Elevar Therapeutics Announces First Patients Dosed in Phase 2 Study of Lirafugratinib Among Non-CCA Solid Tumors With FGFR2 Fusion or Rearrangement

Elevar Doses First Patients in Phase 2 Lirafugratinib Study for Non-CCA Solid Tumors

Elevar Therapeutics has initiated its global Phase 2 ReFocus202 study of lirafugratinib, dosing the first patients in Seoul, South Korea, and Tampa, Florida. This open-label, single-arm trial aims to evaluate the efficacy and safety of lirafugratinib in non-cholangiocarcinoma (CCA) solid tumors characterized by FGFR2 fusion or rearrangement, confirming its potential as a tumor-agnostic therapy. Lirafugratinib previously received Orphan Drug and Fast Track designations from the FDA for CCA, and its New Drug Application for CCA is currently under priority review with a PDUFA date set for September 27, 2026.

• The ReFocus202 trial (NCT07359820) is designed as a global, multi-site, open-label, single-arm Phase 2 study. Its primary objective is to evaluate the objective response rate of lirafugratinib across a broad spectrum of non-cholangiocarcinoma solid tumors harboring FGFR2 fusion or rearrangement, with the overarching goal of confirming the drug's tumor-agnostic therapeutic potential.
• Patient enrollment for the study has commenced, with the first patient receiving a dose at Samsung Medical Center in Seoul, South Korea, and a second patient at Moffitt Cancer Center in Tampa, Florida. The multi-site trial is set to include locations across the U.S., Korea, the UK, Spain, and France, underscoring its international scope to gather comprehensive efficacy and safety data.
• Lirafugratinib has previously demonstrated meaningful antitumor activity in a Phase 1/2 ReFocus study, which included 42 non-CCA solid tumor patients across 13 different tumor types. Building on this prior data, Elevar plans to conduct an interim analysis for the current Phase 2 study, focusing on at least seven tumor types with a minimum of five patients per tumor type.

Addressing Unmet Needs in FGFR2-Altered Non-CCA Solid Tumors

Beyond cholangiocarcinoma, FGFR2 fusions and rearrangements have been identified across a range of solid tumor types where therapeutic options remain limited and prognosis is poor. The field is actively investigating both selective small-molecule inhibitors and monoclonal antibodies to address these gaps, with several clinical trials underway targeting genomically defined patient subpopulations.

• Gastric and gastroesophageal junction (G/GEJ) cancer represents the most clinically advanced non-CCA target, with FGFR2 amplification (FGFR2amp) present in fewer than 4% of GEC patients per the Guardant Health database and associated with a median overall survival of only 13.1 months. FGFR2amp tumors most commonly involve the gastroesophageal junction and frequently co-occur with mutations in TP53, CTNNB1, CDH1, and RHOA. The FGFR2b protein isoform has emerged as a validated therapeutic target, with bemarituzumab — a selective anti-FGFR2b monoclonal antibody — demonstrating clinical benefit in combination with chemotherapy in HER2-negative gastric adenocarcinoma, particularly in patients with FGFR2b positivity ≥10%.

• The WJOG18524G trial (RAINBIRD) is a single-arm, multicenter Phase II study evaluating bemarituzumab combined with ramucirumab and paclitaxel in FGFR2b-positive advanced gastric or GEJ cancer patients who are refractory or intolerant to first-line fluoropyrimidine-based chemotherapy. The primary endpoint is objective response rate by blinded independent central review, with translational research planned to identify predictive biomarkers and resistance mechanisms via tumor DNA (PleSSiSion-Neo) and circulating tumor DNA (Guardant360) sequencing at multiple time points. The rationale for this combination includes potential synergistic inhibition of both VEGF-VEGFR and FGF-FGFR angiogenic and proliferative signaling pathways.

• Tasurgratinib (E7090), a potent and selective FGFR1–3 inhibitor approved in 2024, was evaluated in gastric cancer patients harboring FGFR gene alterations at a recommended dose of 140 mg once daily. In a Phase I Part 2 cohort of 10 gastric cancer patients, one partial response (11.1%) was observed, with a median progression-free survival of 3.25 months (95% CI: 0.95–4.86) and median overall survival of 4.27 months (95% CI: 2.23–7.95). The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia.

• Urothelial carcinoma with FGFR2/3 genetic alterations represents another key target population with limited treatment alternatives. The BLC2001 study evaluated erdafitinib in 212 participants with locally advanced unresectable or metastatic urothelial carcinoma; in the 8 mg regimen group, tumors decreased in size or disappeared completely in 40% of participants, approximately 55% were alive at one year, and approximately 31% at two years, with approximately 80% achieving some level of disease control.

• Adenoid cystic carcinoma (ACC), an uncommon and aggressive head and neck malignancy primarily affecting minor salivary glands, predominantly in women in their 60s and 70s, has emerged as a target of interest. A patient harboring a specific FGFR2 mutation demonstrated a significant response to futibatinib, suggesting potential for biomarker-driven patient selection. Further investigation is required to optimize treatment protocols, explore combination strategies, identify predictive biomarkers, and address potential resistance mechanisms.

• Other solid tumor types, including colorectal, prostate, and breast cancers, harbor FGFR2 fusion genes at lower frequencies than CCA, and represent emerging target populations. Liquid biopsy-based ctDNA profiling is being positioned as a tool to characterize the genomic landscape of these cancers and facilitate identification of patients eligible for FGFR2-directed therapies. Next-generation and highly selective FGFR2 inhibitors are in development and anticipated to improve outcomes across this broader spectrum of FGFR2 fusion-positive solid tumors.

ReFocus202: Designing a Global Phase 2 for Lirafugratinib

Non-CCA solid tumors harboring FGFR2 fusions or rearrangements represent a clinically heterogeneous population across which several histology-specific and basket trial designs have been evaluated. The evidence base spans phase I/II trials, patient-derived xenograft studies, and signal-finding basket protocols, with objective response rate (ORR) serving as the predominant primary endpoint across interventional studies. The table below consolidates key design parameters and efficacy outcomes from the most clinically relevant trials.

Lirafugratinib's FGFR2 Selectivity in a Crowded Landscape

Several FGFR-selective inhibitors are currently in clinical development for FGFR2-driven malignancies — most notably intrahepatic cholangiocarcinoma and other FGFR2-altered solid tumors — sharing a broadly analogous mechanism of action to lirafugratinib as isoform-selective FGFR kinase inhibitors. These next-generation agents are distinguished from approved pan-FGFR inhibitors by their selectivity profiles, reduced risk of hyperphosphataemia, and potential to overcome resistance mutations. However, specific intervention models (e.g., parallel assignment, single-group, crossover) for these trials were not reported in the available literature.

Selective FGFR2 Inhibition: Charting a Tumor-Agnostic Course

Elevar Therapeutics' decision to advance lirafugratinib into a global Phase 2 study for non-cholangiocarcinoma (CCA) solid tumors with FGFR2 fusions or rearrangements marks a pivotal moment for this highly selective inhibitor. This move underscores a strategic ambition to position lirafugratinib as a tumor-agnostic therapy, leveraging its unique profile in a broader patient population.

Lirafugratinib stands out as a first-in-class FGFR2-selective inhibitor, a characteristic that could translate into a more favorable safety profile compared to pan-FGFR inhibitors, which are often associated with dose-limiting toxicities like hyperphosphatemia. Crucially, research indicates that lirafugratinib retains activity against several FGFR2 kinase domain mutations that confer resistance to other FGFR inhibitors, including the recalcitrant V565L/F/Y mutations. This capability addresses a significant unmet need for patients whose tumors have progressed on existing targeted therapies.

However, the path to broad tumor-agnostic success is not without its challenges. While effective against certain resistance mutations, studies show that diverse acquired resistance mechanisms can still emerge, including novel FGFR2 kinase domain mutations and the activation of RTK-MAPK bypass pathways. This molecular heterogeneity, particularly in FGFR2-driven malignancies, necessitates ongoing research into optimal patient selection and the development of robust biomarker strategies to predict response and guide treatment decisions. Furthermore, while selectivity may reduce some off-target effects, the overall safety profile in a diverse, tumor-agnostic population will require careful monitoring.

Looking ahead, the existing regulatory momentum for lirafugratinib in CCA, with its Orphan Drug and Fast Track designations and priority review, provides a strong foundation. If the tumor-agnostic trial demonstrates compelling efficacy and safety, it could pave the way for significant label expansion. Future strategies may also involve exploring combination therapies, potentially with immune checkpoint inhibitors or agents targeting identified bypass pathways, to overcome resistance and enhance durable responses, further solidifying lirafugratinib's role in precision oncology.