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Background: Inhibiting PI3K/AKT pathway activation may hinder the occurrence and progression of cancer. The aim of this study was to evaluate the efficacy and safety of the PI3K/AKT inhibitors and determine the most appropriate inhibitor for different cancer types., Methods: Electronic databases up to June 2024 were used to examine the efficacy and safety of PI3K inhibitors (alpelisib, copanlisib, duvelisib, and idelalisib) and AKT inhibitors (capivasertib, ipatasertib and MK-2206) for the treatment of cancer. Data was assessed with a random-effect pairwise and network meta-analysis. Randomized controlled trials and retrospective studies were eligible if they compared PI3K or AKT inhibitors with non-PI3K/AKT controls with no restriction., Results: The results were based on 34 studies from 34 published articles and 6 online registration trials (6710 patients). According to pairwise meta-analysis, PI3K/AKT inhibitors showed to be highly effective, especially for treating mutant cancers, but had poor safety profiles. According to our network meta-analysis, PI3K/AKT inhibitors, especially the AKT inhibitor capivasertib, are effective for treating solid cancers such as breast cancer (BC). Moreover, PI3K inhibitors, especially idelalisib, were effective for treating hematologic cancers such as chronic lymphocytic leukemia (CLL)., Conclusions: The PI3K/AKT inhibitors are effective in patients with genetic mutations. For solid cancers such as BC, capivasertib was efficacy and safety. For hematological cancers represented by CLL, idelalisib was efficacy and safety. The above studies can be used when recommending appropriate targeted therapies for patients with different cancer types., Competing Interests: Declaration of competing interest The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Molecular targeted tyrosine kinase inhibitors (TKIs) have produced unprecedented treatment response in cancer therapy for patients harboring specific oncogenic mutations. While the TKIs are mostly well tolerated, they were reported to increase serum levels of creatine kinase (CK) and cause muscle metabolism-related toxicity. CK is an essential enzyme involved in cellular energy metabolism and muscle function. Elevated serum CK levels can arise from both physiological and pathological factors, as well as triggered by specific drug classes. The incidence of serum CK elevation induced by a few approved TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib combination [Food and Drug Administration, United States]; aumolertinib, and sunvozertinib [only approved by National Medical Products Administration, China]) were over 35%. CK elevation-related symptoms include myopathy, myositis, inclusion body myositis (IBM), cardiotoxicity, rhabdomyolysis, rash, and acneiform dermatitis. High-level or severe symptomatic CK elevation may necessitate dose reduction and indirectly dampen TKI efficacy. This review presents an updated summary about the prevalence rate and recent research about mechanisms leading to TKI-induced serum CK elevation in cancer patients. The utility of monitoring serum CK levels for predicting TKI-induced adverse effects and their management will also be discussed., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis., Methods: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed., Findings: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group., Interpretation: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug., Funding: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases"., Competing Interests: Declaration of interests JCK reports a grant from the Deutsche Gesellschaft für Muskelkranke and consulting fees from AbbVie, Biogen, Ipsen, Roche, and Zambon. RG reports grants from the Deutsche Gesellschaft für Muskelkranke, Initiative SMA, and Bundesministerium für Bildung und Forschung, as well as consulting fees from Biogen, Roche, ITF Pharma, and Zambon. DZ has received consulting fees from Novartis and Angelini Pharma and has served on an advisory board for Biogen. NB has received compensations from Mitsubishi Tanabe Pharma. PC serves on the editorial advisory boards of ALS and The Revue Neurologique; reports consultancy work or participation on advisory boards for Amylyx, Biogen, Cytokinetics, Ferrer, Mitsubishi Tanabe Pharma, VectorY, and Zambon; serves on the drug safety monitoring board for Quralis, and has received a research grant from Biogen. EDLC has received travel grants from Biogen and EFFIK. PW reports grants from the Boris Canessa Foundation and the Bundesministerium für Bildung and Forschung; and has received consulting fees from ITF Pharma, Zambon, Novartis, Biogen, and Roche. TM reports institutional grants from Cytokinetics, Ferrer, AL-S Pharma, Sanofi, Amylyx, Mitsubishi Tanabe, and Apellis Pharmaceuticals, as well as personal fees from Biogen, Amylyx, and ITF Pharma; and is co-founder and shareholder of the Ambulanzpartner Soziotechnologie APST. JG has received personal fees from UCB, Alexion, Amylyx, Roche, and Zambon; and is a member of advisory boards of the European Network to Cure ALS, Neuroimaging Society in amyotrophic Lateral Sclerosis, EU ALS coalition, and the World Federation of Neurology Motoneuron Disease group. M-HS received compensations for consulting from Amylyx, Zambon, EFFIK-Italfarmaco, and SOS Oxygene. M-LR reports grants from FightMND, MND Research Australia and the US National Institutes of Health. CN has received fees for non-related services for Biogen, Mitsubishi Tanabe, Roche, and Argenx. JW reports grants from the US National Institutes of Health. JS has received payments for participation on advisory boards, talks, travel, and research projects from Abcuro, Alnylam, Argenx, Biotest, CSL Behring, Grifols, Johnson & Johnson, Kezar, LFB, Lupin, Momenta, Novartis, Octapharma, and UCB, all unrelated to the present study. TF has received personal fees from Actimed, Bayer, Bristol Myers Squibb, Cardior, CSLBehring, Daiichi Sankyo, Galapagos, Immunic, KyowaKirin, LivaNova, Minoryx, Novartis, RECARDIO, Relaxera, Roche, Servier, Viatris, Vifor, Fresenius Kabi, PINK gegen Brustkrebs, Aslan, BionsenseWebster, Enanta, VICO Therapeutics, Pharmaceutical Product Development, and IQVIA, as well as institutional grants from Deutsche Forschungsgemeinschaft, Gemeinsamer Bundesausschuss, and the European Commission. MB reports grants from the US National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; as well as consulting fees for Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and uniQure; the University of Miami has licensed intellectual property to Biogen to support the design of the ATLAS trial (NCT04856982), for which MB is academic lead. PL reports grants from the Bundesministerium für Bildung und Forschung and the Deutsche Forschungsgemeinschaft; consulting fees from AbbVie, Amylyx, Bial, Desitin, ITF Pharma, Novartis, Stadapharm, Raya Therapeutic, Woolsey Pharmaceuticals, and Zambon; and is co-inventor on a patent for the use of fasudil in amyotrophic lateral sclerosis (EP 2825175 B1, US 9.980,972 B2). All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Ovarian cancer is the deadliest gynecological malignancy, representing 2.5 % of all female cancers and accounting for 5 % of female cancer-related fatalities. Despite numerous strategies in its treatment, the disease shows a high recurrence rate and a low survival rate. Consequently, there is a growing focus on targeted therapies in ovarian cancer treatment. It is well-known that VEGFR and LPA pathways undergo alterations in ovarian cancer and stimulate survival, adhesion, migration, invasion, tumor growth and angiogenesis. Cabozantinib (CBZ) is a multi-receptor tyrosine kinase inhibitor that effectively targets MET, VEGFR-1, 2, 3, FLT3, c-KIT, and RET. Ki16425 is a selective inhibitor of LPA receptors 1, 2, and 3. Therefore, targeting LPA receptors and combining with VEGFR inhibitor is a strategic approach for ovarian cancer treatment. In this study, it was aimed to prepare polymer-drug nanoconjugate for both VEGFR and LPAR inhibition. For this, O-(2-Carboxyethyl) polyethylene glycol (PEG 5000 ) which advantages are known in cancer studies, was chosen as the carrier system, and a nanoconjugate containing Ki16425 and CBZ (Ki-PEG-CBZ) was synthesized and its potential was evaluated. Initially, CBZ and Ki16425 were conjugated to the PEG 5000 through pH-sensitive hydrazone and ester bonds. After nanoconjugate characterization, in vitro release and its ovarian cancer treatment potential were evaluated on A2780, OVCAR3 and SKOV3 ovarian cancer cell lines. A nanoconjugate was obtained with a particle size of 169 ± 15.23 nm, a zeta potential of -13.5 ± 1.21 mV, and a release profile lasting 48 h, containing CBZ and Ki16425 with drug loading efficiencies of 73.71 ± 0.53 % and 77.72 ± 2.51 %, respectively. In vitro studies have demonstrated that Ki-PEG-CBZ is highly effective against ovarian cancer. We suggest that the developed polymer-drug nanoconjugate is an effective and safe nanoconjugate for the treatment of ovarian cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14 C-radiolabeled envonalkib in healthy Chinese male subjects., Methods: A single oral dose of 600 mg (150 µCi) [ 14 C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification., Results: After dosing, the median T max of radioactivity was 4 h and the mean t 1/2 was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study., Conclusion: Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Locoregional treatment with transarterial chemoembolization (TACE) or hepatic artery infusion chemotherapy (HAIC) and systemic targeted immunotherapy with tyrosine kinase inhibitors (TKI) and programmed cell death protein-1 (PD-1) inhibitors in the treatment of unresectable hepatocellular carcinoma (uHCC) have achieved promising efficacy. The retrospective study aimed to evaluate the efficacy and safety of TACE and HAIC plus TKI with or without PD-1 for uHCC., Patients and Methods: From November 2020 to February 2024, the data of 44 patients who received TACE-HAIC + TKI + PD-1 (THKP group) and 34 patients who received TACE-HAIC + TKI (THK group) were retrospectively analyzed. Primary outcomes were overall survival (OS) and progress-free survival (PFS), and secondary outcomes were objective response rate (ORR), disease control rate (DCR), conversion rates, and adverse events (AEs)., Results: A total of 78 patients were recruited in our single-center study. The patients in THKP group had prolonged median OS [25 months, 95% confidence interval (CI) 24.0-26.0 vs 18 months, 95% CI 16.1-19.9; p = 0.000278], median PFS [16 months, 95% CI 14.1-17.9 vs 12 months 95% CI 9.6-14.4; p = 0.004] and higher ORR (38.6% vs 23.5%, p = 0. 156) and DCR (88.6% vs 64.7%, p = 0.011) compared with those in THK group. Multivariate analysis showed that treatment option and alpha-fetoprotein (AFP) level were independent prognostic factors of OS and PFS. The frequency of AEs were similar between the two groups., Conclusions: The THKP group had better efficacy for uHCC than the THK group, with acceptable safety., (© 2024. Society of Surgical Oncology.)

Background and Aims: The combination of atezolizumab plus bevacizumab (Atz/Bev) has radically changed the treatment strategy for advanced hepatocellular carcinoma (HCC) but raises questions. Our objectives were to determine survival outcomes and safety in a real-life multicenter French cohort, to investigate the on-treatment prognostic value of the bioinflammatory RECA score, and to perform a matched comparison with patients who previously received tyrosine kinase inhibitors (TKIs)., Methodology: A retrospective analysis of 109 consecutive patients enrolled from September 2020 to January 2023 and a post matched comparison with a TKI cohort ( n  = 79) by the propensity score matching method., Results: The Atz/Bev population was mainly nonviral disease patients (69%) with Child-Pugh grade A (90%), performance status 0/1 (90%), and Barcelona Clinic Liver Cancer stage B (38%) or stage C (62%) classification. After a median follow-up of 6.5 months (3.6-11.7), overall survival (OS) was 13.0 (5.1-28.7) months. OS was independently associated with metastasis, increased alkaline phosphatase, and serum bilirubin levels. Treatment-related adverse events were reported in 78% of patients, mostly grade 1 or 2. The RECA score clearly revealed two different prognosis groups after three cycles. No difference in OS was observed after matching between sequential treatment with TKIs and Atz/Bev., Conclusion: This real-life study highlights the importance of liver function when using Atz/Bev combination and the necessity of identifying predictive markers of response to HCC therapies. Our findings suggest a change in practices, with a marked proportion of intermediate stages, and support the on-treatment prognostic value of an inflammatory score., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Adavosertib (AZD1775) is a potent small-molecule inhibitor of Wee1 kinase. This analysis utilized pharmacokinetic data from 8 Phase I/II studies of adavosertib to characterize the population pharmacokinetics of adavosertib in patients (n = 538) with solid tumors and evaluate the impact of covariates on exposure. A nonlinear mixed-effects modeling approach was employed to estimate population and individual parameters from the clinical trial data. The model for time dependency of apparent clearance (CL) was developed in a stepwise manner and the final model validated by visual predictive checks (VPCs). Using an adavosertib dose of 300 mg once daily on a 5 days on/2 days off dosing schedule given 2 weeks out of a 3-week cycle, simulation analyses evaluated the impact of covariates on the following exposure metrics at steady state: maximum concentration during a 21-day cycle, area under the curve (AUC) during a 21-day cycle, AUC during the second week of a treatment cycle, and AUC on day 12 of a treatment cycle. The final model was a linear 2-compartment model with lag time into the dosing compartment and first-order absorption into the central compartment, time-varying CL, and random effects on all model parameters. VPCs and steady-state observations confirmed that the final model satisfied all the requirements for reliable simulation of randomly sampled Phase I and II populations with different covariate characteristics. Simulation-based analyses revealed that body weight, renal impairment status, and race were key factors determining the variability of drug-exposure metrics., (© 2024, The American College of Clinical Pharmacology.)

Small-molecule drug development faces the challenge of low success rate. In this paper, we propose one potential cause that may occur in the preclinical phase and has rarely been brought up before - the neglected target-mediated low plasma exposure, and the subsequent lead compound mis-selection due to conventional pharmacokinetic criteria requiring sufficient plasma exposure and desired half-life. To evaluate the concept of target-mediate low plasma exposure, we established a minimal physiologically-based pharmacokinetic (mPBPK) model to evaluate the concentration-time profiles of a group of virtual lead series analogs in plasma and in tissues with and without pharmacological target expression. Simulation results demonstrated that the candidate with the highest target binding has the lowest plasma exposure due to target-mediated tissue retention. The traditional PK criteria, such as the requirement of sufficient plasma exposure and desired half-life, may potentially result in lead compound mis-selection by discarding the appropriate and best candidate(s). The mPBPK model was partially validated using 4 tyrosine kinase inhibitors based on our in-house PK and tissue distribution data obtained in animals. The association rate constant (K ass ) was estimated to be 49.8 h -1 , 31.4 h -1 , 8.58 h -1 , and 1.91 h -1 for afatinib, dasatinib, gefitinib, and sorafenib, respectively. Among these four model drugs, a strong correlation was observed between their K ass values and AUC high-perfused tissue /AUC plasma ratios, a metric of tissue retention. Our mPBPK modeling and simulation results indicated that the concept of target-mediated low plasma exposure should be kept in mind during the lead compound selection process., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

IRAK4 inhibitors have been sought for the treatment of a host of diseases, however, recent evidence suggests a protein degradation approach might have advantages over an inhibitor. This viewpoint summarizes the discovery of KT-474─a selective and orally bioavailable interleuken receptor-associated kinase 4 proteolysis-targeting chimera in Phase 2 clinical trials for autoimmune indications.

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an attractive approach for the treatment of autoimmune diseases. The activity of this serine/threonine kinase is dependent on its kinase and scaffolding activities; thus, degradation represents a potentially superior approach to inhibition. Herein, we detail the exploration of structure-activity relationships that ultimately led to the identification of KT-474, a potent, selective, and orally bioavailable heterobifunctional IRAK4 degrader. This represents the first heterobifunctional degrader evaluated in a nononcology indication and dosed to healthy human volunteers. This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.

Background: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC)., Methods: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review., Results: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib., Conclusions: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)., (Copyright © 2024 Massachusetts Medical Society.)

64-year-old woman with a history of esophageal strictures presented in 2015 for evaluation of progressive depigmented patches that developed over the preceding year. She was prescribed topical steroids with no improvement. Narrow-band ultraviolet B (NB-UVB) and topical tacrolimus were eventually added to the topical steroids accompanying an oral steroid taper. The patient discontinued topical tacrolimus because of irritation. The patient was lost to follow-up for the next 3 years, during which she did not take any treatment and her vitiligo had worsened (Figure 1). At her visit 3 years later, she repeated an oral prednisone taper and restarted mid-potency topical steroid. In January 2020, the patient was approved for and started oral tofacitinib 5 mg twice daily. Consistent improvement was observed on the subsequent visits in March 2020 and November 2020. The only adverse reaction reported by the patient was an increase in furuncles on her pelvis and thighs.

Background: This study aims to compare the cost-effectiveness of sintilimab in combination with chemotherapy, with or without bevacizumab biosimilar IBI305, versus chemotherapy alone for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) who have progressed on tyrosine-kinase inhibitor (TKI) treatment from the perspective of the Chinese healthcare system., Methods: 10-year Markov model was developed using a 21-day cycle length. Transition probabilities were derived from the ORIENT-31 trial, while cost and health state utilities were obtained from publicly databases, local hospitals, and published literature. Incremental cost-effectiveness ratios (ICERs) were calculated as the primary model output and compared to a willingness-to-pay (WTP) threshold range of $15,289.34 to $38,223.34 per quality-adjusted life-years (QALY). Sensitivity analyses were performed to assess the robustness of the model., Results: In the base-case analysis, sintilimab plus IBI305 and chemotherapy had an ICER of $53,266.32/QALYs, exceeding the upper WTP threshold. Sintilimab plus chemotherapy had an ICER of $15,329.11/QALY, slightly above the lower WTP threshold. Subgroup analysis yielded consistent results. Deterministic sensitivity analyses found no ICER for sintilimab plus chemotherapy beyond the upper WTP threshold. Most model input changes did not decrease the ICER of sintilimab plus IBI305 and chemotherapy below the upper WTP threshold. Probabilistic sensitivity analyses further demonstrated the cost-effectiveness superiority of sintilimab plus chemotherapy over sintilimab plus IBI305 and chemotherapy., Conclusion: This study supports the cost-effectiveness of using sintilimab in combination with chemotherapy. Nevertheless, the cost-effectiveness of combining sintilimab with IBI305 and chemotherapy in this particular patient group may be lacking., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Peng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The development of transforming growth factor β receptor inhibitors (TGF β Ri) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGF β RI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGF β in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGF β Ri classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT: Only a few TGF β Ri have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients., (Copyright © 2024 by The Author(s).)

Background: Anlotinib was approved as a third line therapy for advanced non-small cell lung cancer in China. However, the impact of concurrent administration of various clinical drugs on the drug-drug interaction (DDI) potential of anlotinib remains undetermined. As such, this study aims to evaluate the DDI of anlotinib as a victim by establishing a physiologically based pharmacokinetic (PBPK) model., Methods: The PBPK model of anlotinib as a victim drug was constructed and validated in the Simcyp ® incorporating parameters derived from in vitro studies, pre-clinical investigations, and clinical research encompassing patients with cancer. Subsequently, plasma exposure of anlotinib in cancer patients was predicted for single- and multi-dose co-administration with typical perpetrators mentioned in Food and Drug Administration (FDA) industrial guidance., Results: Based on predictions, the CYP3A potent inhibitor ketoconazole demonstrated the most significant DDI with anlotinib, regardless of whether anlotinib is administered as a single dose or multiple doses. Ketoconazole increased the area under the concentration-time curve (AUC) and maximum concentration (C max ) of single-dose anlotinib to 1.41-fold and 1.08-fold, respectively. In contrast, rifampicin, a potent inducer of CYP3A enzymes, exhibited a relatively higher level of DDI, with AUC R and C maxR values of 0.44 and 0.79, respectively., Conclusion: Based on the PBPK modeling, there is a low risk of DDI between anlotinib and potent CYP3A/1A2 inhibitors, but caution and enhanced monitoring for adverse reactions are advised. To mitigate the risk of anti-tumor treatment failure, it is recommended to avoid concurrent use of strong CYP3A inducers. In conclusion, our study enhances understanding of anlotinib's interaction with medications, aiding scientists, prescribers, and drug labels in gauging the expected impact of CYP3A/1A2 modulators on anlotinib's pharmacokinetics., Competing Interests: The authors declared no potential conflicts of interest in this work., (© 2024 Bu et al.)

Purpose: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion., Patients and Methods: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events., Results: Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events., Conclusions: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. See related commentary by Hage Chehade et al., p. 4549., (©2024 American Association for Cancer Research.)

Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE., Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ- CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires., Results: 44 patients enrolled and 42 started trametinib. TAZ- CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094-19.0], median PFS was 10.4 months (95%CI, 7.1-NA), and 2-year OS rate was 33.3%(95%CI, 19.1-58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib., Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552., (©2024 American Association for Cancer Research.)

The effect of immune-based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273., (© 2024. The Author(s).)

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910 , a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can cause diverse clinical manifestations in multiple organ systems. Child-onset SLE (cSLE) is associated with significantly higher morbidity and mortality than adult-onset SLE. The traditional treatments for SLE (glucocorticoids, antimalarials, conventional and biological disease-modifying antirheumatic drugs) often have significant adverse effects and may not fully control disease activity. Tofacitinib is an oral Janus kinase (JAK) inhibitor that inhibits the JAK-STAT pathway and has the potential to reduce SLE severity., Methods: cSLE patients who received tofacitinib and had at least one follow-up visit were retrospectively examined. Case histories, laboratory test results, and treatment regimens were analyzed at disease onset, initiation of tofacitinib treatment, and 1, 3, 6, 9, 12, 18, and 24 months after starting tofacitinib., Results: We examined 9 patients with refractory cSLE. All patients were female and the average age at diagnosis was 10.67 years. At initiation of tofacitinib, the average age was 13.28 years and the average disease duration was 2.62 years. Four patients experienced alleviation of symptoms and reduced their daily prednisone dosages; one of them also discontinued cyclosporine A and two of them also discontinued belimumab. The other 5 patients experienced no apparent benefit., Conclusion: Tofacitinib may provide clinical benefits for some patients with refractory cSLE, and can also allow reduction in the glucocorticoid dosage. Tofacitinib has the potential as an adjunctive treatment for some patients with cSLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hou, Zhou, Zhao, Wang and Du.)

Background and Objective: Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers., Methods: A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks., Results: A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics., Conclusions: The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model., Clinical Trial Registration: NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192., (© 2024. The Author(s).)

Background: Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib., Methods: In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed., Findings: Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8-65·4) for the treatment-naïve patients and 66·9 months (56·7-73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0-79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1-54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported., Interpretation: These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC., Funding: Novartis Pharmaceuticals., Competing Interests: Declaration of interests JW reports research grant support (to their institution) from Bristol Myers Squibb, Janssen Pharmaceutica, Novartis, and Pfizer; and consulting fees or honoraria for lectures and for attending meetings from Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre Fabre, Roche, Seattle Genetics, Takeda, and Turning Point. MH declares personal honoraria for lectures and presentations from Boehringer Ingelheim, AstraZeneca, Takeda, Amgen, MSD, and Roche. J-YH reports research grants from Pfizer, Takeda, and ONO; consulting fees or honoraria for lectures and presentations from AstraZeneca, Jassen, Amgen, Oncobix, Daiichi Sankyo, Merck, Norvatis, Abion, Takeda, Pfizer, and Yuhan; participation in data safety monitoring board for AstraZeneca, Jassen; and a leadership role for National Cancer Drug Assessment Committee. NR declares research grants from Artidis, MSD, Amgen, and Roche; honoraria for lectures and presentations from Amgen, AstraZeneca, Bristol Myers Squibb, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Takeda, and Regeneron; support for attending the meetings from Takeda, Regeneron, and Roche; and participation in a data safety monitoring and advisory board for AbbVie, Amgen, AstraZeneca, Bayer, Boehringer, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Takeda, and Regeneron. P-JS reports the research grants received (to their institution) from AstraZeneca, Bristol Myers Squibb, Genentech, and Gilead; and consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, Pfizer, and Takeda. EFS reports consulting fees support to their institution from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche, Sanofi, Takeda, and Merck; honoraria for lectures and presentations for self from Boehringer Ingelheim and Daiichi Sankyo; and participation in a data safety monitoring and advisory board for Daiichi Sankyo and Taiho for institution. JV declares consulting fees received from Bristol Myers Squibb, Janssen, and PDCline; honoraria for lectures and presentations from AstraZeneca, Daiichi Sankyo, and Merck; and participation in a data safety monitoring and advisory board for AstraZeneca, Boehringer, and Transgene. MN reports honoraria received for lectures and presentations from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Lilly, AstraZeneca, MSD, AbbVie, Takeda Pfizer, Boehringer, Ingelheim, Novartis, Nippon, Kayaku, Merck, and Janssen; and support for attending meetings from Novartis. WA declares research grants received from Bristol Myers Squibb, AstraZeneca, Bioatla, Imugene, Astride, BridgeBio, AbbVie, and Novocure; and participation in data safety monitoring and advisory board for Lilly. EBG reports research grants received (to their institution) from ABL-Bio, Arrivent, AstraZeneca, Bristol Myers Squibb, Daiichi, Sanko, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Prelude, Regeneron, and Synthekine; consulting fees from AbbVie, Arcus, AstraZeneca, Arrivent, Atreca, BridgeBio, Bristol Myers Squibb, EMD Serono, Eli Lilly, Gilead, GlaxoSmithKline, Hookipa, LianBio, Merckl Merus, Novartis, Nuvalent, Personalis, Regeneron, Sanofi, Seagan, Sensei, Sumitomo, Strata, Summit, Synthekine, Xilio, and Zymeworks; support for attending meetings from A2 and Novartis; patents issued (to their institution); and other financial support for independent medical education from Daiichi Sankyo and Ipsen. DSWT reports research grants support to their institution from ACM Biolabs, Amgen, AstraZeneca, Bayer, and Pfizer, outside of the submitted work; consulting fees from Amgen, AstraZeneca, Bayer, Boehringer, Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, and Takeda; honoraria for lectures and presentations from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda, BeiGene, Regeneron, and Zymeworks; and support for attending meetings from Bayer, Merck, Pfizer, Regeneron, and Zymeworks. TS declares honoraria for lectures from Amgen, AnHeart Therapeutics, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, GlaxoSmithKline, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Takeda Pharmaceutical, and Towa Pharmaceutical. GMF declares the stocks and shareholder for Roche. AR, MC, SLM, CB, YY, LJ, LF, and AY are employees of Novartis. AB reports stocks and stock options from Novartis and Daiichi Sankyo. RSH declares research grants received to their institution for clinical trials from AbbVie, Agios, Corvus, Daichii Sankyo, Erasca, Lilly, Mirati, Mythic, Novartis, and Turning Point; and consulting fees for self from AbbVie, Astrazeneca, Biohaven, Claim Therapeutics, Daichii Sankyo, EMD Serono, Lilly, Merck, Novartis, Regeneron, and Sanofi. SVO, HJMG, and MJ declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAF V600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients., Methods: In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C)., Results: Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases-free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76)., Conclusions: In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.).

Objectives: Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, causes distinct adverse events (AEs), including hyperlipidemia and central nervous system (CNS) disorders. Although dose modifications are recommended to manage these AEs, whether dose modifications can achieve optimal blood lorlatinib concentrations and reduce the incidence of lorlatinib-induced AEs remains unclear. Therefore, we investigated the association between lorlatinib exposure and AEs in each patient., Materials and Methods: We retrospectively reviewed patients with advanced ALK-rearranged non-small cell lung cancer treated with lorlatinib between November 2018 and July 2022. Serum lorlatinib concentrations were assessed using high-performance liquid chromatography-tandem mass spectrometry. All AEs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0., Results: The median age of the 55 eligible patients was 59 years (range: 23-79 years). All patients were administered lorlatinib after first line ALK-tyrosine kinase inhibitor failure. Grade ≥ 3 AEs occurred in 25 patients (25/55, 45 %), including hyperlipidemia in 17 (17/55, 31 %), CNS disorders in 7 (7/55, 13 %), and edema in 6 (6/55, 11 %). Dose modification was required in 23 patients (23/55, 42 %). Among the 36 patients with available data on serum lorlatinib levels at day 28 (±14) and no drug dose modifications, lorlatinib serum concentrations were significantly higher in patients with grade ≥ 3 AEs than in those without AEs (median: 462 ng/mL vs. 177 ng/mL, p < 0.01). In eight patients with data on serial lorlatinib serum concentrations following dose modifications, lorlatinib serum concentrations were effectively reduced, facilitating the ongoing administration of lorlatinib. Additionally, no significant difference was observed in the landmark analysis of progression-free survival between patients with dose modification within the first 16 weeks and those without (median: 24.8 months vs. 10.1 months, p = 0.46)., Conclusion: Dose modification of lorlatinib was associated with successful management of AEs and decreased serum concentration of lorlatinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Understanding drug behavior within the skin, especially for photosensitive compounds, is crucial for developing effective and safe topical therapies. This study employs Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) and Liquid Chromatography-Mass Spectrometry (LC-MS/MS) to investigate the skin permeation and photostability of selumetinib, a MEK inhibitor used in treating type 1 neurofibromatosis (NF1). The highest amounts of selumetinib in the skin sections were obtained when using the gel formulation, suggesting that it is to be preferred to cream formulations to achieve higher permeation of the drug. Our study also revealed that selumetinib is amenable to photodegradation in ex vivo skin explants, and yields one main degradation product, whose degradation is likely triggered by hydrogen abstraction. MALDI-MSI results showed selumetinib and its degradation product concentrate in skin appendages, indicating these structures might serve as drug reservoirs, potentially prolonging retention and efficacy. This study demonstrates that combining MALDI-MSI with LC/MS-MS can highly contribute to the characterization of the fate of photosensitive compounds in the skin, an essential prerequisite to the development of compound-specific photoprotective measures. It will also pave the way for innovative topical delivery strategies for NF1 treatment.

Introduction: In the era of chemo-immunotherapy, high-risk factors unequivocally predicted inferior outcomes for patients with CLL. The widespread adoption of BTK inhibitors has challenged the practical implications of such testing, as many patients have improved outcomes despite the presence of high-risk features. The impact of adverse prognostic factors, such as unmutated IGHV , on survival has been ameliorated by continuous treatment with BTK inhibitors, but not by finite-duration therapy with venetoclax-based combinations. Furthermore, TP53 abnormalities continue to be associated with worse outcomes in the era of novel agents. New treatment modalities, such as pirtobrutinib, lisocabtagene maraleucel, and ongoing studies combining BTK inhibitors with venetoclax, raise new questions on the significance of prognostic factors of survival for patients with CLL., Areas Covered: Herein, we summarized the available literature on patients with CLL harboring high-risk biomarkers, with a focus on data from key clinical trials., Expert Opinion: Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials.

Purpose: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma., Patients and Methods: Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from days 1 to 14 every 3 weeks until disease progression or intolerable adverse events (AE) occurred. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate, and disease control rate (DCR). The safety profile was also evaluated., Results: Forty patients were enrolled from April 2019 to June 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI), 4.17-8.71] and the median OS 27.40 months (95% CI, 16.43-not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for liposarcoma patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%)., Conclusions: The findings suggest a potential benefit in using front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the liposarcoma subgroup of patients were encouraging. See related commentary by Napolitano et al., p. 4257., (©2024 The Authors; Published by the American Association for Cancer Research.)

Cobb syndrome is a rare neurocutaneous disease characterized by vascular anomalies involving the skin and spinal cord at the same metamere. The most common initial symptoms are neurological manifestations such as pain, monoparesis, headache, scoliosis, and motor damage. We present two patients with Cobb syndrome and severe disease burden harboring somatic mutations in KRAS. The two patients were subsequently treated with the MEK inhibitor trametinib, indicating the potential therapeutic benefit of this treatment for patients with life-threatening Cobb syndrome who are currently considered incurable., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase., Methods: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI., Results: Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%)., Conclusion: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities., (© 2024 American Cancer Society.)

Background: Efficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC)., Objective: To evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies., Design, Setting and Participants: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany., Interventions: Cabozantinib was administered as a standard of care., Outcome Measurements and Statistical Analysis: Adverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized., Results and Limitations: About 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study., Conclusions: Cabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment., Competing Interests: Disclosure VG: Compensated lectures: AstraZeneca, Astellas, BMS, EISAI, Ipsen, Janssen-Cilag, Merck, MSD, Pfizer, ONO Pharmaceutical, Novartis/AAA. Advisory Board: Apogepha, BMS; EISAI, EUSA Pharm, Cureteq, Debiopharm, Gilead, Janssen-Cilag, Merck, MSD, Pfizer, Novartis, Oncorena, PCI Biotech. Research Grant: AstraZeneca, BMS, MSD, Ipsen, Pfizer. Travel support: AstraZeneca, Ipsen, Merck, Janssen, Pfizer MB: RR: Advisory Board: Apogepha,Ipsen, Merck .Pfizer Travel support: Janssen, Pfizer GN: compensated lectures: Roche Pharma, MEDAC, Pfizer, BMS, AstraZeneca, Merck, Janssen-Cilag, Astellas; Advisory Boards: Roche Pharma, Sanofi, BMS, Merck Serono, Pfizer, MEDAC, Ipsen, Janssen, Travel support:Roche Pharma, Pfizer, Merck, Janssen, maunscript writing: Pfizer, BMS, Merck MJS: Compensated lectures: Astellas, Apogepha, Bayer, BMS, EISAI, Hexal, Ipsen, Merck, Pfizer, Medac, MSD, Janssen-Cilag. Advisory board: BMS, Gilead, Ipsen, Merck, Novartis, Pfizer, MSD, Janssen-Cilag. Congress: Apogepha, Janssen-Cilag, Ipsen, Pfizer. Research Grants: Gilead, Ipsen, Janssen-Cilag, AstraZeneca, QED, MSD. FA: none, MM: none, MC: none, MOZ: none AW: Compensated lectures: AIO, BMS, Gilead, Janssen, Lilly, iOMEDICO Advisory Board: BMS;Gilead, Lilly Merck, MSD, Pfizer,Janssen Research Grant: AIO, iOMEDICO AH: none JC: none CD: Compensated lectures from Janssen-Cilag, Ipsen. Advisory Board: Janssen-Cilag, Ipsen. Travel support: Janssen-Cilag, Ipsen and Bayer HT: none, MS: none, DS: none PI: Compensated lectures: AstraZeneca, BMS, EISAI, Merck, MSD, Pfizer, Novartis/AAA. Advisory Board: Apogepha, BMS; EISAI, EUSA Pharm, Gilead, Ipsen, Merck, MSD, Pfizer, Novartis, Oncorena, PCI Biotech. Research Grant: AstraZeneca, BMS, MSD, Ipsen, Pfizer. Travel support: AstraZeneca, Ipsen, Merck, Pfizer, (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate-release (IR) tablets, modified-release (MR) tablets, and IR solution. A once daily MR microsphere formulation was developed for use in pediatric patients. Demonstration of bioequivalence (BE) between the 10 mg once daily (q.d.) MR microsphere formulation and 5 mg twice daily (b.i.d.) IR solution is needed to enable the exposure-response analyses-based bridging to support regulatory approval. To assess BE between MR microsphere and IR solution, an innovative approach was utilized with physiologically-based pharmacokinetic (PBPK) virtual BE trials (VBE) in lieu of a clinical BE trial. A PBPK model was developed to characterize the absorption of different formulations of tofacitinib using Simcyp ADAM module. VBE trials were conducted by simulating PK profiles using the verified PBPK model and integrating the clinically observed intrasubject coefficient of variation (ICV) where BE was assessed with a predetermined sample size and prespecified criteria. The VBE trials demonstrated BE between IR solution 5 mg b.i.d. and MR microsphere 10 mg q.d. after a single dose on day 1 and after multiple doses on day 5. This research presents an innovative approach that incorporates clinically observed ICV in PBPK model-based VBE trials, which could reduce unnecessary drug exposure to healthy volunteers and streamline new formulation development strategies., (© 2024 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3-5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib-lenalidomide-dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12-month overall survival (12-month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow-up of 2.37 months (95% CI 0.92-6.47), the 12-month OS was 13%. The rate of grade 3-4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced-stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton's tyrosine kinase (BTK) inhibitors., Data Sources: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca , and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed., Study Selection and Data Extraction: Relevant English-language clinical trials were evaluated., Data Synthesis: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib., Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors., Conclusion: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The administration of proton pump inhibitors (PPIs) is a common practice to reduce gastro-esophageal adverse events associated with drug treatments but may impair absorption and exposure to oncology drugs. This study investigated the effect of concomitant administration of PPIs and pazopanib, sunitinib and cabozantinib on survival of patients with metastatic clear cell renal carcinoma (mRCC)., Patients and Methods: Total 451 patients receiving pazopanib, sunitinib and cabozantinib as first line treatment were enrolled in this retrospective study. Patients were defined as "no concomitant PPIs (PPI-)" if no PPIs were administered during TKIs, and as "concomitant PPIs (PPI+)" if the administration of PPIs was at least 75% of the time during which TKIs were given., Results: Eighty patients administered pazopanib were PPI- and 86 PPI+; no difference in PFS was observed (10.7 vs. 11.9 months, P = .79). If patients were stratified as short (n = 89) and long (n = 77) responders, there was a significant difference in terms of PFS in PPI+ (n = 47) versus PPI- (n = 30) in long responders, being 24.7 versus 38 months (P = .04), respectively. In the sunitinib cohort, no significant difference of PFS in PPI+ (n = 102) versus PPI- (n = 131) was found, being 11.3 versus 18.1 months, respectively (P=0.15). In the cabozantinib cohort, there was a statistically significant difference in PFS of PPI+ versus PPI- (6 months vs. not reached, P = .04). No correlation with adverse events was found., Conclusions: This study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use., Competing Interests: Disclosure CP acted as a consultant and/or a speaker for Angelini Pharma, Biorek, BMS, Eisai, General Electric, Ipsen, Medendi, and MSD, and as a protocol steering committee member for BMS, Eisai, and MSD. MR received honoraria as a speaker/consultant by Astra Zeneca, MSD, BMS, Janssen, Merck and Gilead. MDR received fees from Astellas, AstraZeneca, Celgene, Novartis, Pfizer, Bio-Rad, Janssen, Sanofi-Aventis, Roche, and Ipsen; RD reports receiving speaker bureau/advisor's fee from Ipsen, Novartis, Pfizer, Sanofi Genzyme, AstraZeneca, Janssen, Gilead, Lilly, Gilead, and EUSA Pharma. All other authors have declared no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Nintedanib is used to treat both idiopathic and progressive pulmonary fibrosis (IPF/PPF). Evidence of both an exposure-response relationship and an exposure-toxicity relationship has been found, suggesting the potential value of therapeutic drug monitoring (TDM). We aimed to define the therapeutic window of nintedanib in a real-world cohort., Methods: Data from two clinical studies were pooled for this analysis. To quantify exposure to nintedanib, a population-pharmacokinetic (PK) model was developed. Associations between PK and decline in forced vital capacity (FVC) and diffusing capacity (DLCO) were performed using linear-mixed-effect models (LMEM). The exposure-toxicity relationship was evaluated using a Cox proportional hazards model., Results: In total, 911 PK samples from 99 patients were used to develop the PK model. The LMEM with random slopes and intercepts included 517 pulmonary function tests (PFT) from 81 patients. The average administered nintedanib dose was associated with the rate of FVC decline (p=0.002). Per 50 mg decrease of daily dosage, the rate of FVC decline increased by 53.5 mL/year. Neither nintedanib exposure nor dose significantly affected DLCO decline and they were also not significantly associated with the occurrence of a dose-limiting toxicity (DLT). This may be explained by a large inter- and intrapatient variability in nintedanib PK., Conclusion: Nintedanib dose was significantly associated with FVC loss. However, no significant relationship between nintedanib exposure and the occurrence of DLTs was found in this real-world population, and no therapeutic window could be established. The findings in this study indicate that nintedanib is an unsuitable candidate for performing TDM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aims: The aim of the study is to report the clinical and pharmacological observations from a pregnant patient treated with erlotinib in the second and third trimesters of pregnancy., Methods: Maternal and neonatal blood levels and safety of erlotinib and its metabolites were evaluated. Child development was monitored for 6 years., Results: A 31-year-old woman with stage IV lung adenocarcinoma with EGFR exon19 deletion began treatment with erlotinib 150 mg/day at 17 weeks of gestation. Although foetal growth retardation and oligohydramnios were observed at several times during the pregnancy, treatment was continued due to the severity of the maternal presentation, with ongoing foetal monitoring. The foetus seemed to tolerate and recover well without specific interventions. A healthy baby boy was delivered at 37 weeks gestation. The child grew and developed without any obvious issues. At last follow-up, at age 6 years, he was attending school at a grade appropriate for his age without health or developmental problems. Blood levels of erlotinib were 397-856 ng/mL at 18-37 weeks of gestation and 1190 ng/mL at 8 weeks postpartum. The blood concentration ratios of OSI-413-to-erlotinib ranged from 0.167 to 0.253 at 18-37 weeks of gestation, excluding 24 weeks, and 0.131 at 8 weeks postpartum. The maternal-to-foetal transfer rate of erlotinib, OSI-420 and OSI-413 were 24.5, 34.8 and 20.3%, respectively., Conclusion: Erlotinib use during the second and third trimester of pregnancy did not seem to cause any untoward effects on the developing foetus, or any long-lasting effects that could be detected during 6 years of follow-up of the child., (© 2024 British Pharmacological Society.)

Background:  Treatment options for patients with differentiated thyroid cancer (DTC) who experience disease progression on lenvatinib treatment are limited. Although dose escalation of treatment with tyrosine kinase inhibitors at disease progression has been reported across cancer types, clinical significance in patients with DTC has not been investigated., Methods: We retrospectively reviewed patients with DTC who experienced disease progression on lenvatinib treatment from September 2011 to June 2022. We compared subjects who received dose-escalation treatment with standard treatment of termination at the time of initial disease progression. The escalated dose was decided by referencing to the previous effective and tolerated dose., Results: Thirty-three patients were identified, 15 with dose escalation and 18 with lenvatinib termination. In both groups, the starting dose of lenvatinib was 24 mg/day, and the median dose at initial disease progression was 10 mg/day. In the former, the median dose escalation was 6 mg/day (range: 4-12). Objective response rate, clinical benefit rate by escalation, and median treatment duration of the dose-escalation phase were 13.3%, 73.3%, and 9.9 months (95% confidence interval [CI] 5.71-27.6), respectively. Median overall survival from initial disease progression was significantly longer in the dose-escalation group (median OS: 20.4 months [95% CI 7.0-NA] vs. 3.9 months [95% CI 1.7-7.9], log-rank p-value; 0.0004, hazard ratio; 0.22 [95% CI 0.09-0.55]). There were no grade 5 adverse events, and one patient discontinued due to a grade 3 lung abscess., Conclusion: The dose-escalation strategy appears to be a safe and effective treatment option after disease progression in patients treated with lenvatinib for DTC., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

We evaluated the possibility of treatment-free remission (TFR) and durability of deep molecular response (DMR) with asciminib treatment by monitoring major BCR::ABL mRNA on the International Scale (BCR::ABL-IS) in 4 patients who needed to reduce or discontinue asciminib due to adverse event concerns, intolerance, or personal circumstances. IS increased in all 4 patients after discontinuation of asciminib, but 3 patients who resumed asciminib achieved DMR again. None of the patients achieved TFR with asciminib, but DMR could be achieved again by restarting asciminib after TFR failure. As this was a retrospective study in a small number of patients, no conclusions can be drawn regarding the possibility of TFR with asciminib. However, this study included patients with short treatment duration and DMR maintenance periods, so strict conditioning may be necessary. Safe dose reduction or TFR with asciminib may need to be considered in more cases., (© 2024. Japanese Society of Hematology.)

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy., (© 2024. The Author(s).)

Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7-97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan-Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46-90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90-8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0-51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Real-world evidence comparing clinical outcomes between venetoclax and Bruton tyrosine kinase inhibitors (BTKis) in patients with frontline (1 L) chronic lymphocytic leukaemia (CLL) is lacking. We compared treatment effectiveness of 1 L venetoclax plus obinutuzumab (VenO) versus BTKi-based regimens. This retrospective observational study using Optum Clinformatics Data Mart® included adult patients with CLL (≥2 outpatient or ≥1 inpatient claim) who received VenO or BTKi-based regimens in 1 L (1/2019-9/2022). Baseline characteristics were balanced using stabilised inverse probability weighting. Outcomes included duration of therapy (DoT), persistence, time to next treatment or death (TTNT-D), and time off-treatment. Among 1506 eligible patients (VenO: 203; BTKi: 1303), the median follow-up duration was 12.6 (VenO) and 16.2 months (BTKi). Median DoT for VenO was 12.3 months; persistence remained higher in VenO versus BTKi through expected 1 L fixed treatment duration. Median TTNT-D was not reached for VenO; however, more VenO- versus BTKi-treated patients had not switched therapies/experienced death through Month 12 (87.1% vs. 75.3%). Among patients that discontinued, median time to discontinuation was 11.7 vs. 5.9 months for VenO versus BTKi and median time off-treatment was 11.3 vs. 4.3 months. In this real-world study, VenO was associated with better effectiveness outcomes than BTKi-based regimens in 1 L CLL., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Importance: New, effective, and well-tolerated oral therapies are needed for treating psoriasis. Zasocitinib, a highly selective allosteric tyrosine kinase 2 (TYK2) inhibitor, is a potential new oral treatment for this disease., Objective: To assess the efficacy, safety, and tolerability of zasocitinib in patients with moderate to severe plaque psoriasis., Design, Setting, and Participants: This phase 2b, randomized, double-blind, placebo-controlled, multiple-dose randomized clinical trial was conducted from August 11, 2021, to September 12, 2022, at 47 centers in the US and 8 in Canada. The study included a 12-week treatment period and a 4-week follow-up period. Key eligibility criteria for participants included age 18 to 70 years; a Psoriasis Area and Severity Index (PASI) score of 12 or greater; a Physician's Global Assessment score of 3 or greater; and a body surface area covered by plaque psoriasis of 10% or greater. Of 287 patients randomized, 259 (90.2%) received at least 1 dose of study treatment., Intervention: Patients were randomly assigned (1:1:1:1:1) to receive zasocitinib at 2, 5, 15, or 30 mg or placebo orally, once daily, for 12 weeks., Main Outcomes and Measures: The primary efficacy end point was the proportion of patients achieving 75% or greater improvement in PASI score (PASI 75) at week 12. Secondary efficacy end points included PASI 90 and 100 responses. Safety was also assessed., Results: In total, 259 patients were randomized and received treatment (mean [SD] age, 47 [13] years; 82 women [32%]). At week 12, PASI 75 was achieved for 9 (18%), 23 (44%), 36 (68%), and 35 (67%) patients receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, and 3 patients (6%) receiving placebo. PASI 90 responses were consistent with PASI 75. PASI 100 demonstrated a dose response at all doses, with 17 patients (33%) achieving PASI 100 with zasocitinib, 30 mg. Treatment-emergent adverse events occurred for 23 patients (44%) receiving placebo and 28 (53%) to 31 (62%) patients receiving the 4 different doses of zasocitinib, with no dose dependency and no clinically meaningful longitudinal differences in laboratory parameters., Conclusions and Relevance: This randomized clinical trial found that potent and selective inhibition of TYK2 with zasocitinib at oral doses of 5 mg or more once daily resulted in greater skin clearance than placebo over 12 weeks., Trial Registration: ClinicalTrials.gov Identifier: NCT04999839.

Purpose: Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with estrogen receptor-positive (ER+), HER2- metastatic breast cancer and tumors harboring estrogen receptor 1 (ESR1) mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration and in clinical subgroups with prior ET+CDK4/6i ≥12 months., Patients and Methods: EMERALD, an open-label phase III trial, randomly assigned patients with ER+, HER2- metastatic breast cancer who had received 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant). PFS was assessed across subgroups in post hoc exploratory analyses without adjustment for multiple testing., Results: In patients with ESR1-mutated tumors and prior ET+CDK4/6i ≥12 months, the median PFS for elacestrant versus SOC was 8.6 versus 1.9 months (HR, 0.41; 95% confidence interval, 0.26-0.63). In this population, the median PFS (in months) for elacestrant versus SOC was 9.1 versus 1.9 (bone metastases), 7.3 versus 1.9 (liver and/or lung metastases), 9.0 versus 1.9 (<3 metastatic sites), 10.8 versus 1.8 (≥3 metastatic sites), 5.5 versus 1.9 (PIK3 catalytic subunit α mutation), 8.6 versus 1.9 (tumor protein p53 gene mutation), 9.0 versus 1.9 (HER2-low), 9.0 versus 1.9 (ESR1D538G-mutated tumors), and 9.0 versus 1.9 (ESR1Y537S/N-mutated tumors). Subgroup safety was consistent with the overall population., Conclusions: The duration of prior ET+CDK4/6i ≥12 months in metastatic breast cancer was associated with a clinically meaningful improvement in PFS for elacestrant compared with SOC and was consistent across all subgroups evaluated in patients with ER+, HER2-, ESR1-mutated tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)

This study aimed to analyze potential ethnic disparities in the dose-exposure-response relationships of trilaciclib, a first-in-class intravenous cyclin-dependent kinase 4/6 inhibitor for treating chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (ES-SCLC). This investigation focused on characterizing these relationships in both Chinese and non-Chinese patients to further refine the dosing regimen for trilaciclib in Chinese patients with ES-SCLC. Population pharmacokinetic (PopPK) and exposure-response (E-R) analyses were conducted using pooled data from four randomized phase 2/3 trials involving Chinese and non-Chinese patients with ES-SCLC. PopPK analysis revealed that trilaciclib clearance in Chinese patients was approximately 17% higher than that in non-Chinese patients with ES-SCLC. Sex and body surface area influenced trilaciclib pharmacokinetics in both populations but did not exert a significant clinical impact. E-R analysis demonstrated that trilaciclib exposure increased with a dosage escalation from 200 to 280 mg/m 2 , without notable changes in myeloprotective or antitumor efficacy. However, the incidence of infusion site reactions, headaches, and phlebitis/thrombophlebitis rose with increasing trilaciclib exposure in both Chinese and non-Chinese patients with ES-SCLC. These findings suggest no substantial ethnic disparities in the dose-exposure-response relationship between Chinese and non-Chinese patients. They support the adoption of a 240-mg/m 2 intravenous 3-day or 5-day dosing regimen for trilaciclib in Chinese patients with ES-SCLC., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Early molecular response at 3 months is predictive of improved overall survival and progression-free survival in patients with chronic myeloid leukemia in the chronic phase. Although about one-third of patients treated with first-line imatinib do not achieve an early molecular response, long-term overall survival and progression-free survival are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved an early molecular response after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib than those randomized to imatinib (77% vs. 44%, P<0.001). The median time to MMR was 13.9 months with dasatinib versus 19.7 months with imatinib. The safety profile was consistent with previous reports. These results demonstrate that switching to dasatinib after a suboptimal response to imatinib at 3 months leads to faster MMR, provides earlier deep molecular responses, and improves some outcomes in patients with chronic myeloid leukemia in the chronic phase.

Objective: To evaluate the bioequivalence of two different afatinib dimaleate formulations in healthy Chinese subjects under fasting conditions and to assess their pharmacokinetic and safety profiles., Materials and Methods: This randomized, open-label, 2-period, crossover, bioequivalence study included 32 healthy Chinese subjects. The subjects were assigned to receive a single 40-mg dose of generic or brand-named afatinib dimaleate tablet. Blood samples were collected pre-dose and up to 120 hours after dosing. Healthy subjects orally took the trial preparation (T) (afatinib maleate tablets developed by Jiangxi Shanxiang Pharmaceutical Co., Ltd., Gan Zhou, China) and the reference preparation (R) (afatinib maleate tablets developed by Boehringer Ingelheim Pharma GmbH & Co., Ingelheim, Germany) under fasting conditions in the appropriate period according to the randomization. We measured the blood concentrations, calculated the pharmacokinetic parameters of the two preparations in the human body, and evaluated whether formulations were bioequivalent. Safety of the preparations in healthy subjects was monitored during the whole trial. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, i.e., from the time the subject received the test drug to the end of the last visit., Results: Under fasting conditions, the 90% confidence intervals (CIs) of the geometric mean ratios of the test/reference for afatinib dimaleate were 93.34 - 103.92% for AUC 0-t , 90.26 - 105.52% for C max , and 93.49 - 104.05% for AUC 0-∞ ., Conclusion: The 90% CI for the geometric mean ratios (test/reference) of C max , AUC 0-t , and AUC 0-∞ were within the range of 80.00 - 125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under fasting conditions. Both products were similar in terms of safety.