First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆

Annals of Oncology, Journal Year: 2021, Volume and Issue: 33(2), P. 169 - 180

Published: Nov. 18, 2021

•First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or pembrolizumab.•Vibostolimab plus pembrolizumab was well tolerated tumors.•Vibostolimab demonstrated antitumor activity tumors. BackgroundIn this first-in-human (NCT02964013; MK-7684-001), we investigated the safety and efficacy of anti-TIGIT (T cell immunoglobulin ITIM domain) antibody as monotherapy combination pembrolizumab.Patients methodsPart A enrolled tumors, part B non-small-cell lung cancer (NSCLC). Patients 2.1-700 mg 200 B. Primary endpoints were tolerability. Secondary included pharmacokinetics objective response rate (ORR) per RECIST v1.1.ResultsPart 76 (monotherapy, 34; therapy, 42). No dose-limiting toxicities reported. Across doses, 56% receiving 62% therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred 9% 17% patients, respectively. The most common fatigue (15%) pruritus (17%) rash (14%) therapy. Confirmed ORR 0% 7% In B, 39 anti-PD-1 (programmed death protein 1)/PD-L1 death-ligand 1)-naive NSCLC (all therapy), 67 anti-PD-1/PD-L1-refractory 33). anti-PD-1/PD-L1-naive NSCLC: 85% TRAEs–the (38%) hypoalbuminemia (31%); confirmed 26%, responses occurring both PD-L1-positive PD-L1-negative 70% (21% each) (36%) (24%) therapy; 3% therapy.ConclusionsVibostolimab including NSCLC. pembrolizumab. Part v1.1. Vibostolimab

Language: Английский

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PD-1 and PD-L1: architects of immune symphony and immunotherapy breakthroughs in cancer treatment

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Dec. 1, 2023

PD-1 (Programmed Cell Death Protein-1) and PD-L1 Ligand-1) play a crucial role in regulating the immune system preventing autoimmunity. Cancer cells can manipulate this system, allowing them to escape detection promote tumor growth. Therapies targeting PD-1/PD-L1 pathway have transformed cancer treatment demonstrated significant effectiveness against various types. This study delves into structure signaling dynamics of its ligands PD-L1/PD-L2, diverse inhibitors their efficacy, resistance observed some patients. Furthermore, explored challenges associated with inhibitor approach. Recent advancements combination immunotherapy chemotherapy, radiation, surgical procedures enhance patient outcomes also been highlighted. Overall, offers an in-depth overview significance future implications oncology.

Language: Английский

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Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: a special focus on nivolumab and pembrolizumab

The Lancet Oncology, Journal Year: 2022, Volume and Issue: 23(12), P. e552 - e561

Published: Nov. 29, 2022

Language: Английский

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Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2023, Volume and Issue: 13(5), P. 691 - 709

Published: Nov. 16, 2023

Project Optimus is a US Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, other stakeholders. Although there much promise this initiative, are several challenges that need be addressed, including multidimensionality problem oncology, heterogeneity cancer patients, importance evaluating long-term tolerability beyond dose-limiting toxicities, lack reliable biomarkers for efficacy. Through lens Totality Evidence with mindset model-informed development, we offer insights into by building quantitative knowledge base integrating diverse sources data leveraging modeling tools build evidence dosage considering exposure, disease biology, efficacy, toxicity, factors. We believe rational can achieved improving outcomes maximizing therapeutic benefit while minimizing toxicity.

Language: Английский

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Pembrolizumab hybrid dosing is non-inferior to flat dosing in advanced non-small cell lung cancer: a real-world, retrospective bicenter cohort study

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e010065 - e010065

Published: Feb. 1, 2025

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but come with high costs. Alternative ICI dosing strategies could reduce costs without losing efficacy. However, clinical efficacy data are lacking. Methods In this retrospective cohort trial, consecutive patients advanced non-small cell lung (NSCLC) who received ≥1 cycle pembrolizumab±chemotherapy at two tertiary institutions were included. Hybrid dosed either 100, 150 or 200 mg pembrolizumab every 3 weeks double 6 depending on their weight: <65 kg, 65–90 kg >90 respectively. Standard-of-care flat 400 weeks. Overall survival (OS) and progression-free (PFS) assessed by Kaplan-Meier estimation, compared log-rank test HRs calculated the Cox proportional hazards model in both unweighted inverse probability of weighted (IPTW) cohorts. Non-inferiority margin was set an HR 1.15. Results total, 375 391 included median follow-up 43.1 61.0 months hybrid dose cohort, OS non-inferior cohort: 17.7 (95% CI 14.9 to 20.9) vs 11.8 9.3 13.8, 0.76, 95% 0.65 0.90, p<0.0001 for non-inferiority). After correcting confounders IPTW, remained (HR 0.63 0.91, PFS also a 6.4 5.7 7.7) 4.6 3.9 5.5, 0.82, 0.70 0.96, 26.2% (or 52.5 per cycle, p<0.0001) saved accounting US$36 331.36 patient. Conclusions analysis large NSCLC treated pembrolizumab±chemotherapy, patients. after possible confounding factors. This regimen resulted significant savings

Language: Английский

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Toward Project Optimus for Oncology Precision Medicine: Multi‐Dimensional Dose Optimization Enabled by Quantitative Clinical Pharmacology

Clinical Pharmacology & Therapeutics, Journal Year: 2022, Volume and Issue: 112(5), P. 927 - 932

Published: Oct. 20, 2022

Project Optimus is a major US Food and Drug Administration (FDA) initiative aimed at dose optimization in oncology drug development, moving away from the maximum tolerated (MTD) paradigm prospectively characterizing dose–response for efficacy safety patient-focused maximization of benefit vs. risk.1 The critical role clinical pharmacology principles prospective ahead designing pivotal registration-enabling trials have been reinforced recent seminal publications,2 White Papers,3 cross-sector public workshops4 that galvanized development community offered call to action reforming current approaches. Clinical Pharmacology Therapeutics (CPT) has home research articles reviews illustrating contemporary integrative approaches inform selection therapeutics, including molecularly targeted small molecules,5-7 immunotherapies,8-11 antibody-drug conjugates,12-14 cell therapies.15-17 Several examples catalyzed active scientific discussion contributing growing appreciation biological complexity, population variability, analytical methodology demand careful consideration robust development.18-24 In issue CPT, Combes et al.25 illustrate quantitative optimizing precision medicine through their study on asciminib, an allosteric inhibitor BCR-ABL1 chronic myeloid leukemia – phase (CML-CP). Asciminib against wild-type several mutant forms kinase, T315I mutation, albeit with lower potency as established proliferation assays vitro, preclinical vivo xenograft models using patient-derived CML lines.26 An MTD was not reached I escalation assessed by Bayesian logistic regression modeling dose-related data.26, 27 Dose studies asciminib CML-CP considered molecular biology disease mechanism without adopting one-dose-fits-all approach. Based pharmacological analyses totality available data, doses 80 mg/day non-T315I 200 mg b.i.d. (400 mg/day) harboring were recommended. describe mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) longitudinal transcript levels ~ 300 patients across III program, model-based simulations reinforcing confidence these recommended currently approved use defined populations. A three-compartment tumor kinetic model dynamic interplay among proliferating, quiescent, resistant cells formulated, effect estimated proliferating compartment. Covariate indicated mutation associated greater number (where had no effect), (sensitive asciminib), decreased magnitude antiproliferative effect. trajectory final model, covariate effects translated higher dosage requirements clinically meaningful efficacy, response (MMR) rates. Furthermore, < 5% coverage exposures above effective concentration 90% (EC90) (the patients); whereas, > 95% EC90 predicted all evaluated exposure metrics. Taken together data27 relatively flat exposure-safety relationship,26 presented instrumental providing justification differential dosing based underlying pathology disease, fivefold BCR-ABL1. Viewed broader perspective, example represents application Totality Evidence28 approach, where evidence substantiated gained consistency multiple data sources integrated mechanism-informed manner simulation. Prior knowledge vitro effectively guided appropriate ranges (10 q.d.) (20–200 b.i.d.) evaluation exposure-response understanding asciminib's dynamics 10 range incorporating T315 status covariate. True purpose agent, first-in-human focused establishing II dose(s) opposed defining MTD. fact, arms evaluating up 280 b.i.d., supporting favorable therapeutic window. What some key enablers allowed learning regarding study? Unlike many investigational agents novel nonvalidated targets may be heterogeneous populations various advanced malignancies trials, trial conducted myelogenous (CML), molecule clearly target context point design. hallmark, monitoring representing used approach treatment relapse. As such, biomarker end available, enabling PK/PD modeling. Another dose-ranging feasible therapies myeloma, circulating M-protein serves measure burden (analogous CML). Indeed, successful I/Ib schedule described anti-CD38 monoclonal antibody isatuximab.29 question whether this can applied solid-tumor settings imaging-based assessments are primarily utilized evaluation. if selected or enriched drug's action, it should possible evaluate antitumor activity (e.g., sum longest diameters lesions). one example, phosphoinositide 3-kinase antagonist alpelisib performed solid tumors, amplification PIK3CA gene, resulting could kinetics informing selection.30 scenario envisioned conjugate (ADC) cancer type (i) expresses tumor-associated antigen ADC, (ii) known sensitive pharmacologic ADC-associated payload. With advances technologies cell-free plasma-derived DNA (ctDNA) measurements, leverage such measurements semimechanistic frameworks selection. Tumor ctDNA concentrations methods driver resistance mutational profiles described.31 However, relationships remains largely untapped opportunity. Progress will require collaboration disciplines sciences early efficient dose/exposure-response via dynamics. Such learning, coupled complementary dose/exposure-safety understanding, would particularly valuable aid decisions kinase inhibitors designed inhibit oncogenic variants receptor tyrosine kinases, profiling characterize mechanisms often into protocols. Of note, FDA recently issued Draft Guidance early-stage development.32 This discusses raises following opportunity: "ctDNA signal finding potentially sponsors plans." natural extension opportunity explore assessment development. feasible, expected valuably contribute timely problem multidimensional optimization. Some dimensions along which desired include dose/schedule, patient mutational/molecular profile), (iii) (histology), (iv) line treatment, (v) combination partner selection, (vi) dose/schedule partner. Besides profile (which dimension case other pertinent features relevant warrant under #2 strategy. For expression ADC low high) immunophenotype cold inflamed) factors consider depending agent. demonstrated optimal vary context. Emerging like systems models11, 33-35 increasingly enhance our ability tackle complexity developing optimized pharmacotherapy. (Relatedly, Pharmacometrics & Systems Pharmacology, another ASCPT journal, Call Papers themed Optimization Oncology, publish fourth quarter 2023. You read more about here: https://www.ascpt.org/Journals/Call-for-Papers.) Confidence supported three inter-dependent anchors (Figure 1): rigorous contextualization foundational base, indicative benefit, long-term multi-cycle) tolerability incidence modifications experience. Cultural success comfort iterative "learning" optimization, commitment Evidence mindset, multidisciplinary pharmacologists, scientists, biologists, pharmacometricians, statisticians, trialists, oncologists, voice design analysis trials. Just longer cases, elegantly illustrated al.,25 case-by-case warranted discipline being move needle realize promise journey toward 2). authors declared competing interest work. No funding received

Language: Английский

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Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

Pharmaceutics, Journal Year: 2021, Volume and Issue: 13(3), P. 422 - 422

Published: March 21, 2021

With more than 90 approved drugs by 2020, therapeutic antibodies have played a central role in shifting the treatment landscape of many diseases, including autoimmune disorders and cancers. While showing advantages such as long half-life highly selective actions, still face outstanding issues associated with their pharmacokinetics (PK) pharmacodynamics (PD), high variabilities, low tissue distributions, poorly-defined PK/PD characteristics for novel antibody formats, rates resistance. We witnessed successful cases applying modeling to answer critical questions antibodies’ development regulations. These models yielded substantial insights into properties. This review summarized progress, challenges, future directions highlighted potential mechanistic addressing questions.

Language: Английский

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Advances in pharmacokinetics and pharmacodynamics of PD-1/PD-L1 inhibitors

International Immunopharmacology, Journal Year: 2022, Volume and Issue: 115, P. 109638 - 109638

Published: Dec. 30, 2022

Immune checkpoint inhibitors (ICIs) are a group of drugs designed to improve the therapeutic effects on various types malignant tumors. Irrespective monotherapy or combinational therapies as first-line and later-line therapy, ICIs have achieved benefits for Programmed cell death protein-1 (PD-1) / ligand 1 (PD-L1) is an immune that suppresses antitumor immunity, especially in tumor microenvironment (TME). PD-1/PD-L1 block tumor-related downregulation system, thereby enhancing immunity. In comparison with traditional small-molecule drugs, exhibit pharmacokinetic characteristics owing their high molecular weight. Furthermore, different pharmacodynamic characteristics. Hence, been approved indications by Food Drug Administration (FDA) National Medical Products (NMPA). This review summarizes studies PD-1/ PD-L1 provide reference rational clinical application.

Language: Английский

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Bioequivalence of alternative pembrolizumab dosing regimens: current practice and future perspectives

Cancer Communications, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Immune checkpoint inhibitors (ICIs), including humanized anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) monoclonal antibodies (mAbs), such as pembrolizumab, have transformed cancer treatment. Pembrolizumab was initially approved a three-weekly (Q3W) 2 mg/kg weight-based dose by the Food and Drug Administration (FDA), which later replaced 200 mg Q3W fixed-dose, mainly based on in silico simulations. Later, fixed 400 six-weekly (Q6W) regimen pharmacokinetic simulations [1]. Due to increasing ICI use high costs per treatment, increasingly large portions of healthcare budgets are shifted Therefore, it is important handle ICIs efficiently cost-effectively possible. Hence, Q6W introduced, lowering total amount administrations patient strain capacity, improving convenience. The cost-effectiveness treatment could be optimized further using alternative dosing strategies (ADS) Some these ADS already been tested for pembrolizumab some countries [2, 3]. Recently, FDA provided bioequivalence guidelines ADS, specifically anti-PD-1/PD-L1 mAbs [4]. These support pharmacokinetic-modeling simulate steady-state trough concentrations (Ctrough,ss) area under curve (AUC; exposure) establish mAbs. In guidelines, considered bioequivalent when both Ctrough,ss exposure at most 20% lower compared used while establishing efficacy clinical trials (i.e. reference regimen). A maximum 25% increase concentration (Cmax) upper boundary, unless adequate evidence shows that Cmax does not toxicity. For incidences toxicities were generally consistent across 2-10 range multiple [5]. To verify whether various (Figure 1, Supplementary Table S1) following current we assessed modelling. Using data from real-world cohort, best performing model selected with extrapolations this cohort ("extrapolation") also virtual ("simulation") cohort. Details cohorts, well modelling procedures, depicted Material Methods. As reference, used, original approval. Results analyses shown Figure 1. simulated given every 3 or 4 weeks (Q3/4W) according guidelines. Interestingly, despite meeting criteria exposure, none (non-registered) bioequivalent, met. Pharmacokinetic usually utilized ensure equivalent efficacy. However, applicability thresholds proposed questioned, disregards pharmacological regarding exposure-response relationships (except Cmax). Consequently, implications non-adherence unclear. explore possible non-adherence, shall examine arguments favor against FDA-guidelines next section. Firstly, derived small molecules. do show similar mAb pharmacokinetics probably necessary example, no significant differences observed Besides, adequately powered prospective study has validated (nor Ctrough,ss) This exemplified during registration rejected regimen, predicted Nonetheless, conditional approval granted, limited descriptive interim analysis (n = 44) objective response rates non-randomized literature values Furthermore, suggests doses higher than required may caused focus tolerated phase I trials, instead lowest maximally effective dose. instance, demonstrated ≥ 0.1 result near-complete (> 95%) receptor occupancy blood. Early research nivolumab showed achieved reached [1, 6]. Nevertheless, only subsequent would intra-tumoral after first administration, surrogate marker Two hundred results geometric mean 10.7 µg/mL much required, resulting levels (corresponding 0.85 2.58 Q6W, Methods) [7]. It reported associated poorer outcomes, suggesting an relationship. post-hoc Keynote-002 Keynote-010 studies however worse outcomes increased clearance [8]. findings explain absence relationship, illustrated overall survival, substantial variation (2 (Ctrough,ss range: 1.13-127 µg/mL) 5]. underlines always indicative outcome reports prolonged responses cessation I-II Clinical different tumor types non-bioequivalent EMA/FDA retrospective patients non-small lung (NSCLC) found administration Q3W-Q6W 604) resulted comparable survival standard 1,362) [2]. three Canadian retrospectively analyzed cohorts NSCLC treated (combined n 139) concluded equally [3]. there uncertainty measuring vivo because complex technical endeavor. performed vitro developed never vivo. its predictive value remains unclear [6]. Moreover, even occupancy, attained optimal conditions, 15%-50% solid tumors respond [5, 9]. indicates effectiveness solely dependent parameters, more array non-pharmacokinetic factors influencing response, type, mutational burden, ability T-cells infiltrate become activated within tumors, PD-L1 expression certain genomic alterations [10]. Randomized controlled (RCTs) golden determining safety ADS. Currently, being conducted, illustrating unmet need (NCT04913025, NCT04295863, NCT05692999, NCT04909684) (detailed descriptions S2). presently, RCT assess < completed yet, time-consuming expensive. conclusion, indications stipulated reflective true relationship thereby underlining potential improve still fully understand driving mechanisms exact threshold elusive. implementing daily practice yet understood. deviate exposures below efficacy, potentially leading reduced More sophisticated methods needed determine minimum effectivity faster way, provide guidance pembrolizumab. future dose-optimization Tannock et al. [11] suggest moving away requirement non-inferiority trials. Additionally, recommend initiating earlier, preferably prior market reimbursement, facilitate validation regulatory acceptance Until then, all available should carefully discussed, balanced, reviewed. Ruben Malmberg: Methodology, Investigation, Validation, Formal analysis, Writing – Original draft, Review & Editing, Visualization. Bram C. Agema: Maaike M. Hofman: Stefani Oosterveld: Editing. Sander Bins: Daphne W. Dumoulin: Arjen Joosse: Joachim G.J.V Aerts: Reno Debets: Birgit C.P. Koch: Astrid A.M. van der Veldt: Roelof W.F. Leeuwen: Conceptualization, investigation, Ron H.J. Mathijssen: Resources, We thank health care professionals Erasmus MC Cancer Institute Rotterdam, Netherlands contributing MULTOMAB-study. None co-authors conflict interest relation manuscript. Malmberg speaker fees Bristol Myers Squibb. Dumoulin consultancy Roche, Squibb, Merck Sharp Dohme, Astra Zeneca, Pfizer, Amgen. G.J.V. Aerts grants Boehringer-Ingelheim, Astra-Zeneca, Eli-Lilly, Verastem, Nutricia, Amphera, CureVac (payments institution personnel). Fees lectures: &Dohme, Eli-Lilly. Travel fees: Dohme Zeneca. Patent issued: allogeneic lysate, combination immunotherapy. Board directors' member International Association Study Lung Mesothelioma Interest Group. Stock: Amphera. Veldt Eisai, Ipsen, Sanofi, Pierre Fabre, Novartis, Roche institution). Leeuwen Squibb Pfizer. Consulting Pierre-Fabre Dohme. Mathijssen institution) Astellas, Bayer, Cristal Therapeutics, Deuter Oncology, Echo Pharmaceuticals, Nordic Pharma, Pamgene, Sanofi Servier. did receive any specific grant funding agencies public, commercial, not-for-profit sectors. conducted accordance Declaration Helsinki local ethics committee Medical Center (METC 16-011). All participants written informed consent their inclusion study. supporting article information files corresponding author upon reasonable request. Please note: publisher responsible content functionality supplied authors. Any queries (other missing content) directed article.

Language: Английский

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Oncology Dose Optimization: Tailored Approaches to Different Molecular Classes

Clinical Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: April 18, 2025

Oncology dose optimization during the era of chemotherapy focused on identifying maximum tolerated (MTD) for registrational trials, often resulting in significant toxicity. The advent molecular targeted drugs and immunotherapies offers potential to achieve similar efficacy with lower doses fewer side effects, as maximal is reached at below MTD. Recent FDA guidance outlines expectations improving oncology drug development. This review presents a framework tailored by categorizing molecules into four distinct classes based their mechanisms action clinical activities: small molecule therapies antibody‐drug conjugates (Class 1), large antagonists 2), cancer immunotherapy agonists 3), limited or no single‐agent activity 4). Unique considerations each class are discussed, supported illustrative case examples. To enhance robust decision‐making optimize patient resource utilization, we propose using proof gate initiating expansion one multiple levels. emphasizes importance integrating all relevant preclinical data, disease knowledge, measurements highlights essential role quantitative pharmacology statistical modeling optimizing doses.

Language: Английский

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