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Recently, Relay Therapeutics announced that its highly specific FGFR2 oral inhibitor RLY-4008 has obtained positive mid-term data in a phase 1 clinical trial in patients with FGFR2 variant cholangiocarcinoma and a variety of other solid tumors
.
FGFR2 is a receptor tyrosine kinase that often mutates in certain cancers
.
However, small molecules that inhibit the activity of FGFR2 usually also inhibit the activity of FGFR1 and other FGFR family members.
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
.
In addition, RLY-4008 shows potent activity against known drug-resistant mutations in cells and in vivo preclinical models
▲RLY-4008 has a very high FGFR2 specificity (picture source: Relay's official website)
As of September 9, 48 of the 49 patients enrolled in the trial had primary FGFR2 mutations
.
Most patients are cholangiocarcinoma patients and have received various treatments including pan-FGFR inhibitors (FGFRi), and some patients carry FGFR2 resistance mutations
The key results of the interim data are as follows:
RLY-4008 has good activity in cholangiocarcinoma patients who have not received FGFR inhibitor treatment.
Three of the six patients achieved partial remission, and the tumor shrank by 56% to 83%
.
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
.
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
.
Among all patients undergoing treatment, about 80% of patients achieved radiological tumor shrinkage
.
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
.
Most of the adverse events after treatment are low-level adverse events and can be managed
▲RLY-4008 has good activity in cholangiocarcinoma patients who have not received FGFR inhibitor treatment (picture source: Relay company official website)
Reference materials:
[1] Relay Therapeutics Announces Interim Clinical Data that Support RLY-4008 as a Highly Selective FGFR2 Inhibitor.
(The original text has been deleted)
