Oral Psoriasis Therapies.

Oral psoriasis therapies include both older traditional immunosuppressants, such as methotrexate, cyclosporine, and acitretin, as well as newer, more targeted agents, such as apremilast, deucravacitinib, and oral interleukin-23 receptor antagonists. Patients may prefer oral therapies to injectable therapies based on the route of administration. Both older and newer oral psoriasis therapies can be utilized effectively in the treatment of psoriasis. Here, we will review oral agents used in the treatment of psoriasis as well as provide commentary on their role in our current, evolving psoriasis treatment paradigm.

Vonoprazan-based therapies versus PPI-based therapies in patients with H. pylori infection: Systematic review and meta-analyses of randomized controlled trials.

BACKGROUND: This study aims to evaluate the efficacy and safety of vonoprazan-amoxicillin (VA), vonoprazan-amoxicillin-clarithromycin (VAC), vonoprazan-based bismuth-containing quadruple therapy (VBQT), and PPI-based triple (PAC) or quadruple therapy (PBQT) for H. pylori infection with the consideration of duration of therapy and amoxicillin dose (H: high; L: low). MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for eligible randomized controlled trials (RCTs) up to December 15, 2023. The efficacy outcome was eradication rate, and safety outcomes included the rates of adverse events and treatment discontinuation. RESULTS: Twenty-seven RCTs were included. The pooled eradication rates were 82.8% for VA, 89.1% for VAC, and 91.8% for VBQT, which increased with the higher amoxicillin frequency of administration and extended duration of therapy within each regimen. There were no significant differences in eradication rate when comparing 7-VA versus 7-VAC and 14-VA versus 14-VAC. VA was at least comparable to PAC. The eradication rate did not differ significantly between 10-H-VA or 14-H-VA versus 14-PBQT. 7-L-VAC demonstrated higher eradication rate versus 7-PAC and comparable rate to 14-PAC. 14-VBQT showed higher eradication rates versus 14-PBQT. The adverse events rate was 19.3% for VA, 30.6% for VAC, and 38.4% for VBQT. VA had similar risk of adverse events versus VAC and significantly fewer adverse events compared to PBQT. The treatment discontinuation rate did not differ significantly between treatments. CONCLUSIONS: The eradication rate of VBQT was the highest at above 90% followed by VAC and VA. VA was as effective as VAC and superior to PPI-based therapies with favorable safety, highlighting the potential of VA therapy as a promising alternative to traditional PPI-based therapies. VPZ-based triple or quadruple therapies was more effective than PPI-based therapies. Further studies are needed to establish the optimal treatment regimen especially in the western countries.

Preparation of the new peptide drug ACTY116-loaded in situ forming implants and evaluation of its efficacy in pulmonary arterial hypertension and right ventricular hypertrophy induced by SU5416/hypoxia in mice.

There is a lack of effective therapeutic drugs for pulmonary arterial hypertension. Previous studies have demonstrated the positive cardiovascular system protective effects of the new peptide ACTY116. However, its stability in ordinary aqueous solution injections is poor and its half-life in the body is short, which has hindered the development of preparations. This study aimed to prepare in situ forming implants (ISFIs) of the peptide ACTY116 and investigate its impact on pulmonary arterial hypertension. We prepared ISFIs using NMP/TA as a solvent and PLGA as a polymer. These ISFIs exhibited low viscosity, low toxicity and sustained release properties. In a mouse model of pulmonary hypertension induced by SU5416/hypoxia, both ISFIs and ACTY116 peptides effectively reduced pulmonary hypertension, cardiac hypertrophy and pulmonary blood vessel wall thickness. In conclusion, this study highlights the potential of ACTY116 as a treatment for pulmonary arterial hypertension and suggests that incorporating it into an in-situ gel implant could be a promising option.

Combination of Doxorubicin and Antiangiogenic Agents in Drug-Eluting Beads: In Vitro Loading and Release Dynamics in View of a Novel Therapeutic Approach for Hepatocellular Carcinoma.

PURPOSE: Antiangiogenic agents have been used for many years as a first-line systemic treatment for advanced HCC. Embolization with cytostatic drugs on the other hand is the first-line treatment for intermediate HCC. The two types of drugs have not been combined for intraarterial delivery yet. The loading and release dynamics and the in vitro effect of their combination are tested in this experimental study. MATERIALS AND METHODS: Drug-eluting beads were loaded with doxorubicin, sunitinib and sunitinib analogue piperazine (SAP) alone and with their combinations. Diameter change, loading, release, and effect in cellular proliferation were assessed. RESULTS: The average microsphere diameter after loading was 473.7 µm (µm) for Doxorubicin, 388.4 µm for Sunitinib, 515.5 µm for SAP, 414.8 µm for the combination Doxorubicin/Sunitinib and 468.8 µm for the combination Doxorubicin /SAP. Drug release in 0.9% NaCl was 10% for Doxorubicin, 49% for Sunitinib, 25% for SAP, 20%/18% for the combination Doxorubicin/Sunitinib, and 18%/23% for the combination Doxorubicin/SAP whereas in human plasma it was 56%, 27%, 13%, 76%/63% and 62%/15%, respectively. The mean concentration of Doxorubicin that led to inhibition of 50% of cellular proliferation in an HCC Huh7 cell line was 163.1 nM (nM), for Sunitinib 10.3 micromolar (µΜ), for SAP 16.7 µΜ, for Doxorubicin/Sunitinib 222.4 nM and for Doxorubicin/SAP 275 nM. CONCLUSIONS: Doxorubicin may be combined with antiangiogenic drugs with satisfactory in vitro loading and release outcomes and effect on cellular lines.

Retrospective evaluation of toceranib phosphate (Palladia) in the treatment of canine carcinomatosis and mesothelioma.

Canine carcinomatosis (CC) and mesothelioma (CM) are rare but aggressive neoplasms that historically have been associated with poor prognoses. There is limited information regarding treatment for CC and CM. The purpose of this retrospective study was to evaluate the efficacy and tolerability of toceranib phosphate (Palladia) in dogs with CC and CM. Cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv and retrospectively reviewed. For eligibility, a cytologic and/or histopathologic diagnosis of CC or CM was required. A total of 23 cases were included (CC = 14, CM = 8, both = 1). Eighty-two percent (19/23) of dogs presented with effusion. The best overall response rate (BORR) was 30.4% (13% complete response [CR], 17.3% partial response [PR]). Stable disease (SD) was appreciated in 14 dogs (60.8%) including the four dogs without effusion. The most common toceranib-related adverse events were either Grade 1 and 2 diarrhea or hyporexia. The median progression-free survival (PFS) was 171 days (range, 7-519 days) and overall median survival time (MST) was 301 days (range, 49-875 days) for all dogs. When evaluating dogs solely with effusion, the median PFS and overall MST were 171 days (range, 7-519 days) and 285 days (range, 49-875 days), respectively. This report demonstrates that toceranib is both well tolerated and a potential treatment for CC and CM. A randomised, controlled, prospective study would be needed to objectively assess the survival benefit of toceranib in the management of CC and CM, with and without effusion.

Tofacitinib Treatment for Pretibial Myxedema.

This case report describes tofacitinib treatment for 2 patients with pretibial myxedema.

Pancreatic adenocarcinoma treated with surgical resection, toceranib phosphate and firocoxib in a dog: a case report.

Exocrine pancreatic carcinomas are rarely reported in dogs. A ductal pancreatic adenocarcinoma in a 10-year-old intact beagle is described in this report. The diagnosis was made based on clinical signs, imaging (abdominal ultrasound and CT scan) and histopathology. Treatment consisted of partial right lobe pancreatectomy followed by adjuvant therapy with toceranib phosphate (Palladia®) and firocoxib (Previcox®) for six months. The treatment was well tolerated, and the survival time was 445 days. To our knowledge, this is the longest survival reported in the literature for a dog diagnosed with exocrine pancreatic adenocarcinoma. The results described here may contribute to provide a better understanding about this neoplasia and potential treatment options.

Vonoprazan-amoxicillin dual therapy with different amoxicillin dosages for treatment-naive patients of Helicobacter pylori infection in China: a prospective, randomized controlled study.

BACKGROUND: The vonoprazan (VPZ)-amoxicillin (AMO) dual therapy (VA) demonstrates a satisfactory eradication rate for Helicobacter pylori (H. pylori ). However, the optimal dosage of AMO in this regimen remains uncertain. The objective of this study is to investigate the efficacy of different doses of AMO in the VA regimen for first-line treatment of H. pylori infection. METHODS: A total of 192 treatment-naive H. pylori -infected patients were randomly assigned to one of three groups: low-dose VA (LD-VA: VPZ 20 mg b.i.d + AMO 750 mg t.i.d), moderate-dose VA (MD-VA:VPZ 20 mg b.i.d + AMO 1000 mg t.i.d), and high-dose VA (HD-VA: VPZ 20 mg b.i.d + AMO 1250 mg t.i.d). All groups received 14 days of treatment. The study evaluated and compared the eradication rates, adverse events (AEs), and patient compliance among the three groups. RESULTS: Eradication rates for LD-VA, MD-VA, and HD-VA were 76.6% (49/64), 79.7% (51/64), and 84.4% (54/64), respectively, as determined by intention-to-treat analysis; 90.6% (48/53), 94.3% (50/53), and 98.1% (53/54) according to per-protocol analysis; 89.1% (49/55), 94.4% (51/54), and 96.4% (54/56) with modified intention-to-treat analysis (all P  > 0.05). Although not statistically significant, numerically higher eradication rates were observed with the higher dose AMO VA regimen. There were no statistically significant differences in the incidence of AEs and compliance among the three VA regimens. CONCLUSION: Fourteen-day VA regimens with AMO doses exceeding 2 g/day demonstrated satisfactory eradication rates. HD-VA therapy is potentially the most effective regimen. Large-sample clinical trials are required to further validate these findings.

Comparative Effectiveness of Tofacitinib and Adalimumab in Axial Spondyloarthritis: A Real-World Clinical Context Multicenter Study.

INTRODUCTION: Tofacitinib, an oral Janus kinase inhibitor, is a putative choice in the treatment of axial spondyloarthritis (AxSpA). The objective of this study was to compare the effectiveness and tolerability of tofacitinib with adalimumab, in AxSpA, in a real-world clinical setting. METHODS: In this multicentric medical records review study, adult patients with active AxSpA treated with either tofacitinib 5 mg twice daily or adalimumab 40 mg subcutaneously fortnightly were recruited. Effectiveness was measured with Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Drug-cost analysis was calculated with Incremental Cost-Effectiveness Ratio (ICER drug ). RESULTS: Among the 266 patients, 135 were treated with tofacitinib and 131 with adalimumab (follow-up: 6.5 ± 1.6 months). Mean improvement of BASDAI (3.39 ± 0.09 vs. 3.14 ± 1.16, respectively) and that of ASDAS (1.78 ± 0.68 vs. 2.07 ± 2.08, respectively) were comparable between the adalimumab and tofacitinib groups. A higher proportion of patients achieved BASDAI50 response in the second (49.5% vs. 31.6%) and fourth month (83.9% vs. 62.8%) and ASDAS low disease activity in the fourth month (71.6% vs. 47.9%) in the adalimumab group. All disease activity measurements were similar by the sixth month in both groups. A higher proportion of patients in the tofacitinib group than in the adalimumab group required change in therapy (14.8% vs. 7.6%, respectively). ICER drug for adalimumab compared with tofacitinib was US $188.8 per patient in the adalimumab group for each person-month with BASDAI <4. CONCLUSIONS: Tofacitinib showed comparable effectiveness with adalimumab in patients with AxSpA at the sixth month, despite lesser response in the initial months, with favorable ICER drug .

Efficacy and Safety of Vonoprazan-Amoxicillin Dual Regimen With Varying Dose and Duration for Helicobacter pylori Eradication: A Multicenter, Prospective, Randomized Study.

BACKGROUND & AIMS: Previous studies confirm vonoprazan-amoxicillin effectiveness for Helicobacter pylori. This study aims to investigate vonoprazan with varying amoxicillin dose and duration. METHODS: This multicenter, prospective, randomized controlled, noninferiority trial enrolled patients with treatment naive H pylori infection from 5 clinical centers. Eligible participants were randomly assigned to H-VA-10 (vonoprazan 20 mg twice a day (b.i.d.) + amoxicillin 750 mg 4 times a day, 10 days), L-VA-10 (vonoprazan 20 mg b.i.d. + amoxicillin 1000 mg b.i.d, 10 days), and H-VA-14 (vonoprazan 20 mg b.i.d + amoxicillin 750 mg 4 times a day, 14 days) in a 1:1:1 ratio. The eradication rate was assessed using the 13C-urea breath test at least 28 days after treatment. RESULTS: Of the 623 eligible patients, 516 patients were randomized. In both the intention-to-treat and per-protocol analyses, eradication rates were comparable between H-VA-10 and H-VA-14 groups (86.6% vs 89.5% and 90.9% vs 94.5%, P = .021 and .013 for noninferiority, respectively). However, eradication rates were significantly lower in the L-VA-10 group than the H-VA-14 group (79.7% vs 89.5% and 82.0% vs 94.5%, P = .488 and .759, respectively). Rates of study withdrawal, loss to follow-up, and adverse events were similar across study groups. CONCLUSIONS: H-VA-10 and H-VA-14 regimens provide satisfactory efficacy for H pylori infection, and the L-VA-10 regimen was inferior. CLINICALTRIALS: gov number: NCT05719831.

Comparison between tofacitinib and ustekinumab as a third-line therapy in refractory ulcerative colitis: A multicenter international study.

BACKGROUND: Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they should be positioned in the therapeutic algorithm. The aim of this study was to compare tofacitinib and ustekinumab as third-line therapies in UC patients in whom anti-TNF and vedolizumab had failed. METHODS: This was a multicenter retrospective observational study. The primary outcome was disease progression, defined as the need for steroids, therapy escalation, UC-related hospitalization and/or surgery. Secondary outcomes were clinical remission, normalization of C-reactive protein, endoscopic remission, treatment withdrawal, and adverse events. RESULTS: One-hundred seventeen UC patients were included in the study and followed for a median time of 11.6 months (q1-q3, 5.5-18.7). Overall, 65% of patients were treated with tofacitinib and 35% with ustekinumab. In the entire study cohort, 63 patients (54%) had disease progression during the follow-up period. Treatment with ustekinumab predicted increased risk of disease progression compared to treatment with tofacitinib in Cox regression analysis (HR: 1.93 [95% CI: 1.06-3.50] p = 0.030). Twenty-eight (68%) patients in the ustekinumab group and 35 (46%) in the tofacitinib group had disease progression over the follow-up period (log-rank test, p < 0.054). No significant differences were observed for the secondary outcomes. Six and 22 adverse events occurred in the ustekinumab and tofacitinib groups, respectively (15% vs. 31%, p = 0.11). CONCLUSIONS: Tofacitinib was more efficacious in reducing disease progression than ustekinumab in this cohort of refractory UC patients. However, prospective head-to-head clinical trials are needed as to confirm these data.

Pharmacokinetics of Ubrogepant in Healthy Japanese and White Adults.

Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. The objectives of this study were to evaluate (1) single-dose pharmacokinetics (PK) and dose proportionality of ubrogepant in Japanese participants, (2) the safety and tolerability of ubrogepant in healthy Japanese and White participants, and (3) to compare the PK of ubrogepant in Japanese versus White participants. A total of 48 participants were enrolled into 4 cohorts (N = 12 [9 active + 3 placebo] per cohort). A single dose was administered on Day 1 following an overnight fast to assess the PK of ubrogepant at 3 dose levels and test dose proportionality between 25 and 100 mg in Japanese participants. White participants were randomly assigned to ubrogepant (100 mg) or placebo. Dose proportionality was observed in the dose range of 25-100 mg in Japanese participants. Systemic exposure was 20% lower in Japanese participants as compared with White participants, but this difference is unlikely to be clinically relevant. Single doses of ubrogepant (25-100 mg) had a safety profile similar to placebo, and no differences in the safety profile of ubrogepant 100 mg were observed between Japanese versus White participants.

Is proton-pump inhibitor effective in preventing postoperative bleeding after esophageal endoscopic submucosal dissection?

Although proton-pump inhibitor (PPI) administration was reported to be effective in preventing delayed bleeding after gastric endoscopic submucosal dissection (ESD), its effectiveness in esophageal ESD is still unknown. We assessed whether PPI or vonoprazan administration was effective in preventing posterior hemorrhage after esophageal ESD. This retrospective cohort study used the Japanese Diagnosis Procedure Combination (DPC) database, and patients who underwent esophageal ESD between January 2012 and December 2020 were enrolled. The participants were divided into two groups: patients who were prescribed PPI or vonoprazan (PPI or vonoprazan group) and those who were not prescribed PPI (no acid suppression). Propensity score matching analysis was performed, and the delayed bleeding rate was compared between the groups. We analyzed 54,345 patients, of whom 8237 (15.16%) were in the no acid suppression group and 46,108 (84.84%) in the PPI or vonoprazan group (PPI: 34,380 and vonoprazan: 11,728). Delayed bleeding occurred in 1126 patients (2.07%). A total of 8237 pairs were created after matching. Delayed bleeding was not significantly different between the no acid suppression group and PPI or vonoprazan group, respectively (odds ratio: 1.20, 95% confidential interval: 0.93-1.54, P = 0.227). A sub-analysis according to the dose of PPI or vonoprazan, tumor location, and prescription of antithrombotic or anticoagulant medications was performed, but no significant effects of PPI or vonoprazan administration were found. PPI or vonoprazan did not prevent delayed bleeding; thus, the prescription of PPI and vonoprazan after esophageal ESD may not be recommended for the prevention of delayed bleeding.

Patient-reported migraine-specific quality of life, activity impairment and headache impact with once-daily atogepant for preventive treatment of migraine in a randomized, 52-week trial.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. METHODS: In this 52-week, multicenter, randomized, open-label trial, adults with 4-14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score. RESULTS: Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16-31.87) at week 12 and 34.70 (95% confidence interval = 32.74-36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52. CONCLUSION: Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact.Trial Registration: NCT03700320.

A Brief Review of Gepants.

PURPOSE OF REVIEW: Gepants are small molecules that antagonize calcitonin gene-related peptide (CGRP) receptors. Due to their favorable side effect profile and versatility in treating headaches acutely and preventively, gepants are preferred over triptans. We will cover the indications for the four FDA-approved gepants in adults: rimegepant, atogepant, ubrogepant, and zavegepant. This review will illustrate how gepants will continue to revolutionize the acute and preventive treatment of headaches. RECENT FINDINGS: Gepants are now available in oral tablet, dissolving tablet, and intra-nasal spray formulations. Recent studies have shown promising utility in treating the pre-headache or prodromal phase. They have favorable tolerability, no evidence for association with medication overuse, and remain a safer alternative in those who have cerebrovascular risk factors. Additional research is needed to explore occurrence of Raynaud's phenomenon in participants treated with gepants, as it has been associated with CGRP monoclonal antibodies, but are not extensively studied in gepants. Gepants are expected to play a significant role in the next generation of migraine treatments.

Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor.

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [3H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 µM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (Ki = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.

Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen-activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1RR549_E554delinsQ ) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and in silico protein modeling suggested that she had a gain-of-function mutation occurring in a region critical for autoinhibition. The patient was treated with pexidartinib, a CSF1R inhibitor, and has had a complete clinical and metabolic response lasting more than 1.5 years to date. To our knowledge, this is the first report to describe successful treatment of a patient with ECD by using an agent that specifically targets CSF1R. This case also highlights the critical role of individualized molecular profiling to identify novel therapeutic targets in ECD.

Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage.

Aged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony-stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection. We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1ß, TNF-α and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.

Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study.

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy. SIGNIFICANCE: This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1-4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population.This article is highlighted in the In This Issue feature, p. 275.