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Trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody-drug conjugate with a topoisomerase I inhibitor connected by a cleavable linker, has been approved for patients with HER2-positive gastric or gastroesophageal junction tumors. This biomarker study assessed HER2 expression and immune cell infiltration in relation to the therapeutic response to T-DXd. This retrospective analysis included samples from patients treated with T-DXd in three clinical trials. We performed RNA sequencing and multiplex immunohistochemistry on archival tumor samples obtained at baseline, during treatment, and after treatment. Flow cytometry was performed on tumor infiltrating immune cells freshly isolated from tumor tissues. Samples from 28 patients were included in this study. ERBB2 mRNA levels and CD20+ cell infiltration in tumors were significantly higher at baseline in responders than in nonresponders. Patients were classified into three biological groups based on their baseline tumor/stroma-infiltrating immune cell densities. Two groups reported similar response rates, but a trend was observed toward a shorter progression-free-survival in the group with more immunosuppressive regulatory T cells and programmed death-ligand 1 (PD-L1) expression at baseline. T-DXd treatment tended to increase the levels of tumor-infiltrating CD8+ T cells and PD1+CD8+ T cells, particularly in responders. Gene expression signatures of CTL and helper T cells increased during treatment, whereas signatures related to hypoxia, MYC targets, collagen formation, and interleukin-10 were downregulated. Our data suggest that HER2 expression levels and baseline tumor microenvironment (TME) characteristics correlate with T-DXd efficacy. Furthermore, this treatment may modulate TME immune profiles. Further validation using a larger sample size is warranted.

Purpose: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC)., Patients and Methods: Part 1 determined the recommended dose for expansion of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate by independent central review., Results: In part 1, seven patients with mBC were enrolled and received T-DXd 3.2 mg/kg (four patients) or 5.4 mg/kg (three patients) plus nivolumab. The recommended dose for expansion for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously every 3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of three administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and four with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the confirmed objective response rates (95% confidence interval) for cohorts 1 to 4 were 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. The median treatment duration (range) with T-DXd in cohorts 1 to 4 was 8.9 (1-23) months, 6.9 (1-21) months, 3.9 (1-21) months, and not assessed, respectively; the most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, and 75.0%, respectively). Adjudicated drug-related interstitial lung disease/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0%, respectively (one grade 5 each, cohorts 1 and 3)., Conclusions: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T-DXd. Interstitial lung disease/pneumonitis is an important risk and requires careful monitoring and prompt intervention., (©2024 The Authors; Published by the American Association for Cancer Research.)

Despite the tremendous effort in the oncology community, the success rate of anticancer development remained low at 30% to 40% from the Phase 3 study to the regulatory approval. The factors associated with the regulatory approval for market authorization have gained interest in the community to improve the success rate of drug development. Using the data from 208 Phase 3 studies for anticancer drugs, we explored the possible factors associated with the US Food and Drug Administration's (FDA's) approval by multivariate logistic regression analysis. The model incorporated 21 factors from therapeutic context, study design, and outcomes. The hazard ratio (HR) for overall survival (OS) showed a significant association with FDA approval (coefficient: -29.907, P < .001), and the age of control drugs in the market followed (coefficient: -2.581, P = .008). In the model, if the HR for OS changes from 0.75 to 0.85, the probability of FDA approval remarkably decreases from 79.6% to 16.4%. A 50% likelihood of FDA approval is predicted at HR 0.795 for OS. Furthermore, the P-value for the OS test and the width of the confidence interval on HR for OS showed a significant association with the probability of FDA approval. These findings consistently underscore the rigorous standard required for new anticancer drugs to obtain regulatory approval from the FDA., (© 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

With immuno-oncology becoming the standard of care for a variety of cancers, identifying biomarkers that reliably classify patient response, resistance, or toxicity becomes the next critical barrier towards improving care. Multi-parametric, multi-omics, and computational platforms generating an unprecedented depth of data are poised to usher in the discovery of increasingly robust biomarkers for enhanced patient selection and personalized treatment approaches. Deciding which developing technologies to implement in clinical settings ultimately, applied either alone or in combination, relies on weighing pros and cons, from minimizing patient sampling to maximizing data outputs, and assessing reproducibility and representativeness of findings, while lessening data fragmentation towards harmonization. These factors are all assessed while taking into consideration the shortest turnaround time. The Society for Immunotherapy of Cancer (SITC) Biomarkers Committee convened to identify important advances in biomarker technologies and to address advances in biomarker discovery using multiplexed immunohistochemistry and immunofluorescence, their coupling to single cell transcriptomics, along with mass spectrometry-based quantitative and spatially resolved proteomics imaging technologies. We summarize key metrics obtained, ease of interpretation, limitations and dependencies, technical improvements, and outward comparisons of these technologies. By highlighting the most interesting recent data contributed by these technologies, and by providing ways to improve their outputs, we hope to guide correlative research directions and assist in their evolution towards becoming clinically useful in IO.

Background: Regulators and oncology healthcare providers are increasingly interested in using observational studies of real-world data (RWD) to complement clinical evidence from randomized controlled trials for informed decision-making. To generate valid evidence, RWD studies must be carefully designed to avoid systematic biases. The clone-censor-weight (CCW) method has been proposed to address immortal time and other time-related biases., Methods: The objective of this manuscript is to de-mystify the CCW method for cancer researchers by describing and presenting its core components in an accessible and digestible format, using visualizations and examples from cancer-relevant studies. The CCW method has been applied in diverse settings, including investigations of the effects of surgery within a certain time after cancer diagnosis, the continuation of annual screening mammography, and chemotherapy duration on survival., Results: The method handles complex data wherein the treatment group to which an individual belongs is unknown at the start of follow-up. The three steps of the CCW method involve cloning or duplicating the patient population and assigning one clone to each treatment strategy, artificially censoring the clones when their observed data are inconsistent with the assigned strategy and weighting the cloned and censored population to address selection bias created by the artificial censoring., Conclusions: The CCW method is a powerful tool for designing RWD studies in cancer that are free from time-related biases and successfully, to the extent possible, emulate features of a randomized clinical trial., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The population pharmacokinetics (PK) of quizartinib and its pharmacologically active metabolite AC886 have been previously described in healthy volunteers (HV) and relapsed/refractory (R/R) FLT3-internal-tandem-duplication-positive (FLT3-IDT-positive) acute myeloid leukemia (AML) patients receiving quizartinib monotherapy. In this analysis, we characterized the population PK of quizartinib and AC886 in newly diagnosed FLT3-ITD-positive AML patients receiving standard induction and consolidation chemotherapy as background treatment, using data from the Phase 3 QuANTUM-First trial and 12 earlier studies. Quizartinib PK were best described by a three-compartment model with sequential zero- and first-order absorption and first-order elimination. A two-compartment model with first-order metabolite formation and first-order elimination best fitted AC886 data. The PK of both moieties showed large interindividual variability (approximately 70% coefficient of variation for systemic clearances). The use of strong cytochrome P450 3A (CYP3A) inhibitors had the largest impact on exposure, increasing the steady-state area under the curve during the dosing interval (AUC ss ) by 1.8-fold. This is consistent with observations in HV and R/R AML patients and confirms the need for dose adjustments during coadministration. A novel finding in newly diagnosed AML patients was the phase-dependent change in steady-state quizartinib exposure: dose-normalized AUC ss values were 0.6-fold during induction, similar during consolidation, and 1.4-fold during continuation compared to R/R AML patients receiving quizartinib monotherapy. The present analysis highlighted the comparison of quizartinib and AC886 PK between newly diagnosed AML patients and previously studied populations, informed dose modifications needed with strong CYP3A inhibitors, and supported the use of derived individual exposure metrics in separate exposure-response analyses., (© 2024 Daiichi Sankyo, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment., Patients and Methods: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. The endpoints included intracranial objective response rate (ORR; complete or partial response in the brain) per blinded independent central review (BICR) by RECIST version 1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety., Results: A total of 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median intracranial DoR was 12.3 [95% confidence interval (CI) 9.1-17.9] months, and for those with untreated/active BMs, it was 17.5 months (95% CI 13.6-31.6 months). The median CNS-PFS and OS were 12.3 months (95% CI 11.1-13.8 months) and not reached (95% CI 22.1 months-not estimable) in those with treated/stable BMs, and 18.5 months (95% CI 13.6-23.3 months) and 30.2 months (95% CI 21.3 months-not estimable) in those with untreated/active BMs, respectively. Drug-related treatment-emergent adverse events grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd., Conclusions: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Datopotamab deruxtecan (Dato-DXd), is a humanized anti-TROP2 IgG1 monoclonal antibody linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCXs) varying in TROP2 expression., Methods: The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors post-neoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines., Results: Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival (EFS) in 8 (73%) models while IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged EFS in 3 (27%) models. TROP2 RNA and protein was significantly higher in Dato-DXd-sensitive models. In isogenic cell lines derived from Dato-DXd-resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the 2 Dato-DXd-sensitive BCXs but not in a Dato-DXd-resistant BCX. In Dato-DXd-sensitive models, antitumor activity was enhanced in combination with PARP inhibitor, olaparib., Conclusion: Dato-DXd is active in breast cancer models. Dato-DXd has TROP2 dependent and independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.

Purpose: The Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) comprises 7 common MF symptom items (fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, bone pain) and is the first patient-reported outcome (PRO) instrument designed to assess MF symptom burden. Given that information on the psychometric properties of this instrument has been limited, we sought to evaluate its measurement properties and validate its use in the phase 3 MOMENTUM trial., Methods: Data were pooled to assess MFSAF item distribution, structural validity, reliability (test-retest and internal consistency), construct validity (convergent, divergent, and known-groups), and sensitivity to change. Other PRO measures included Patient Global Impression of Severity/Change (PGIS/PGIC), EORTC QLQ-C30, PROMIS Physical Function Short Form 10b, and ECOG performance status., Results: Participants (N = 195) showed high completion rates (> 93%) across 24 weeks. Moderate to strong Spearman correlation coefficients among items were mostly observed at baseline (range, 0.289-0.772) and week 24 (range, 0.391-0.829), which supported combining items into a multi-item scale and total score. Internal consistency (Cronbach's α, 0.877 at baseline and 0.903 at week 24) and test-retest reliability (intraclass correlation coefficient, > 0.829) were satisfactory across selected time intervals. Reliability was also supported by McDonald's omega (ω) coefficient (> 0.875). MFSAF moderately correlated with PRO measures of similar content, differentiated between PGIS and ECOG groups (P < .001), and was able to detect change over time., Conclusions: The MFSAF v4.0 is a valid tool to assess MF symptom burden, supporting its use in future trials in similar populations., Competing Interests: Declarations. Ethical approval: The current analysis is based on results of the MOMENTUM trial. MOMENTUM was done in accordance with the Declaration of Helsinki and the International Council for Harmonisation guidelines on Good Clinical Practice. Institutional review boards or independent ethics committees at each site approved the protocol. Consent to participate: Written consent was obtained from all individual participants included in the MOMENTUM study. Consent to Publish: Not applicable. All personal data are deidentified. Competing interests: Christina Daskalopoulou holds an advisory role within IQVIA and reports grants from GSK during the conduct of this study. Boris Gorsh has been employed by GSK and Daiichi Sankyo during the production of this manuscript and has stock or stock options with both companies. Gerasimos Dumi and Jean Paty are employees of IQVIA. Samineh Deheshi is an employee of GSK. Chad Gwaltney has received consulting fees from IQVIA for this MFSAF evaluation. Catherine Ellis is an employee of GSK and reports stock or stock options. Jun Kawashima is an employee of Sierra Oncology, a GSK company. Ruben Mesa reports consulting fees/honoraria from AbbVie, Blueprint, Bristol Myers Squibb, CTI, Genentech, Geron, GSK, Incyte, MorphoSys, Novartis, Sierra, Sierra Oncology, and Telios. All authors acknowledge medical writing support related to this manuscript, funded by GSK., (© 2024. The Author(s).)

Background: Pexidartinib is effective in patients with tenosynovial giant cell tumor (TGCT) for whom surgery is not feasible. Durability of response after discontinuation of pexidartinib and the safety and efficacy of restarting pexidartinib have not been previously recorded. This phase 4 study was designed to mimic the real-world experience with pexidartinib to evaluate the effects of discontinuation of and retreatment with pexidartinib in patients with TGCT who previously benefited from the drug., Methods: This was a global, multicenter, phase 4 study that enrolled patients with TGCT who were experiencing clinical benefit from pexidartinib in one of four prior phase 1 or phase 3 studies investigating pexidartinib in the disease. Patients could choose to continue pexidartinib at the same dose (the treatment-continuation cohort) or discontinue treatment with the option to restart pexidartinib (the treatment-free/retreatment cohort). Tumor progression determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, patient-reported outcomes (the Patient-Reported Outcomes Measurement Information System-Physical Function [PROMIS-PF] questionnaire and the EuroQol 5-dimension, 5-level [EQ-5D-5L] visual analog scale), and safety were assessed every 3 months. The primary end point was the proportion of patients in the treatment-free/retreatment cohort who remained treatment-free at month 12 and 24; this did not depend on disease progression., Results: Thirty-two patients were enrolled: 21 chose to enter the treatment-continuation cohort, and 11 entered the treatment-free/retreatment cohort. During the treatment-free period, six of 11 (54.5%) patients in the treatment-free/retreatment cohort had progressive disease (PD) according to RECIST, version 1.1, whereas no patient in the treatment-continuation cohort had disease progression. Over the 24-month study, three of 11 (27.3%) patients in the treatment-free/retreatment cohort restarted treatment because of RECIST version 1.1 PD, symptomatic progression, or both (n = 1 each). The probability of remaining treatment-free in the treatment-free/retreatment cohort was 73% (95% confidence interval, 37%-90%). In the treatment-free/retreatment cohort, the median progression-free survival of the treatment-free period was 22.8 months (95% confidence interval, 1.6 months to not estimable). By 6 months of retreatment, all retreated patients achieved new disease stabilization with no new safety concerns; two patients had clinically significant improvements in PROMIS-PF and EQ-5D-5L visual analog scale scores. The mean PROMIS-PF and EQ-5D-5L scores remained stable throughout the study. There was no hepatotoxicity and no new safety signal in either cohort., Conclusions: In this small phase 4 study designed to evaluate outcomes in patients who stopped and restarted pexidartinib, 54.5% of patients who discontinued pexidartinib showed PD, with a median progression-free survival of 22.8 months. Each of the three patients who restarted pexidartinib stopped progressing, and some reported a new gain in physical function. No PD was detected in patients who remained on treatment, and the safety profile did not indicate long-term hepatotoxicity or any new safety concerns., Plain Language Summary: Pexidartinib is a medication for people with tenosynovial giant cell tumor (TGCT) for whom surgery is not recommended. This study examined what happens when patients stop taking pexidartinib (after it has helped them) to see whether it is safe and effective to restart if needed. Thirty-two patients were followed for 2 years: 21 chose to continue pexidartinib and did not experience disease progression, while 11 chose to stop pexidartinib; 54.5% of them had disease progression within 2 years. Three patients who stopped pexidartinib restarted treatment after their tumor size increased or their symptoms worsened. Restarting pexidartinib was safe and effective in these patients., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Edoxaban is an orally active inhibitor of activated factor X (FXa). Population pharmacokinetic (PK) and pharmacodynamic (PD) analyses were performed to characterize the PK and PK-PD relationships of edoxaban in pediatric patients to identify the covariates that may contribute to inter-subject variability in PK and PD of edoxaban in pediatric patients, and to compare the PK and PD data between pediatric and adult patients. The pediatric PK of edoxaban was best described by a two-compartment model with transit compartments, first-order oral absorption, and linear elimination. The estimated glomerular filtration rate (eGFR), body weight, and post-menstrual age were the significant covariates explaining variability in edoxaban PK among pediatric patients. A function based on renal maturation was applied to edoxaban clearance. The clearance for a 70 kg patient with an eGFR of 110 mL/min/1.73 m 2 was estimated to be 42.9 L/h (CV ~ 31.8%). PK simulation showed that exposures across five pediatric age groups were comparable to that in adult patients receiving 60 mg once daily dose. The PK-PD relationship for anti-factor Xa was best fit with an E max (8.65 IU/mL) model with an EC 50 of 631 ng/mL. The PK-PD relationships for activated partial thromboplastin time and prothrombin time were best fit with linear models (slopes of 0.0467, and 0.0415 s mL/ng, respectively). In addition, due to the small number of efficacy and safety events, an exploratory analysis did not detect a correlation between efficacy events (recurrent venous thromboembolism) or safety events (clinically relevant bleeding) and edoxaban exposure., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma., Methods: Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms., Results: Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF -mutant and BRAF -wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy., Conclusion: In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.

Quizartinib prolongs QT interval through inhibition of the slow delayed rectifier potassium current (I Ks ). We used non-linear mixed-effects modeling to explore the relationship between quizartinib and its pharmacologically active metabolite AC886 and the Fridericia-corrected QT interval (QTcF) in newly diagnosed acute myeloid leukemia (AML) patients. We evaluated linear and non-linear drug effect models, using triplicate QTcF measurements with available time-matched pharmacokinetic samples from the Phase 3 QuANTUM-First trial. The effect of intrinsic and extrinsic factors on model parameters was tested using stepwise covariate model building. Simulations were conducted to predict the change from baseline in QTcF (ΔQTcF) at the maximum concentration at steady-state (C max,ss ) for quizartinib maintenance daily doses of 30 and 60 mg. The concentration-QTcF (C-QTcF) relationship was best described by a sigmoidal maximum effect model. After accounting for the effect of quizartinib, including AC886 concentrations did not further explain changes in QTcF. Circadian variations in QTcF were described using an empirical change from baseline based on clock times. Age and hypokalaemia were identified as statistically significant covariates on baseline QTcF; no covariates were found to impact the C-QTcF relationship. The median model-predicted ΔQTcF at C max,ss was 18.4 ms (90% confidence interval (CI): 16.3-20.5) at 30 mg and 24.1 ms (90% CI: 21.4-26.6) at 60 mg. In conclusion, in newly diagnosed AML patients, ΔQTcF increased non-linearly with increasing quizartinib concentrations. The predicted ΔQTcF increase at C max,ss supports the proposed dose adaptation based on observed QTcF and the dose reduction in case of strong cytochrome P450 3A (CYP3A) inhibitors coadministration., (© 2024 Daiichi Sankyo, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age-dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age-related differences in disease and response to treatment; (2) consideration of age-related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub-populations., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Stan is a powerful probabilistic programming language designed mainly for Bayesian data analysis. Torsten is a collection of Stan functions that handles the events (e.g., dosing events) and solves the ODE systems that are frequently present in pharmacometric models. To perform a Bayesian data analysis, most models in pharmacometrics require Markov Chain Monte Carlo (MCMC) methods to sample from the posterior distribution. However, MCMC is computationally expensive and can be time-consuming, enough so that people will often forgo Bayesian methods for a more traditional approach. This paper shows how to speed up the sampling process in Stan by within-chain parallelization through both multi-threading using Stan's reduce&#95;sum() function and multi-processing using Torsten's group ODE solver. Both methods show substantial reductions in the time necessary to sufficiently sample from the posterior distribution compared with a basic approach with no within-chain parallelization., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Physiologically-based pharmacokinetic (PBPK) modeling offers a viable approach to predict induction drug-drug interactions (DDIs) with the potential to streamline or reduce clinical trial burden if predictions can be made with sufficient confidence. In the current work, the ability to predict the effect of rifampin, a well-characterized strong CYP3A4 inducer, on 20 CYP3A probes with publicly available PBPK models (often developed using a workflow with optimization following a strong inhibitor DDI study to gain confidence in fraction metabolized by CYP3A4, f m,CYP3A4 , and fraction available after intestinal metabolism, Fg), was assessed. Substrates with a range of f m,CYP3A4 (0.086-1.0), Fg (0.11-1.0) and hepatic availability (0.09-0.96) were included. Predictions were most often accurate for compounds that are not P-gp substrates or that are P-gp substrates but that have high permeability. Case studies for three challenging DDI predictions (i.e., for eliglustat, tofacitinib, and ribociclib) are presented. Along with parameter sensitivity analysis to understand key parameters impacting DDI simulations, alternative model structures should be considered, for example, a mechanistic absorption model instead of a first-order absorption model might be more appropriate for a P-gp substrate with low permeability. Any mechanisms pertinent to the CYP3A substrate that rifampin might impact (e.g., induction of other enzymes or P-gp) should be considered for inclusion in the model. PBPK modeling was shown to be an effective tool to predict induction DDIs with rifampin for CYP3A substrates with limited mechanistic complications, increasing confidence in the rifampin model. While this analysis focused on rifampin, the learnings may apply to other inducers., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Context.—: Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-targeted therapy, has demonstrated durable anticancer activity in patients with advanced, metastatic HER2 (also known as ERBB2)-mutant (HER2m) non-small cell lung cancer (NSCLC) who have limited treatment options and poor prognosis., Objective.—: To analytically validate and assess the clinical utility of the Oncomine Dx Target (ODxT) Test as a companion diagnostic to identify patients with HER2m NSCLC., Design.—: Tumor samples from patients in DESTINY-Lung01 and DESTINY-Lung02 were retrospectively analyzed alongside commercially procured samples using the ODxT test and compared to the assays used for screening in these clinical trials., Results.—: Positive percent agreement (PPA) and negative percent agreement (NPA) between the ODxT Test and TruSight Tumor 170 assay when testing DESTINY-Lung01 and commercially procured samples met prespecified thresholds (PPA and NPA ≥90%) for analytical accuracy (100% and 99.1%). The ODxT Test results were highly concordant with clinical trial assays (CTAs) used in DESTINY-Lung01 (PPA and NPA, 98.0% and 100%) and DESTINY-Lung02 (PPA and NPA, 96.7% and 100%) to identify activating HER2 mutations in tumor samples. Confirmed objective response rates were similar between patients with HER2m tumors identified by the ODxT Test and by CTAs in DESTINY-Lung01 (58.3% and 54.9%) and DESTINY-Lung02 (53.6% and 53.8%). Response duration was 12.0 and 9.3 months for patients identified by the ODxT Test and CTAs, respectively, in DESTINY-Lung01., Conclusions.—: The ODxT Test detected HER2 mutations in NSCLC with high analytical and clinical accuracy and identified HER2m populations with response rates similar to populations identified by CTAs, supporting clinical utility of the ODxT Test to inform treatment decisions for HER2m NSCLC., Competing Interests: Karnoub, Pereira, and Shiga are employees of Daiichi Sankyo, Inc. Qi, Feng, and Khambata-Ford are employees of and hold stock and stock options in Daiichi Sankyo, Inc. Ha and Velasco Roth are employees of Thermo Fisher Scientific. Smit has received consulting fees paid to his institution from Daiichi Sankyo, Inc, and has participated in advisory boards for Daiichi Sankyo, Inc. Y. Goto has received research grants paid to his clinical trial group or institution from Daiichi Sankyo, Inc, speaker payments or honoraria from Thermo Fisher Scientific, and has participated in advisory boards for Daiichi Sankyo, Inc. K. Goto has received research grants paid to his institution from Daiichi Sankyo, Inc, speaker payments or honoraria from Daiichi Sankyo, Inc, and Thermo Fisher Scientific, and has participated in advisory boards for Daiichi Sankyo, Inc. De Langen has no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

In patients with prevalent or incident atrial fibrillation (AF) after successful transcatheter aortic valve implantation (TAVI) enrolled in the EdoxabaN Versus standard of care and theIr effectS on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation - in Atrial Fibrillation (ENVISAGE-TAVI AF) trial, the incidence of ischemic stroke (IS) and any stroke was numerically less in the edoxaban group than in the vitamin K antagonist (VKA) group. The present study aimed to identify risk factors associated with IS in an on-treatment subanalysis in patients from ENVISAGE-TAVI AF who received ≥1 dose of edoxaban or VKA. Baseline patient characteristics were compared in patients with and those without IS. Numerical variables were compared using a 1-way analysis of variance; categorical variables were compared using Fisher's exact test. Stepwise Cox regression determined patient characteristics associated with the first IS event. Of 1,377 patients, 41 (3.0%) experienced an IS, and 1,336 (97.0%) did not; baseline demographics and clinical characteristics were well balanced between groups. Most ISs occurred within 180 days of TAVI for edoxaban (57.9%) and VKA (68.2%). The rate of IS was 2.0/100 person-years for edoxaban versus 2.7/100 person-years for VKA. Independently associated with IS were history of systemic embolic events (hazard ratio 2.96, 95% confidence interval 1.26 to 7.00, p = 0.01) and pre-TAVI use of VKAs (hazard ratio 2.17, 95% confidence interval 1.12 to 4.20, p = 0.02). In conclusion, although the overall incidence of IS was small for patients with AF on edoxaban or VKA after successful TAVI, patients with a history of systemic embolic events or pre-TAVI use of VKAs may be at greater risk of IS after TAVI., Competing Interests: Declaration of competing interest Dr. Hengstenberg is a clinical proctor for Boston Scientific and Edwards Lifesciences and reports payment for speaker bureaus, support for attending meetings, and advisory board participation from Daiichi Sankyo in addition to institutional funding from Abbott Vascular, Amgen, Biosensors, Biotronik, Boehringer Ingelheim Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Ferrer, Medtronic, Novartis, Philips, Siemens, and Terumo. Dr. Unverdorben and Dr. Jin are employees of Daiichi Sankyo. Dr. Möllmann received personal fees from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, and Pfizer and support for attending meetings from Abbott, AstraZeneca, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, and Pfizer. Dr. Van Mieghem reports grants or contracts from Abbott, Abiomed, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Medtronic, PulseCath BV, and Siemens. Dr. Thiele is the president of the German Society of Cardiology. Dr. Nordbeck reports speaker honoraria from Bayer, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, and Pfizer. Dr. Rassaf reports personal and other fees from AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, and Novartis. Dr. Moreno reports personal fees from Abbott Vascular, Amgen, Biosensors, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Ferrer, Medtronic, Philips, and Terumo. Dr. Mehran reports research grants to institution, support for attending meetings from Bayer and Daiichi Sankyo, and consulting fees from Daiichi Sankyo. Dr. Veltkamp reports grants or contracts from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, and Medtronic and consulting or advisory board participation for AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Javelin Ventures, and Portola Pharmaceuticals. Dr. Dangas reports research grants to institution, support for attending meetings from Bayer and Daiichi Sankyo, and consulting fees from Daiichi Sankyo. Dr. Lang has no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Recurrent small-cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted., Patients and Methods: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety, tolerability, and a recommended phase II dose (RP2D). The phase II primary objective was overall response rate (ORR), with secondary objectives of determining duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Correlative analyses included immunohistochemistry of pretreatment and on-treatment tumor biopsies and pharmacokinetics analysis., Results: Twenty-two patients were enrolled (phase I, n = 12; phase II, n = 10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLT) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; three patients discontinued treatment for toxicity. Three of the first 10 patients in phase II experienced DLTs triggering a stopping rule. The ORR was 4/19 or 21% [95% confidence interval (CI), 6%-46%]. The median DoR, PFS, and OS were 4.6 months, 2.2 months (95% CI, 1.3-7.6 months), and 6.6 months (95% CI, 4.3 to not reached), respectively. SLFN11/EZH2 expression and SCLC subtyping markers did not correlate with response, but MHC-I expression did increase with treatment. Two responders demonstrated subtype switching on treatment., Conclusions: Combination valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat, combined with agents without overlapping toxicity, warrants further investigation in SCLC., (©2024 American Association for Cancer Research.)

This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 to < 6 months (N = 12), 0.5 to < 2 years (N = 13), 2 to < 6 years (N = 13), 6 to < 12 years (N = 13), and 12 to < 18 years (N = 15)) receiving tablet or oral suspension of edoxaban at doses expected to be equivalent to 30 or 60 mg once daily (q.d.) in adult subjects with VTE. Sixty-six pediatric subjects were enrolled and completed the study. Edoxaban plasma concentration peaked between 1 and 3 hours and declined rapidly until 4-8 hours. The range of mean total apparent clearance across 5 age cohorts at low and high doses was 0.47 to 1.11 L/h/kg. The ranges of mean volume of central compartment and apparent peripheral volume were 2.31 to 3.59 L/kg and 1.92 to 4.14 L/kg, respectively. Across all age groups, the estimated median exposures were within the 0.5- to 1.5-fold of the median area under the plasma drug concentration-time curve (AUC) in adult subjects receiving corresponding doses (30 mg q.d. for low dose and 60 mg q.d. for high dose). In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time, and anti-Factor Xa activity) showed a linear PK-PD relationship and were in line with previous adult data. The results support further evaluation of the pediatric doses in larger pivotal trials., (© 2024 Daiichi Sankyo Inc. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: For patients with metastatic non-small cell lung cancer, timely molecular testing is essential to determine the appropriate course of therapy. Initial treatment with platinum chemotherapy and/or an immune checkpoint inhibitor (ICI) is the standard of care for patients without actionable genomic alterations., Objective: We aimed to assess treatment patterns and clinical outcomes among patients with metastatic non-small cell lung cancer, no actionable genomic alterations, and with prior ICI and platinum-based chemotherapy in a community oncology setting., Methods: This retrospective observational study examined electronic health records from adult patients with an initial metastatic non-small cell lung cancer diagnosis without actionable genomic alterations from 2017 to 2019. Patients had received a subsequent line of therapy (LOT) [index] after discontinuing platinum-based chemotherapy plus an ICI in the previous one or two LOTs. Patient demographics and clinical characteristics were analyzed descriptively. Clinical outcomes were evaluated using Kaplan-Meier analyses., Results: Among the study population (n = 961), the most common index LOT regimens were non-platinum-based chemotherapies (57.3%), platinum-based chemotherapies (12.9%), ICI-based chemotherapies (12.7%), platinum + ICI-based chemotherapies (9.4%), and other (7.7%). The most common post-index LOT regimens were non-platinum based (61.2%), ICI based (15.3%), platinum based (10.7%), platinum + ICI based (3.2%), and other (2.5%). Median time to treatment discontinuation, time to next treatment, and overall survival were numerically longest with index LOT ICI-based regimens (6.5, 9.9, and 18.9 months, respectively) and shortest with platinum-based regimens (2.8, 5.3, and 8.0 months, respectively) and non-platinum-based regimens (2.6, 5.0, and 7.8 months, respectively)., Conclusions: Among patients with metastatic non-small cell lung cancer without actionable genomic alterations previously treated with platinum + ICIs, non-platinum chemotherapy agents were most commonly prescribed in the index LOT. Clinical outcomes including time to treatment discontinuation, time to next treatment, and overall survival were short, highlighting the unmet need for more effective later-line treatments., (© 2024. The Author(s).)

The global phase 3 DESTINY-Breast03 study (ClinicalTrials.gov; NCT03529110) showed statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) with trastuzumab deruxtecan (T-DXd) over trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. Here, we report a subgroup analysis of Asian patients enrolled in DESTINY-Breast03. In total, 309 patients (149 in the T-DXd arm and 160 in the T-DM1 arm) from Asian countries and regions were randomized. At data cutoff (July 25, 2022), the median duration of follow-up in the Asian subpopulation was 29.0 months with T-DXd and 26.0 months with T-DM1. The PFS (determined by blinded independent central review) hazard ratio was 0.30 (95% confidence interval 0.22-0.41) favoring T-DXd over T-DM1 (median PFS 25.1 vs. 5.4 months). Median OS was not reached in the T-DXd arm and was 37.7 months in the T-DM1 arm. The median treatment duration was 15.4 months with T-DXd and 5.5 months with T-DM1. The incidence of grade ≥3 drug-related treatment-emergent adverse events was similar between both treatment arms (49.0% vs. 46.5%) and was consistent with the overall DESTINY-Breast03 population. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.9% of patients treated with T-DXd and 2.5% treated with T-DM1, with a higher incidence in Japanese patients; none of these were grade ≥4 events. These efficacy and safety data reinforce the favorable benefit-risk profile of T-DXd in HER2-positive mBC, including in the Asian subgroup., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Current treatment guidelines for patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (mNSCLC) recommend EGFR tyrosine kinase inhibitors (TKIs) as the standard of care for first-line treatment, with third-generation osimertinib the preferred choice. However, most patients develop resistance to targeted therapy, and subsequent systemic chemotherapy is recommended. The aim of this study was to characterize the subsequent line of therapy (LOT) following osimertinib in patients with EGFR-mNSCLC., Methods: Medical and pharmacy claims of adults who initiated a subsequent LOT (index) after initial osimertinib discontinuation between November 2015 and September 2019 were analyzed retrospectively., Results: A total of 135 patients met the inclusion criteria. After metastatic diagnosis, 22.2% and 49.6% of patients were treated with osimertinib in the first and second line, respectively. After osimertinib discontinuation, most patients were treated with a platinum-based chemotherapy regimen (57%), of which 40.3% included immuno-oncology therapy. Reuse or continuation of EGFR TKIs was also common (24%). Overall, the median time to treatment discontinuation for the index LOT was 2.4 months. Proportions of patients with ≥ 1 inpatient or emergency department visit were 31.9% and 35.6%, respectively., Conclusions: The duration of the LOT following osimertinib was short and associated with tolerability issues underscoring a high unmet need for new therapies to address EGFR TKI resistance., (© 2024. The Author(s).)

Introduction: Although oncology has seen large scientific and clinical advances over the last decade, it also has one of the lowest success rates for novel agents across therapeutic areas. Adaptive clinical trial design has been a popular option for increasing clinical trial efficiency and the chances of trial success. Seamless clinical trial design are studies in which two or more clinical trial phases are combined into a single study with a pre-specified transition between stages. This integration of phases may enhance efficiency., Methods: To understand the precedent for the use of seamless designs, this working group was formed to conduct a comprehensive literature search on seamless clinical trials conducted with confirmatory intent in oncology. Trial design features were extracted into a database and analyzed with descriptive statistics., Results: A literature search identified 68 clinical trials meeting inclusion and exclusion criteria. The most common design feature was a gate on treatment efficacy, where the trial would only proceed to the second stage if sufficient efficacy was observed in the first. The next most common feature was a selection of a dose or treatment regimen. Inferentially and operationally seamless designs were approximately equally represented., Discussion: Key statistical considerations for seamless phase II/III designs include optimizing design choices by evaluating and comparing operating characteristics across design alternatives as well as showing control of overall Type I error rates. Executing the transition between phases should be evaluated for issues related to accrual, drug production, and procedures to maintain trial integrity., Conclusions: While there are unique statistical, regulatory, and operational considerations for seamless designs they are also uniquely suited to many development settings. These include, for example, addressing dose selection under FDA's Project Optimus and addressing the growing use of biomarkers and personalized medicine approaches in cancer treatment., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24-0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56-0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 ., (© 2024. The Author(s).)

Over the past decade, there has been an increase in accelerated drug development with successful regulatory approval that has provided rapid access of novel medicines to patients world-wide. This has created the opportunity for the pharmaceutical industry to continuously improve the process of quickly bringing new medicines to patients with unmet medical needs. This can be accomplished through sharing the learnings and advancements in drug development, enhancing regulatory interactions, and collaborating with academics on developing the underlying science to reduce drug development timelines. In this paper, the IQ Consortium - Accelerated Drug Development working group members intend to share recommendations for optimizing strategies that build efficiencies in accelerated pathways for regulatory approval. Information was obtained by surveying member pharmaceutical companies with respect to recent expedited submissions within the past 5 years to gain insights as to which development strategies were successful. The learnings from this analysis are provided, which includes shared learnings in formulation development, stability, analytical methods, manufacturing, and importation testing as well as regulatory considerations. Each of these sections provide a summary illustrating the key data collected as well as a discussion that is aimed to guide pharmaceutical companies on strategies to consider streamlining development activities and expedite the drug to market., 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. The approaches and conclusions in this manuscript have not been formally disseminated by the U.S. Food and Drug Administration and should not be construed to represent any agency determination or policy. This manuscript was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community., (Copyright © 2024 American Pharmacists Association. All rights reserved.)

Introduction: For patients with epidermal growth factor receptor-mutated (EGFRm) locally advanced/metastatic non-small cell lung cancer (mNSCLC) whose disease has progressed on or after osimertinib and platinum-based chemotherapy (PBC), no uniformly accepted standard of care exists. Moreover, limited efficacy of standard treatments indicates an unmet medical need, which is being addressed by ongoing clinical investigations, including the HERTHENA-Lung01 (NCT04619004) study of patritumab deruxtecan (HER3‑DXd). However, because limited information is available on real-world clinical outcomes in such patients, early-phase trials of investigational therapies lack sufficient context for comparison. This study describes the real-world clinical characteristics, treatments, and outcomes for patients with EGFRm mNSCLC who initiated a new line of therapy following previous osimertinib and PBC, including a subset matched to the HERTHENA-Lung01 population., Methods: This retrospective analysis used a US database derived from deidentified electronic health records. The reference cohort included patients with EGFRm mNSCLC who had initiated a new line of therapy between November 13, 2015 and June 30, 2021, following prior osimertinib and PBC. A subset of patients resembling the HERTHENA-Lung01 population was then extracted from the reference cohort; this matched subset was optimized using propensity score (PS) weighting. Endpoints were real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). Confirmed real-world objective response rate (rwORR; partial/complete response confirmed ≥ 28 days later) was calculated for the response-evaluable subgroups of patients (with ≥ 2 response assessments spaced ≥ 28 days apart)., Results: In the reference cohort (N = 273), multiple treatment regimens were used, and none was predominant. Median rwPFS and rwOS were 3.3 and 8.6 months, respectively; confirmed rwORR (response evaluable, n = 123) was 13.0%. In the matched subset (n = 126), after PS weighting, median rwPFS and rwOS were 4.2 and 9.1 months, respectively; confirmed rwORR (response evaluable, n = 57) was 14.1%., Conclusion: The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit., (© 2024. The Author(s).)

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer., (© 2024. The Author(s).)

Introduction: Identifying contributors to lung transplant survival is vital in mitigating mortality. To enhance individualized mortality estimation and determine variable interaction, we employed a survival tree algorithm utilizing recipient and donor data., Methods: United Network Organ Sharing data (2000-2021) were queried for single and double lung transplants in adult patients. Graft survival time <7 d was excluded. Sixty preoperative and immediate postoperative factors were evaluated with stepwise logistic regression on mortality; final model variables were included in survival tree modeling. Data were split into training and testing sets and additionally validated with 10-fold cross validation. Survival tree pruning and model selection was based on Akaike information criteria and log-likelihood values. Estimated survival probabilities and log-rank pairwise comparisons between subgroups were calculated., Results: A total of 27,296 lung transplant patients (8175 single; 19,121 double lung) were included. Stepwise logistic regression yielded 47 significant variables associated with mortality. Survival tree modeling returned six significant factors: recipient age, length of stay from transplant to discharge, recipient ventilator duration post-transplant, double lung transplant, recipient reintubation post-transplant, and donor cytomegalovirus status. Eight subgroups consisting of combinations of these factors were identified with distinct Kaplan-Meier survival curves., Conclusions: Survival trees provide the ability to understand the effects and interactions of covariates on survival after lung transplantation. Individualized survival probability with this technique found that preoperative and postoperative factors influence survival after lung transplantation. Thus, preoperative patient counseling should acknowledge a degree of uncertainty given the influence of postoperative factors., (Published by Elsevier Inc.)

Purpose: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker., Patients and Methods: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported., Results: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts., Conclusion: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2 + ) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2 + gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies., (© 2024. The Author(s).)

Background: Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes., Methods: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes., Results: Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction., Interpretation: Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Despite the prevalence of depression in lactating mothers, there is a lack of knowledge about the excretion of antidepressants into breast milk and its potential adverse effects on infants. This creates concern, making depressed lactating mothers more likely to avoid pharmacological treatment. Clinical lactation studies are the most accurate and direct method to predict and demonstrate the excretion of antidepressants into human breast milk, and results from clinical studies can be included in drug labels to help physicians and patients make decisions on antidepressant use during lactation. However, there are limited clinical trials and studies on the pharmacokinetics of antidepressants in lactating women because of a lack of enrollment and ethical and confounding factors, creating a lack of knowledge in this area. To bridge this gap in knowledge, alternative methods should be sought to help estimate the antidepressant concentration in breast milk, which is used to assess the safety and transfer of antidepressants into breast milk. We provide a comprehensive review of the usage of these cost-effective, time-efficient, and ethically feasible methods that serve to provide a valuable estimation of the safety and transfer of antidepressants into breast milk before conducting clinical studies.

4-[(5-[2-Methyl-5-(methylsulfonyl)pentan-2-yl]sulfonylpyrimidin-4-yl)amino]benzonitrile 2 was identified as a novel potent aldosterone synthase inhibitor. Compound 2 was found to inhibit human CYP11B2 in the nanomolar range, and showed an aldosterone-lowering effect in a furosemide-treated cynomolgus monkey model. Although human CYP11B2 has the high homology sequence with human CYP11B1, compound 2 showed more than 80 times higher selectivity over human CYP11B1 in vitro., 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 Ltd. All rights reserved.)

Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163 + PD-L1 + macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68 + , CD163 + , and CK + cells with PD-L1 + phenotypes had higher B7-H3 expression compared to PD-L1 - cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies.

Background: Real-world data for advanced/metastatic non-small-cell lung cancer (NSCLC) with mutations in human epidermal growth factor 2 (HER2) are scarce. We aimed to assess treatment patterns and outcomes among patients with HER2-mutant advanced/metastatic NSCLC., Patients and Methods: This retrospective nationwide electronic health record study evaluated patient characteristics, treatment patterns, treatment duration, and overall survival for adults with HER2-mutant advanced/metastatic NSCLC without epidermal growth factor receptor mutation., Results: Of 55 included patients, median (quartile 1 [Q1]-quartile 3 [Q3]) age was 63.0 (58.0-72.0) years, 42 (76%) were women, and 39 (71%) were current/former smokers. In first-line therapy, 14 regimens were used for median (Q1-Q3) duration of 3.1 (2.4-6.2) months, with most patients (n = 39, 71%) receiving platinum-based chemotherapy alone or in combination with other agents. Median (95% CI) overall survival from first-line treatment initiation was 19.0 (12.2-not estimable) months, with no significant association with age, sex, or smoking status. Thirty-five (64%) patients received second-line therapy for median (Q1-Q3) duration of 3.3 (2.0-5.2) months. Fourteen second-line regimens were used; most commonly immunotherapy alone or in combination with other agents (n = 16, 46%). Sixteen (46%) patients received third-line therapy for median (Q1-Q3) duration of 1.9 (1.3-2.7) months. Nine third-line regimens were used, with 7 (44%) patients receiving HER2-directed agents., Conclusion: First- and second-line treatments for HER2-mutant NSCLC varied widely and treatment duration was short. The approval of trastuzumab deruxtecan for NSCLC supports wider HER2 testing to identify eligible patients for HER2-directed therapy., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objective: Iron deficiency is the most common cause of anemia. We compared the effect of ferric carboxymaltose (FCM), low-dose intravenous (IV) iron (LDI), and iron sucrose on total cost of care in patients with iron-deficiency anemia (IDA) from a US health plan perspective., Methods: We conducted a retrospective claims analysis using the IQVIA PharMetrics Plus database. Patients with index (first) claims of FCM and LDI and a medical claim associated with IDA between 1 January 2017 and 31 December 2019 were included. Monthly total healthcare and inpatient and outpatient costs after receiving index IV iron for patients in the treatment cohorts were compared using a generalized linear model with gamma distribution and log-link., Results: The overall study cohort included 37,655 FCM, 44,237 LDI, and 27,461 iron sucrose patients. Mean per-patient-per-month numbers of IV iron infusions for FCM, LDI, and iron sucrose were 0.20, 0.34, and 0.37, respectively. Compared with baseline, the FCM group had greater reductions in the number of hospital admissions and smaller increases in the number of outpatient visits in the 12 months post-IV iron therapy than LDI and iron sucrose, translating to significantly lower total healthcare cost (post-index adjusted cost ratio for total cost: 0.96 and 0.92, respectively; both P < 0.0001)., Conclusions: Higher drug acquisition cost of FCM relative to LDI and iron sucrose was offset by significantly lower inpatient and outpatient costs in the 12 months post-IV iron therapy. These results support the economic value of FCM for patients with IDA receiving IV iron therapy., (© 2024. The Author(s).)

In DESTINY-Breast04 (DB-04), safety and efficacy of HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in previously treated HER2-low unresectable/metastatic breast cancer were established. This manuscript describes the analytical validation of PATHWAY Anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (PATHWAY HER2 (4B5)) to assess HER2-low status and its clinical performance in DB-04. Preanalytical processing and tissue staining parameters were evaluated to determine their impact on HER2 scoring. The recommended antibody staining procedure provided the optimal tumor staining, and deviations in cell conditioning and/or antibody incubation times resulted in unacceptable negative control staining and/or HER2-low status changes. Comparisons between antibody lots, kit lots, instruments, and day-to-day runs showed overall percent agreements (OPAs) exceeding 97.9%. Inter-laboratory reproducibility showed OPAs of ≥97.4% for all study endpoints. PATHWAY HER2 (4B5) was utilized in DB-04 for patient selection using 1340 tumor samples (59.0% metastatic, 40.7% primary, (0.3% missing data); 74.3% biopsy, 25.7% resection/excisions). Overall, 77.6% (823/1060) of samples were HER2-low by both central and local testing, with the level of concordance differing by sample region of origin and collection date. In DB-04, the efficacy of T-DXd over chemotherapy of physician's choice was consistent, regardless of the characteristics of the sample used (primary or metastatic, archival, or newly collected, biopsy or excision/resection). These results demonstrate that PATHWAY HER2 (4B5) is precise and reproducible for scoring HER2-low status and can be used with multiple breast cancer sample types for reliably identifying patients whose tumors have HER2-low expression and are likely to derive clinical benefit from T-DXd., (© 2023. The Author(s).)

Many targeted cancer therapies rely on biomarkers assessed by scoring of immunohistochemically (IHC)-stained tissue, which is subjective, semiquantitative, and does not account for expression heterogeneity. We describe an image analysis-based method for quantitative continuous scoring (QCS) of digital whole-slide images acquired from baseline human epidermal growth factor receptor 2 (HER2) IHC-stained breast cancer tissue. Candidate signatures for patient stratification using QCS of HER2 expression on subcellular compartments were identified, addressing the spatial distribution of tumor cells and tumor-infiltrating lymphocytes. Using data from trastuzumab deruxtecan-treated patients with HER2-positive and HER2-negative breast cancer from a phase 1 study (NCT02564900; DS8201-A-J101; N = 151), QCS-based patient stratification showed longer progression-free survival (14.8 vs 8.6 months) with higher prevalence of patient selection (76.4 vs 56.9%) and a better cross-validated log-rank p value (0.026 vs 0.26) than manual scoring based on the American Society of Clinical Oncology / College of American Pathologists guidelines. QCS-based features enriched the HER2-negative subgroup by correctly predicting 20 of 26 responders., (© 2024. The Author(s).)

Background: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd., Patients and Methods: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC., Results: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified., Conclusions: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy., Competing Interests: Disclosure HAY has received consulting fees from AstraZeneca, Daiichi Sankyo, Cullinan, Blueprint Medicines, Janssen, Black Diamond, and Takeda. CB has received consulting fees from AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Takeda, Turning Point Therapeutics, Guardant Health, Regeneron, and Silverback Therapeutics; institutional research funding grants/contracts from Loxo, AstraZeneca, Pfizer, Spectrum Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo, Rain Therapeutics, AbbVie, Turning Point Therapeutics, Lilly, and Janssen. D-WK has received institutional research funding grants/contracts from Alpha Biopharma, AstraZeneca, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, Turning Point Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim, Amgen, Daiichi Sankyo, Chong Kun Dang Pharmaceutical, BridgeBio Pharma, GSK, and Merck. MLJ has received consulting fees from Genentech/Roche, AstraZeneca, Calithera Biosciences, Merck, Sanofi, Mirati Therapeutics, Ribon Therapeutics, AbbVie, GSK, Gritstone Bio, Janssen Oncology, Lilly, Amgen, Daiichi Sankyo, Eisai, Axelia Oncology, Black Diamond Therapeutics, CytomX Therapeutics, EcoR1 Capital, Editas Medicine, Genmab, IDEAYA Biosciences, ITeos Therapeutics, Oncorus, Regeneron, Turning Point Therapeutics, Astellas Pharma, Checkpoint Therapeutics, Genocea Biosciences, Molecular Axiom, Novartis, Revolution Medicines, Takeda, and VBL Therapeutics; payment/honoraria from AbbVie, AstraZeneca, Genentech, Incyte, Merck, Pfizer, and Sanofi; research funding/grants from EMD Serono, Kadmon, Janssen, Mirati Therapeutics, Genmab, Pfizer, AstraZeneca, Stemcentrx, Novartis, Array BioPharma, Regeneron, Merck, Hengrui Pharmaceutical, Lycera, BeiGene, Tarveda Therapeutics, Loxo, AbbVie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, Sanofi, CytomX Therapeutics, Dynavax Technologies, Corvus Pharmaceuticals, Incyte, Genocea Biosciences, Gritstone Bio, Amen, Genentech/Roche, Adaptimmune, Syndax, Neovia Oncology, Takeda, Shattuck Labs, GSK, Apexigen, Atreca, OncoMed, Lilly, Immunocore, University of Michigan, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, BerGenBio, Calithera Biosciences, Tmunity Therapeutics, Seven and Eight Biopharmaceuticals, Rubius Therapeutics, Curis, Silicon Therapeutics, Dracen, PMV Pharma, Artios, BioAtla, Elicio Therapeutics, Erasca, Harpoon, Helsinn Healthcare, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Memorial Sloan Kettering Cancer Center, NeoImmune Tech, Numab, RasCal Therapeutics, Relay Therapeutics, Revolution Medicines, Tempest Therapeutics, Tizona Therapeutics, Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics, Exelixis, Fate Therapeutics, Merus, Black Diamond Therapeutics, Kartos Therapeutics, Carisma Therapeutics, Rain Therapeutics, Nuvalent, Palleon Pharmaceuticals, IMPAC Medical Systems, and EQRx. HH has received grants/contracts from AstraZeneca K.K., Astellas Pharma, MSD K.K., Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma K.K., Pfizer Japan, Bristol Myers Squibb, Eli Lilly Japan K.K., Chugai Pharmaceutical, Daiichi Sankyo, Merck Serono, Merck Biopharma, Takeda, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, inVentiv Health Japan, ICON Japan K.K., Gritstone Bio, Parexel International, Kissei Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare, Quintiles/IQVIA Services Japan K.K., EP-CRSU CO, Linical, Eisai, CMIC Shift Zero K.K., Kyowa Hakko Kirin, Bayer Yakuhin, EPS International, and Otsuka Pharmaceutical; payment/honoraria from Amgen K.K, AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan K.K., Guardant Health, Kyorin Pharmaceutical, Merck Biopharma, MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical, Shanghai Haihe Biopharma, Taiho Pharmaceutical, Pfizer, and Takeda outside the submitted work. MN has received payment/honoraria from Pfizer, Bristol Myers Squibb Japan, Ono Pharmaceutical, Chugai Pharma, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Lilly, Nippon Kayaku, Takeda, Merck, Janssen, and Amgen; institutional research funding grants/contracts from Bristol Myers Squibb, Taiho Pharmaceutical, Pfizer, AstraZeneca, Lilly, MSD, Merck, Takeda, Amgen, and Janssen. JC-HY has received grants, personal fees, and advising/consulting institutional fees from AstraZeneca; personal fees and advising/consulting institutional fees from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, MSD, Novartis, Roche/Genentech, Takeda, and Yuhan Pharmaceuticals; advising/consulting institutional fees from Eli Lilly and Johnson & Johnson; advising/consulting fees from Ono Pharmaceutical, Pfizer, Puma Technology, Gilead, and GSK. W-CS has received advising/consulting fees from Bayer Schering Pharma, MSD Oncology, Lilly, and Merck. KAG has received advising/consulting fees from Takeda, AstraZeneca, Rakuten Medical, Regeneron; research funding grants/contracts from Pharmacyclics, AstraZeneca, AbbVie, BerGenBio, and Pfizer. MK has received payment/honoraria from AstraZeneca and Celgene. EFS has received personal fees from AstraZeneca, Daiichi Sankyo, Merck KGaA, and Boehringer Ingelheim; advising/consulting and research funding grants/contracts and institutional fees from Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol Myers Squibb, Merck KGaA, MSD Oncology, Takeda, Bayer, Novartis, Daiichi Sankyo, and Seattle Genetics. CES has received personal fees and advising/consulting from AbbVie, BerGenBio, ARMO BioSciences, Lilly, Mirati Therapeutics, Sanofi/Regeneron, Caris Life Sciences, and Merck; research funding grants/contracts from Vaccinex, Seattle Genetics, Daiichi Sankyo, and Infinity Pharmaceuticals. EF has received institutional research funding grants/contracts from Grant for Oncology Innovation, Merck Healthcare KGaA, and Fundación Merck Salud; consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GSK, Ipsen, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Sanofi, Takeda, and Turning Point; payment/honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, MSD, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; other financial aid from Grifols as an independent member of the board. HM has received grants, personal fees, and advising/consulting institutional fees from Chugai Pharma, GAIA BioMedicine, Taiho Pharmaceutical, AstraZeneca, Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Takeda, Novartis, Daiicho Sankyo, Eisai, Nippon Kayaku, Pfizer, Boehringer Ingelheim, and AbbVie; institutional research funding grants/contracts from AstraZeneca, AbbVie, Takeda, Daiichi Sankyo, IQVIA, and Chugai Pharma. XS, SS, P-DF, MF, YT, PP, DWS, and DS are employees of and have stock ownership in Daiichi Sankyo. PAJ has received royalties for licenses from Labcorp; consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceutical, Eli Lilly, SFJ Pharmaceuticals, VORONOI, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Takeda, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, and AbbVie; had stock ownership in Gatekeeper Pharmaceuticals. S-WK has declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)