Recognition and management of dermatologic adverse effects are critical to minimizing morbidity in the setting of life-prolonging oncologic treatments. Given the limitations of a single-case inference, further surveillance and study are needed to determine whether patients with pre-existing psoriasis may be at increased risk.

In this study, by incorporating diverse molecular glue handles and amino acid-based degrons into the solvent-exposed exit vectors of infigratinib, we synthesized a library of 30 candidate MGDs...Mechanistic investigations revealed that the covalent engagement of the gluing handle is a critical determinant for successful proteasomal degradation of FGFR2. This work provides a framework for the rational transformation of kinase inhibitors into covalent molecular glue degraders, underscoring the potential of FGFR degradation as a next-generation precision medicine strategy for FGFR2-driven malignancies.

Pemigatinib (approved in 2021) demonstrated a response rate of 35.5%, futibatinib (approved in 2023) showed a response rate of 42%, and tasurgratinib (approved in 2024) achieved a response rate of 30.2%. Polyclonal on-target resistance to pan-FGFR inhibitors and increasing of FGFR2 kinase domain resistance mutations based on treatment history has been reported. Novel therapeutics, such as highly selective FGFR2 inhibitors and next-generation inhibitors, are developed and are expected to improve prognosis for patients with FGFR2 fusion-positive solid tumors.

This was the largest, first-line, randomized, phase 3 trial of a targeted therapy for advanced FGFR2-rearranged cholangiocarcinoma. Pemigatinib demonstrated prolonged median PFS compared with chemotherapy, with no new safety findings.

We conducted a phase 2 trial of pan-fibroblast growth factor receptor inhibitor rogaratinib in patients with sarcoma and report here on the cohort of patients with advanced SDH-deficient GIST...This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation. Clinicaltrials.gov identifier: NCT04595747 .

P1, N=18, Not yet recruiting, Northwestern University

Despite additive anti-tumor activity for FGFR and MEK inhibition in KRASmt NSCLC lines, the trial was stopped after dose escalation, as no RP2D was identified for futibatinib/binimetinib due to reversible retinopathies. Trial register number. NCT04965818. Trial registration date. 20-September-2021.

Instead, a pooled CRISPR kinome knockout screen uncovered FGFR1 as a key resistance driver, and indeed intrinsic BRAFi resistance was partially to fully reversible in 6 cell lines by the FDA-approved pan-FGFR inhibitor pemigatinib. Overall, our results suggest that although changes in pS6 are an excellent marker of intrinsic BRAFi resistance, the S6K1/2-S6 axis itself is not primarily responsible, and instead that FGFR1 is worth further translational study in the context of intrinsic BRAFi resistance.

Notably, among these derivatives, compound 1a emerged as a potent inhibitor of four distinct FGFR subtypes, demonstrating superior efficacy in suppressing the proliferation of Huh7 hepatocellular carcinoma cells compared to BGJ398, a clinically validated FGFR inhibitor...In Balb/c mice bearing Huh7 xenografts, 1a achieved a 90.5% tumor growth inhibition rate at a dose of 50 mg/kg, with no discernible signs of systemic toxicity. Collectively, these findings indicate that 1a holds great potential as a broad-spectrum FGFR inhibitor for cancer treatment, supporting its further development in clinical settings.

Importantly, triple therapy with PI-88, gemcitabine, and Abraxane significantly suppressed tumor growth and prolonged survival relative to all mono- and doublet regimens. Immune profiling revealed that this combination reduced PSC activation, contracted M2 macrophage and regulatory T cell populations, and expanded M1 macrophages, CD8⁺ T cells, and NK cells. In conclusion, these data underscore HPSE as a key driver of fibrosis and chemoresistance in PDAC and support HPSE inhibition as a promising strategy to enhance therapeutic efficacy.

P2, N=80, Recruiting, Advenchen Pharmaceuticals, LLC. | N=36 --> 80 | Trial completion date: Dec 2026 --> Dec 2028 | Trial primary completion date: Dec 2025 --> Dec 2027 | Active, not recruiting --> Recruiting

P2/3, N=201, Recruiting, Janssen Cilag International | Active, not recruiting --> Recruiting