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REFOCUS — Lirafugratinib in FGFR2-fusion cholangiocarcinoma

Headline: Lirafugratinib (Relay Therapeutics) delivered durable responses in an ~100-patient Phase 2 of FGFRi-naive FGFR2-fusion intrahepatic cholangiocarcinoma, with a cleaner hyperphosphatemia and ocular-toxicity profile than first-generation pan-FGFR TKIs. Positions the molecule as the best-in-class candidate for next-generation FGFR2-selective TKIs in CCA.

At a glance

  • Sponsor / PI / institution: Relay Therapeutics; presented by Lipika Goyal (Stanford) / Milind Javle (MD Anderson) — REFOCUS investigators
  • NCT ID: NCT05576662
  • Phase / arms / N: Phase 1/2 single-arm; ~100 evaluable FGFR2-fusion CCA patients in Phase 2 expansion (FGFRi-naive cohort)
  • Primary endpoint(s): ORR (BICR), DoR, safety
  • Indication / line: Locally advanced or metastatic FGFR2-fusion+ cholangiocarcinoma, prior systemic therapy, FGFRi-naive
  • Comparator: None (single-arm); historical reference frame pemigatinib / futibatinib
  • Session: Day 2 (Fri Jan 9, 2026), Hepatobiliary General Session, Moscone West

Headline result

Phase 2 expansion showed durable confirmed responses in FGFRi-naive FGFR2-fusion CCA with response rate and duration competitive with first-generation FGFR inhibitors (pemigatinib, futibatinib). Critically, the FGFR2-selective design (sparing FGFR1) yielded markedly lower hyperphosphatemia and ocular AE rates — the dose-limiting toxicities that drive treatment interruption with pan-FGFR TKIs.

Mechanism / class

Lirafugratinib (RLY-4008) is an irreversible, highly selective FGFR2 inhibitor designed using Relay's motion-based drug design platform to discriminate FGFR2 from FGFR1/3/4. Selectivity avoids the FGFR1-driven hyperphosphatemia and FGFR3/4-driven dermatologic/GI toxicity of pan-FGFR agents.

Trial design deep dive

Study architecture. Phase 1/2 single-arm, open-label, multi-cohort. Phase 2 expansion enrolled ~100 FGFRi-naive FGFR2-fusion/rearrangement intrahepatic CCA patients (separate cohort for FGFRi-pretreated patients with acquired resistance mutations). RP2D 70 mg QD. No randomization; historical reference frame is pemigatinib (FIGHT-202) and futibatinib (FOENIX-CCA2).

Endpoint definitions. Primary ORR by BICR per RECIST 1.1; secondary DoR, PFS, safety. Confirmed responses (≥4 weeks separation) required for ORR primary analysis. Resistance-mutation coverage (FGFR2 V564 gatekeeper, molecular brake mutations N549/E565) tracked in pretreated cohort. AE grading by CTCAE v5.0 with prespecified hyperphosphatemia and ocular-event categorical reporting.

Key subgroup analyses.

  • FGFR2 fusion partner: BICC1 vs non-BICC1 partners reported separately — ORR consistent across partner classes per Relay program notes.
  • Number of prior lines: 2L vs 3L+ — durability reported strongest in earlier-line; TBD on stratified ORR numbers.
  • Co-occurring TP53 / CDKN2A mutations: TBD on co-mutation subgroup analysis.
  • Hyperphosphatemia rate (Grade ≥3): reported markedly lower than pemigatinib/futibatinib historical (~25-30% Grade ≥3 with pan-FGFR); TBD on exact lirafugratinib numbers but framed as low-single-digit Grade ≥3.

Comparator context. Pemigatinib (Pemazyre, Incyte) and futibatinib (Lytgobi, Taiho) are the two approved 2L+ FGFR2-fusion CCA agents with ORR ~37-42% and significant FGFR1-driven toxicity. Lirafugratinib's class-differentiating premise is tolerability + V564 resistance-mutation coverage.

FDA / regulatory implications. Lirafugratinib carries FDA Breakthrough Therapy Designation in FGFR2-fusion CCA (granted 2023). NDA filing expected H2 2026 based on REFOCUS Phase 2 data; accelerated approval pathway. Head-to-head vs pemigatinib not run — comparison will rely on cross-trial framing.

Discussant takeaway

Robin Kate Kelley / Ghassan Abou-Alfa anchored the hepatobiliary discussant slot. Framing: FGFR2 CCA is moving from a single first-generation TKI era (pemigatinib / futibatinib) into a class-differentiated era where AE tolerability and resistance-mutation coverage (gatekeeper V564, molecular brake mutations) become the decision axis.

Practice-changing verdict

Likely yes, pending regulatory. Accelerated-approval-grade ORR/DoR in a biomarker-selected niche; class differentiation on tolerability is real. Watch for regulatory submission and head-to-head data vs pemigatinib / futibatinib.

  • ASCO 2026 — possible regulatory / accelerated-approval read-through at May GI track
  • AACR 2026 — FGFR2 resistance mutations (V564) and motion-based drug design sessions
  • ESMO 2026 — EU regulatory follow-up expected Oct
  • JPM 2026 — Relay Therapeutics investor framing same week

Sources