and can be managed
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There were no grade 4 or grade 5 adverse events
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▲RLY-4008 has good activity in cholangiocarcinoma patients who have not been treated with FGFR inhibitors (picture source: Relay’s official website) Dr.
Don Bergstrom, Executive Vice President of Relay R&D, said: “The preliminary clinical evidence of RLY-4008 shows its The potential to have a positive impact on the disease progression of FGFR2 mutant cancer patients
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We will continue to evaluate the once-daily dosing regimen in order to enter the extended cohort study before the end of the year
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"Reference: [1] Relay Therapeutics Announces Interim Clinical Data that Support RLY-4008 as a Highly Selective FGFR2 Inhibitor.
Retrieved October 8, 2021, from https:// 08/2311038/0/en/Relay-Therapeutics-Announces-Interim-Clinical-Data-that-Support-RLY-4008-as-a-Highly-Selective-FGFR2-Inhibitor.
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