As of the Data Cut-off Date, 48 of the 49 patients enrolled had a primary FGFR2 alteration, of which a majority were FGFR2 fusion cholangiocarcinoma. Most patients had high disease burden with multiple prior treatments including pan-FGFR inhibitors, and several had FGFR2 resistance mutations detected by circulating tumor DNA (“ctDNA”), at baseline. Patients were treated at nine different once daily (“QD”), or twice daily (“BID”) dose levels, ranging from 20 mg QD to 70 mg QD and 20 mg BID to 100 mg BID. As of the Data Cut-off Date, duration of treatment ranged from 4 to 45 weeks.
Initial Safety Analysis
The interim clinical data of the RLY-4008-101 Trial indicate that RLY-4008 has generally been well tolerated in the 49 patients treated as of the Data Cut-Off Date. With regard to dosing, the QD dosing schedule has been prioritized due to its preferable tolerability (as only one dose limiting toxicity (“DLT”) was observed across all dose levels) and high target coverage (lowest dose of 20 mg exceeded 85% receptor occupancy). Within the BID dosing schedule there were five DLTs observed, and receptor occupancy ranged from 90% to 98% across the BID doses.
Across all QD doses only 16% of patients, all Grade 1 or 2, experienced hyperphosphatemia, a toxicity that has been shown to limit dose intensity for pan-FGFR inhibitors in other studies. These data indicate that RLY-4008 had little or no FGFR1 inhibition at the examined dose levels. Additionally, little or no diarrhea was observed with RLY-4008 treatment suggesting minimal or no FGFR4 inhibition in treated patients to date across dose levels. Together, the interim data suggest that RLY-4008 is a highly selective FGFR2 inhibitor in humans.
Most treatment emergent adverse events were low-grade adverse events and manageable. There have been no Grade 4 or 5 adverse events. Given that retinal toxicity has been observed with FGFR inhibitor treatment, the trial is designed to assess retinopathy and retinal pigment epithelial dystrophy adverse events, which have been observed in seven patients (14%), three of which occurred in the QD dosing regimen. All seven of these events were Grade 1-2, which were self-limiting or resolved upon treatment interruption.
Initial Efficacy Analysis
The interim clinical data of the RLY-4008-101 Trial indicate that RLY-4008 has the potential to provide tumor reduction across a number of FGFR2 alterations and lines of treatment. Key interim data include:
| | • | | Promising early activity in FGFR inhibitor naïve cholangiocarcinoma FGFR2 fusion patients, with confirmed RECISTv1.1 partial responses observed in 3 out of 6 patients with deep tumor regressions (-56% to -83%) and 3 out of 6 patients continuing on treatment and a fourth who went on to surgery with curative intent. |
| | • | | Radiographic tumor shrinkage and complete clearance of ctDNA in 70% of patients with acquired resistance mutations (N=10), including molecular brake (N550) and gatekeeper (V565) mutations, suggesting the potential for RLY-4008 to treat or prevent on-target acquired resistance. |
| | • | | Early signs of activity observed outside of FGFR2 fusion positive cholangiocarcinoma, including tumor reduction in 6 out of 8 evaluable patients with activating mutations (1 confirmed partial response, (“PR”), 1 unconfirmed PR, and 4 stable disease (“SD”) (based on RECISTv1.1 criteria)) and 3 out of 3 patients with amplifications (all SD). |
| | • | | Approximately 80% of all patients treated achieved radiographic tumor regressions; this was observed across all dose levels, tumor types and FGFR2 alterations, and in patients with prior FGFR inhibitor treatment. |
Consistent with the preclinical profile of RLY-4008, these early clinical data support the Company’s belief that RLY-4008 has broad therapeutic potential across FGFR2 alterations and tumor types.
Cautionary Note Regarding Forward Looking Statements
This Current Report on Form 8-K and certain of the materials furnished or filed herewith contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding: the Company’s strategy, business plans and focus; the progress and timing of updates on the clinical development of the programs across the Company’s portfolio, including the timing of selecting a recommended phase 2 dose, initiating expansion cohorts of its first-in-human clinical trial of RLY-4008 and the timing of initiation of a first-in-human clinical trial of RLY-2608; potential therapeutic effects and clinical benefits of RLY-2608 and RLY-4008, and whether preclinical or preliminary results from the Company’s ongoing trials of its product candidates will be predictive of the final results of the trial or any future clinical trials; and the potential target patient population of RLY-2608. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
