FGFR Inhibitor Clinical Trial Tracker

Approved Agents: Indications and Key Data

Phase 3 Trials: The Bemarituzumab Gastric Opportunity

Key Phase 2 Trials

Understanding the FGFR Biology

The fibroblast growth factor receptor (FGFR) family comprises four receptor tyrosine kinases (FGFR1–4) that regulate cell proliferation, differentiation, survival, and angiogenesis. In cancer, FGFR alterations occur through four mechanisms:

• FGFR2 fusions/rearrangements: The dominant alteration in cholangiocarcinoma (~10–15% of ICC). Fuse the FGFR2 kinase domain to diverse partners (BICC1, AHCYL1, PPHLN1), creating constitutively active kinases. Pemigatinib and futibatinib both target FGFR2 fusions.
• FGFR2/3 mutations: Point mutations in FGFR2 (e.g., S252W, P253R in endometrial cancer) or FGFR3 (e.g., R248C, S249C in bladder cancer) — activating mutations targeted by erdafitinib.
• FGFR2b overexpression: Amplification or transcriptional upregulation of the FGFR2b isoform in ~30% of gastric and GEJ cancers — the target for bemarituzumab antibody therapy.
• FGFR3-TACC3 fusions: Present in ~3% of glioblastoma and bladder cancers — an actionable fusion for FGFR inhibitors.

Cholangiocarcinoma: Two Approved Agents, Competition for Sequencing

Intrahepatic cholangiocarcinoma (ICC) was among the first solid tumors to become "precision medicine"-tractable for FGFR inhibition. FGFR2 fusions are the most common actionable mutation in ICC, present in ~10–15% of cases and virtually absent in extrahepatic CCA or gallbladder cancer. Both pemigatinib and futibatinib are approved for this indication, creating the question of optimal sequencing:

• Pemigatinib (Pemazyre) — reversible, selective FGFR1/2/3 inhibitor. FIGHT-202 Phase 2 showed ORR 36% in FGFR2 fusion/rearrangement cohort. Approved 2020. Most commonly used first FGFR inhibitor.
• Futibatinib (Lytgobi) — covalent, irreversible FGFR1–4 inhibitor. FOENIX-CCA2 showed ORR 42% and mPFS 9.0 months in FGFR2 fusion cohort. Approved 2022. The covalent mechanism may provide activity against some gatekeeper resistance mutations that emerge after pemigatinib.

The FGFR2 inhibitor sequencing question — pemigatinib first or futibatinib first? — is being actively studied. No head-to-head data exists; cross-trial comparisons suggest similar efficacy, with futibatinib potentially retaining activity in some pemigatinib-refractory patients due to the covalent mechanism.

Bladder Cancer: Erdafitinib and the FGFR3 Opportunity

Urothelial carcinoma (bladder cancer) is the largest addressable FGFR-altered solid tumor market. FGFR3 activating mutations are present in ~15–20% of metastatic urothelial carcinoma, with higher rates in non-muscle-invasive bladder cancer (NMIBC). Erdafitinib targets both FGFR2 and FGFR3 alterations and received FDA approval in 2019 based on BLC2001 Phase 2 data.

The THOR Phase 3 trial (NCT03390504) provides comparative effectiveness data against docetaxel/vinflunine (chemotherapy) and pembrolizumab (checkpoint inhibitor) in the second-line setting. Emerging competitors:

• TYRA-300 (Tyra Biosciences, NCT06995677): A highly selective FGFR3 inhibitor in Phase 2, designed to minimize FGFR1 off-target toxicity (hyperphosphatemia is a dose-limiting effect with pan-FGFR inhibitors)
• LOXO-435/LY3866288 (Eli Lilly, NCT05614739): FORAGER-1 Phase 1/2 next-generation FGFR inhibitor with differentiated binding profile
• Erdafitinib intravesical delivery (Janssen, NCT05316155): Delivering FGFR inhibitor directly into the bladder for non-muscle-invasive disease — avoiding systemic exposure and the hyperphosphatemia that limits oral dosing

Gastric Cancer: Bemarituzumab and the FGFR2b Market

Bemarituzumab (Amgen) represents a different approach to FGFR targeting: rather than inhibiting the FGFR kinase with a small molecule, it is a monoclonal antibody that binds the FGFR2b extracellular domain, blocking ligand binding and inducing antibody-dependent cellular cytotoxicity (ADCC). FGFR2b overexpression in ~30% of gastric and GEJ adenocarcinomas makes this a substantially larger potential market than the FGFR2 fusion+ population in CCA.

The FORTITUDE-101 Phase 3 trial represents the most commercially significant FGFR program currently in development. Early Phase 2 data from FIGHT-201/202 predecessors showed that FGFR2b-high patients (IHC 2+ or 3+ in ≥10% of cells) benefited most. If FORTITUDE-101 is positive, bemarituzumab would enter a first-line gastric market that already includes trastuzumab (for HER2+), nivolumab (for all comers), and chemotherapy backbones — validating FGFR2b as a third actionable biomarker in gastric cancer after HER2 and PD-L1.

Next-Generation FGFR Inhibitors and Resistance

The dominant mechanism of resistance to first-generation FGFR inhibitors (pemigatinib, erdafitinib) is the emergence of secondary kinase domain mutations. Futibatinib's covalent mechanism was designed to address some of these, and multiple next-generation programs are in development:

• TYRA-300 (Tyra Biosciences): FGFR3-selective covalent inhibitor for bladder cancer — reduced FGFR1 binding minimizes hyperphosphatemia
• LOXO-435 (Eli Lilly): Potent, selective FGFR inhibitor with an optimized resistance profile
• 3HP-2827 (3H Suzhou, NCT06378593): First-in-human study of a novel FGFR inhibitor
• Tinengotinib (TT-00420, CTTQ): Multi-kinase inhibitor with FGFR activity, Phase 1/2 combinations (NCT06457919)

Related Disease and Drug Class Pages

• Cholangiocarcinoma Clinical Trials — FGFR2, IDH1, HER2 landscape in bile duct cancer
• Bladder Cancer Clinical Trials — FGFR3, enfortumab vedotin, checkpoint inhibitors
• Gastric Cancer Clinical Trials — HER2, FGFR2b, claudin 18.2 landscape
• Hepatocellular Carcinoma Clinical Trials — sorafenib, lenvatinib, IO combinations
• Biliary Tract Cancer Clinical Trials — full pipeline overview
• PARP Inhibitor Clinical Trials — another biomarker-selected targeted therapy class

Frequently Asked Questions

What is the difference between FGFR2 fusions and FGFR2 mutations?

FGFR2 fusions are chromosomal rearrangements that join FGFR2 to a partner gene, creating a constitutively active kinase — the dominant oncogenic alteration in intrahepatic cholangiocarcinoma (~10–15% of ICC). FGFR2 mutations are point mutations in the kinase domain, more common in endometrial cancer and some other tumor types. Pemigatinib and futibatinib's approvals cover both fusions and rearrangements; mutations in FGFR2 can also be targetable but are less studied than fusions in CCA specifically.

Can FGFR inhibitors be combined with checkpoint inhibitors?

Combining FGFR inhibitors with checkpoint inhibitors (PD-1/PD-L1) is under active investigation, with the rationale that FGFR inhibition may modulate the tumor immune microenvironment to enhance IO benefit. The pemigatinib+durvalumab trial (NCT06728410) and several erdafitinib+pembrolizumab combinations (including within THOR Phase 3) are testing this hypothesis. However, overlapping toxicities — particularly hepatotoxicity from FGFR inhibitors plus immune-mediated hepatitis from checkpoint inhibitors — require careful monitoring in combination trials.

What is the FGFR2b immunohistochemistry test used for bemarituzumab selection?

Bemarituzumab patient selection relies on FGFR2b protein expression measured by immunohistochemistry (IHC). The companion diagnostic used in FORTITUDE-101 scores FGFR2b staining by intensity (0–3+) and percentage of positive cells. The optimal cutoff (2+ or 3+ in ≥10% of cells, "FGFR2b-high") was refined from early-phase studies showing that the highest expressors derived the most benefit. This IHC-based selection distinguishes bemarituzumab from small-molecule FGFR inhibitors, which rely on DNA/RNA-based molecular testing for mutations or fusions.