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BACKGROUND: The prognostic impact of dysphagia in multiple system atrophy (MSA) remains controversial. This study aimed to investigate the relationship between dysphagia severity and survival in MSA and to elucidate whether this impact differs between MSA-cerebellar ataxia (MSA-C) and MSA-parkinsonism (MSA-P). METHODS: This retrospective study included 297 patients with MSA: 251 met criteria for clinically established MSA and 46 for clinically probable MSA. Among them, 171 had MSA-C and 126 had MSA-P. We evaluated symptomatic dysphagia within 3 years of onset and quantified dysphagia severity using the Hyodo score (0 to 12) through fibreoptic endoscopic evaluation of swallowing (FEES) and clinical features, including autonomic dysfunction and vocal cord paralysis. Patients were followed up until death or tracheostomy, and survival factors were analysed using the log-rank test and multivariate Cox proportional hazards model. RESULTS: Ninety patients developed symptomatic dysphagia within 3 years of onset, and 75 were evaluated for dysphagia severity using FEES. Survival from onset was shorter in patients with dysphagia within 3 years compared to those without (median: 4.2 years vs. 7.3 years; p < 0.001). Symptomatic dysphagia within 3 years of onset was an independent predictor of shorter survival in the multivariate Cox analysis. While the Hyodo score was higher in MSA-P than in MSA-C patients (p = 0.048), the Hyodo score was associated with survival in both MSA-C and MSA-P patients (log-rank p < 0.001 and p = 0.046, respectively). CONCLUSION: Symptomatic dysphagia within 3 years of onset predicts shorter survival in MSA-C and MSA-P patients.
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PURPOSE: To evaluate the safety/tolerability and pharmacokinetics of simlukafusp alfa (FAP-IL2v), an immunocytokine containing an anti-fibroblast activation protein-α (FAP) antibody and an interleukin (IL)-2 variant, administered alone or with the programmed death-ligand 1 inhibitor atezolizumab, in Japanese patients with advanced solid tumors. PATIENTS AND METHODS: In this phase 1, open-label, dose-escalation study, patients received intravenous (IV) FAP-IL2v at 10 or 15/20 mg alone or 10 mg when combined with IV atezolizumab. Primary objectives were identification of dose-limiting toxicities (DLTs), recommended dose (RD), and maximum tolerated dose (MTD), and evaluation of the safety/tolerability and pharmacokinetics of FAP-IL2v alone and combined with atezolizumab. RESULTS: All 11 patients experienced adverse events (AEs) during FAP-IL2v treatment. Although most AEs were of mild severity, four treatment-related AEs led to study treatment discontinuation in two patients; one with infusion-related reaction, hypotension, and capillary leak syndrome, and the other with aspartate aminotransferase increased. No AE-related deaths occurred. One DLT (Grade 3 hypotension) occurred in a patient receiving FAP-IL2v 15/20 mg alone. The RD and MTD could not be determined. Pharmacokinetics of FAP-IL2v remained similar with or without atezolizumab. The study was terminated early as FAP-IL2v development was discontinued due to portfolio prioritization (not for efficacy/safety reasons). CONCLUSIONS: This study describes the safety/tolerability of FAP-IL2v 10 mg alone and in combination with atezolizumab in Japanese patients with advanced solid tumors; one DLT (hypotension) occurred with FAP-IL2v 15/20 mg. However, dose escalation of FAP-IL2v was not conducted due to early study termination.
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OBJECTIVE: Dysphagia in multiple system atrophy (MSA) is life-threatening and is caused by parkinsonism with cerebellar ataxia as a contributing factor. The present study investigated the relationship between dysphagia severity in MSA and the specific binding ratio (SBR) on dopamine transporter (DaT) SPECT using the Hyodo score, a qualitative scale for use with fiberoptic endoscopic evaluation of swallowing (FEES). METHODS: Hyodo score's ability to predict aspiration during a FEES examination of 88 patients with MSA was first tested. Then the clinical characteristics, Hyodo score, and SBR of patients with either predominant parkinsonism (MSA-P; n = 11) or cerebellar ataxia (MSA-C; n = 25) who underwent FEES and DaT SPECT simultaneously were compared. RESULTS: Logistic regression demonstrated that the Hyodo score was a significant predictive factor of aspiration (p = 0.003). The MSA-P group had a significantly higher Hyodo score (p = 0.026) and lower SBR (p = 0.011) than the MSA-C group while neither group demonstrated any significant difference in disease duration at the FEES examination. Linear regression demonstrated a significant, inverse correlation between the Hyodo score and SBR in the MSA-P (p = 0.044; r = -0.616) and MSA-C (p = 0.044; r = -0.406) groups. When the effect of SBR was removed by analysis of covariance, no significant difference in the Hyodo score remained between the groups. CONCLUSIONS: Our results suggested an association between presynaptic changes in nigrostriatal dopaminergic neurons and dysphagia severity in MSA which largely contributes to the difference in dysphagia severity between MSA-P and MSA-C.
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Transtornos de Deglutição , Proteínas da Membrana Plasmática de Transporte de Dopamina , Atrofia de Múltiplos Sistemas , Índice de Gravidade de Doença , Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/metabolismo , Masculino , Feminino , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Idoso , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Pessoa de Meia-IdadeRESUMO
BACKGROUND: ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments. RESULTS: Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg-0.7 µg/kg, with a half-life of approximately 13-29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1-2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported. CONCLUSIONS: ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases. CLINICAL TRIAL REGISTRATION: NCT04272203.
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Anticorpos Biespecíficos , Complexo CD3 , Carcinoma Pulmonar de Células não Pequenas , Relação Dose-Resposta a Droga , Leucemia Mieloide Aguda , Neoplasias Pulmonares , Receptores de Antígenos de Linfócitos T , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Pessoa de Meia-Idade , Masculino , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/farmacologia , Idoso , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Adulto , Antígeno HLA-A2RESUMO
Antibody-drug conjugates (ADCs) have emerged as a novel class of anticancer treatment. ADCs are composed of three parts: a monoclonal antibody, a linker and a payload. A monoclonal antibody binds to the specific antigen present at the cancer cells, allowing selective delivery of the cytotoxic agents to the tumor site. Several ADCs are approved by the US Food and Drug Administration for the treatment of hematologic cancers and solid tumors with clinically meaningful survival benefit. However, the development of ADCs faces a lot of challenges and there is a need to get better understanding of ADCs in order to improve patient outcomes. Here, we briefly discuss the structure and mechanism of ADCs, as well as the clinical data of current approved ADCs in solid tumors.
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Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/uso terapêuticoRESUMO
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.
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Imunoconjugados , Receptor ErbB-2 , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Pessoa de Meia-Idade , Idoso , Imunoconjugados/uso terapêutico , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Adulto , Receptor ErbB-2/metabolismo , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Receptores de Estrogênio/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Receptores de Progesterona/metabolismo , Antígenos de Neoplasias , Moléculas de Adesão Celular/metabolismo , TrastuzumabRESUMO
BACKGROUND: Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors. METHODS: Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients. RESULTS: Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy. CONCLUSION: Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients.
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Arginase , Neoplasias , Humanos , Feminino , Masculino , Neoplasias/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Arginase/antagonistas & inibidores , Adulto , Japão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , População do Leste AsiáticoRESUMO
Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/terapia , Esclerose Lateral Amiotrófica/diagnóstico , Progressão da Doença , Medicina Baseada em Evidências , JapãoRESUMO
Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor2-negative breast cancer (HR+/HER2- BC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). Improved understanding of the adverse events (AEs) that are associated with Dato-DXd and their optimal management is essential to ensure safe and successful administration. Interstitial lung disease/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, and ocular surface events have been identified as AEs of special interest (AESIs) for which appropriate prevention, monitoring, and management is essential. This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials.
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Antineoplásicos , Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas , Imunoconjugados , Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Imunoconjugados/efeitos adversos , Trastuzumab , Receptor ErbB-2 , Camptotecina , Ensaios Clínicos Fase I como AssuntoRESUMO
BACKGROUND: Parkinson's disease (PD), and other parkinsonian syndromes are known to cause striatonigral dopaminergic system dysfunction and autonomic disturbances, including the vasomotor and sudomotor nervous systems. The detection of 123I-FP-CIT SPECT (DaT scan) imaging and autonomic dysfunction helps differentiate PD from multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). The sympathetic skin response (SSR) is a simple, non-invasive electrophysiological test that assesses the sympathetic sudomotor nervous system. It is reported that the SSR is impaired in patients with PD, MSA, and PSP. OBJECTIVE: To study the relationship between SSR, 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy and DaT scan imaging parameters in patients with PD, MSA, and PSP. METHODS: The study included 62, 25, and 19 patients with PD, MSA, and PSP, respectively. The SSR, MIBG cardiac scintigraphy, and DaT scan imaging were examined. The amplitude and latency of the SSR were measured in all limbs and were compared with the results of MIBG cardiac scintigraphy and DAT scan imaging. RESULTS: The SSR amplitudes were lower than reported normal subjects' reference values in PD, MSA, and PSP. The SSR amplitude only correlated with MIBG cardiac scintigraphy and DaT scan imaging parameters in PD. Multiple regression analyses also showed a significant relationship between the amplitudes of SSR and DaT scan imaging in PD. CONCLUSION: Unlike MSA, and PSP, the sudomotor nervous system is parallelly involved with cardiac sympathetic and central dopaminergic dysfunction from the early stage of PD.
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3-Iodobenzilguanidina , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Masculino , Feminino , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/fisiopatologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Sistema Nervoso Simpático/diagnóstico por imagem , Compostos Radiofarmacêuticos , Resposta Galvânica da Pele/fisiologiaRESUMO
Objective: This study aimed to reveal the diagnostic utility of Gold Coast (GC) criteria in Japanese patients with amyotrophic lateral sclerosis (ALS) by comparing the sensitivity/specificity with revised El Escorial (R-EE) and Awaji criteria, because its utility has not been studied in Asian ALS. Methods: Consecutive 639 patients (529 with ALS and 110 with ALS mimics), who were suspected of ALS and referred to three Japanese ALS centers, were enrolled. Diagnostic accuracy and characteristics of false positive and negative in GC criteria were compared with those of the Awaji and R-EE criteria. Patients were categorized as definite, probable or possible ALS according to each criterion. Results: The sensitivity of GC criteria (96.8%, 95% confidence interval [CI]: 95.3-98.3%) was higher than that of Awaji (89.6%, 95% CI: 87.0-92.2%) and R-EEC (89.2, 95% CI: 86.6-91.8%) criteria (both, p < 0.001). The specificity was also higher with GC criteria (77.3%, 95% CI: 69.5-85.1%) than Awaji (65.5%, 95% CI: 56.6-74.4%) and R-EEC (66.4, 95% CI: 57.6-75.2%) criteria (both, p < 0.01). Using GC criteria, patients with cervical spondylosis and Parkinson's syndrome tended to be diagnosed with ALS (i.e. "false positive"). Additionally, ALS patients diagnosed only by GC criteria less frequently had upper motor neuron (UMN) signs, compared with the other two criteria. Conclusion: Gold Coast criteria improve diagnostic accuracy for ALS in an Asian population, especially in patients with subtle UMN signs.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Ásia , Eletromiografia , Sensibilidade e EspecificidadeRESUMO
PURPOSE: Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926). METHODS: Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity. RESULTS: Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: Cmax 217 µg/mL; Cmin 54.9 µg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 µg·day/mL; t1/2, 17.6 days. Best overall response was stable disease in two patients. CONCLUSION: Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials. TRIAL REGISTRATION NUMBER: jRCT2080224926.