RESUMEN
The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 = ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.
RESUMEN
BACKGROUND: Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear. METHODS: Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle. RESULTS: Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS. CONCLUSION: No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).
Asunto(s)
Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Docetaxel , Neoplasias Pulmonares/patología , Factor A de Crecimiento Endotelial Vascular , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , RamucirumabRESUMEN
BACKGROUND: Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. CONCLUSION: Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/efectos adversos , Antineoplásicos/efectos adversos , Compuestos de Anilina/efectos adversos , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , MutaciónRESUMEN
The continuing investigation of SAR of 3-aminothieno[2,3-b]pyridine-2-carboxamide derivatives has been described. In this study, C4-piperidine derivatives with polar functional groups were synthesized to develop orally available bone anabolic agents. The optimized compound 9o (DS96432529), which exhibited the best PK profile and high in vitro activity, showed the highest in vivo efficacy in this series. Moreover, significant synergistic effects were observed following co-administration of DS96432529 and alendronate or parathyroid hormone. The mechanism of action is most likely mediated through CDK8 inhibition.
Asunto(s)
Anabolizantes/farmacología , Huesos/efectos de los fármacos , Descubrimiento de Drogas , Administración Oral , Anabolizantes/administración & dosificación , Anabolizantes/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
LESSONS LEARNED: Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients.In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population.Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted. BACKGROUND: Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC. RESULTS: A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%-72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1-82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug. CONCLUSION: Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.
Asunto(s)
Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Acrilamidas/farmacología , Anciano , Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Progresión de la Enfermedad , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana EdadRESUMEN
The synthesis and structure-activity relationships of a novel series of 3-aminothieno[2,3-b]pyridine-2-carboxamides were explored. Our efforts were focused on modifying the C-4 substituent of the thienopyridine ring to develop orally available bone anabolic agents. 4-Alkoxy derivatives were found to be novel ALPase enhancers without inhibitory effect on P450 activity. Among these derivatives, compound 6k was orally administered to ovariectomized rats, and it was found to significantly improve areal bone mineral density at a dose of 30â¯mg/kg/day.
Asunto(s)
Fosfatasa Alcalina/uso terapéutico , Osteoporosis/tratamiento farmacológico , Piridinas/síntesis química , Fosfatasa Alcalina/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
Background A global multicenter study demonstrated superiority of carboplatin + nab-paclitaxel (PTX) therapy compared to carboplatin + PTX in terms of response rate (RR) and non-inferiority in terms of progression free survival (PFS) and overall survival (OS) in untreated patients with stage IIIB/IV non-small cell lung cancer; no clinical findings have so far been reported on maintenance therapies with nab-PTX. The aim of this study was to determine the efficacy and safety of maintenance therapy with nab-PTX following carboplatin + nab-PTX combination therapy. Methods Carboplatin (AUC 6) was administered on Day 1; and nab-PTX 100 mg/m2 on Days 1, 8, and 15, and dosing was repeated in 4 courses of 4 weeks each. In patients with clinical response was observed at the end of the 4th course, nab-PTX maintenance therapy was repeated. Results Out of 39 patients included in the efficacy analysis, 19 (48.7%) patients completed the induction therapy and 15 (38.5%) were transitioned to maintenance therapy. The median PFS in the maintenance phase was 6.5 (90%CI 1.4-11.4) months. The median OS in 15 patients was 12.6 (95%CI: 7.4-not reached). Grade ≥ 3 toxicities observed in more than 5% of patients were neutropenia (55.0%), anemia (15.0%), and febrile neutropenia (5.0%), with no increase during the maintenance phase. Conclusions Although statistically significance was not demonstrated presumably due to a limited transition rate from induction to maintenance phase, nab-PTX was suggested to be a useful treatment option following the induction therapy with nab-PTX in patients with advanced NSCLC.
Asunto(s)
Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/administración & dosificación , Anciano , Anciano de 80 o más Años , Albúminas/efectos adversos , Anemia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Paclitaxel/efectos adversosRESUMEN
Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B-cell lymphoma cells harboring gain-of-function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications.
Asunto(s)
Ensayos de Selección de Medicamentos Antitumorales/métodos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteínas del Grupo Polycomb/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Proteína Potenciadora del Homólogo Zeste 2/química , Humanos , Modelos Moleculares , Proteínas del Grupo Polycomb/química , Ratas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Relación Estructura-ActividadRESUMEN
A 66-year-old woman, who had been treated with systemic corticosteroids for four months for vasculitis of unknown etiology, was referred to our department due to a fever, dyspnea and patchy ground-glass opacities on chest computed tomography. As transbronchial biopsy specimens were suggestive of interstitial pneumonia, the prescribed dose of corticosteroids was increased. However, the patient developed pyrexia and presented diffuse ground-glass attenuation in the lungs bilaterally. Antituberculous drugs were administered because a previous blood interferon-gamma release assay was positive, however, the patient died of severe respiratory failure within several days, and cultures of her blood, urine and bone marrow posthumously revealed Mycobacterium tuberculosis. An autopsy revealed multiple foci of air-space pneumonia containing numerous acid-fast bacilli without granuloma formation, accompanied by diffuse alveolar damage. An immunosuppressive condition might inhibit air-space pneumonia to become granulomatous inflammation as an initial stage of pulmonary tuberculosis.
Asunto(s)
Inmunosupresores/efectos adversos , Síndrome de Dificultad Respiratoria/complicaciones , Tuberculosis Miliar/complicaciones , Tuberculosis Miliar/diagnóstico , Anciano , Resultado Fatal , Femenino , Fiebre/etiología , Humanos , Pulmón/diagnóstico por imagen , Mycobacterium tuberculosis/aislamiento & purificación , Radiografía , Tomografía Computarizada por Rayos XRESUMEN
Optimization of a new series of S-adenosyl-L-homocysteine hydrolase (AdoHcyase) inhibitors based on non-adenosine analogs led to very potent compounds 14n, 18a, and 18b with IC50 values of 13 ± 3, 5.0 ± 2.0, and 8.5 ± 3.1 nM, respectively. An X-ray crystal structure of AdoHcyase with NAD(+) and 18a showed a novel open form co-crystal structure. 18a in the co-crystals formed intramolecular eight membered ring hydrogen bond formations. A single crystal X-ray structure of 14n also showed an intramolecular eight-membered ring hydrogen bond interaction.
Asunto(s)
Adenosilhomocisteinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Adenosina/química , Adenosilhomocisteinasa/genética , Adenosilhomocisteinasa/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Enlace de Hidrógeno , Isomerismo , Conformación Molecular , Simulación de Dinámica Molecular , NAD/química , NAD/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-ActividadRESUMEN
PURPOSE: To report novel mutations in the CRB1 gene in two patients with early-onset retinal dystrophy (EORD) and the longitudinal clinical course of EORD. PATIENTS AND METHODS: The patients were two unrelated Japanese children. Standard ophthalmic examinations including perimetry, electroretinography, and optical coherence tomography were performed on both patients. Whole exomes of the patients and their nonsymptomatic parents were analyzed using a next-generation sequence (NGS) technique. RESULTS: Patient 1 was noted to have esotropia and hyperopia at age 3. His decimal best-corrected visual acuity (BCVA) was 0.6 OD and 0.3 OS at age 6 with de-pigmentation of the retinal pigment epithelium (RPE). At age 19, his central vision was still preserved; however, numerous pigment granules were present in the retina. NGS analysis revealed a p.R632X nonsense and c.652 + 1_652 + 4delGTAA splice site mutations in the CRB1 gene. Patient 2 was noted to have hyperopia at age 3. His decimal BCVA at age 6 was 0.3 OD and 0.4 OS with de-pigmented RPE. The degree of retinal pigmentation was increased but his BCVA was good until the age of 14 years. NGS analysis revealed c.652 + 1_652 + 4delGTAA and c.652 + 1_652 + 2insT splice site mutations in the CRB1 gene. CONCLUSIONS: The phenotypes of these novel mutations for EORD are typical of CRB1-associated EORD (LCA8). They were slowly progressive until the second decade of life.
Asunto(s)
Codón sin Sentido/genética , Enfermedades Hereditarias del Ojo/genética , Proteínas del Ojo/genética , Proteínas de la Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Empalme del ARN/genética , Distrofias Retinianas/genética , Niño , Electrorretinografía , Enfermedades Hereditarias del Ojo/diagnóstico , Humanos , Masculino , Distrofias Retinianas/diagnóstico , Tomografía de Coherencia Óptica , Agudeza Visual , Campos VisualesRESUMEN
High throughput screening using Automated Ligand Identification System (ALIS) resulted in the discovery of a new series of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs. The optimization campaign led to very potent and competitive compound 39 with a Ki value of 1.5 nM. Compound 39 could be a promising lead compound for research to reduce elevated homocysteine levels.
Asunto(s)
Adenosilhomocisteinasa/antagonistas & inhibidores , Amidas/farmacología , Aminas/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Monometilhidrazina/farmacología , Adenosina/química , Adenosilhomocisteinasa/metabolismo , Amidas/síntesis química , Amidas/química , Aminas/síntesis química , Aminas/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Ensayos Analíticos de Alto Rendimiento , Humanos , Estructura Molecular , Monometilhidrazina/síntesis química , Monometilhidrazina/química , Relación Estructura-ActividadRESUMEN
BACKGROUND/AIM: The combination of programmed cell death ligand 1 inhibitors and platinum-based chemotherapy has become the standard treatment for first-line therapy in extensive-stage small-cell lung cancer (ES-SCLC). This study compared the efficacy and safety of atezolizumab plus chemotherapy and durvalumab plus chemotherapy in the treatment of ES-SCLC in clinical practice. PATIENTS AND METHODS: We retrospectively analyzed 40 patients with ES-SCLC treated with atezolizumab plus chemotherapy or durvalumab plus platinum-based chemotherapy at the Fukuoka University Hospital between October 2019 and November 2022. RESULTS: Among the 40 patients, 20 were treated with atezolizumab and 20 were treated with durvalumab. There was no significant difference in patient characteristics between the two groups; five patients who received atezolizumab and one who received durvalumab showed a performance status of 2 or higher. The median progression-free survival of patients who received atezolizumab or durvalumab was 5.6 and 5.4 months, respectively (p=0.881). The median overall survival of patients who received atezolizumab or durvalumab was 10.0 and 17.1 months, respectively (p=0.163). The objective response rate of the patients who received atezolizumab or durvalumab was 80.0% and 85.0%, respectively. There was no significant difference in the incidence of immune-related adverse events between the groups. CONCLUSION: This retrospective study was the first to compare the efficacy and safety of PD-L1 antibody, atezolizumab or durvalumab, in combination with carboplatin and etoposide in treatment-naïve ES-SCLC Japanese patients in a real-world setting. Both regimens, atezolizumab or durvalumab with carboplatin and etoposide, were effective and well-tolerated in Japanese ES-SCLC patients, in line with clinical trial findings.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Masculino , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anciano de 80 o más Años , Resultado del Tratamiento , Adulto , Estadificación de NeoplasiasRESUMEN
BACKGROUND/AIM: Nivolumab and ipilimumab combination therapy has been extensively explored for the treatment of advanced non-small-cell lung cancer (NSCLC) through the pivotal phase III trials CheckMate 227 and CheckMate 9LA. However, the relationship between immune-related adverse events (irAEs) and the effectiveness of nivolumab plus ipilimumab-based therapy in a real-world clinical setting remains uncertain. PATIENTS AND METHODS: We performed a retrospective analysis of 28 patients with advanced or recurrent NSCLC who underwent treatment with nivolumab plus ipilimumab, with or without platinum-doublet chemotherapy, from February 2021 to January 2023. The primary objective was to elucidate the clinical association between irAEs and treatment efficacy associated with nivolumab plus ipilimumab-based therapy. RESULTS: Among the 28 patients, 22 (78.6%) experienced irAEs. The median progression-free survival (PFS) was significantly longer for patients with irAEs than for those without (p=0.0158), as was overall survival (OS) (p=0.000394). The severity of irAEs had no significant influence on PFS or OS. The objective response rate tended to be higher in patients with irAEs than in those without (50.0% versus 0.0%, respectively; p=0.0549). Multivariate analysis indicated that irAE occurrence was an independent factor for improved PFS (hazard ratio=0.2084, p=0.01383) and OS (hazard ratio=0.0857, p=0.001588). Interstitial lung disease was inferior to other irAE profiles for both PFS and OS. CONCLUSION: Patients with advanced NSCLC experiencing irAEs demonstrated superior clinical outcomes when treated with nivolumab plus ipilimumab-based therapy compared with those without irAEs. However, immune-related interstitial lung disease may be less linked with PFS and OS than other irAE profiles.
Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Ipilimumab , Neoplasias Pulmonares , Nivolumab , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Supervivencia sin Progresión , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
Introduction: The proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion scores (TPS) ≥ 50%. However, evidence from the clinical trials specifically for older patients is limited. Thus, it is unclear which older patients benefit more from COMBO than MONO. Methods: We retrospectively analyzed 199 older NSCLC patients of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and PD-L1 TPS ≥ 50% who were treated with MONO or COMBO. We analyzed the association between treatment outcomes and baseline patient characteristics in each group, using propensity score matching. Results: Of the 199 patients, 131 received MONO, and 68 received COMBO. The median overall survival (OS; MONO: 25.2 vs. COMBO: 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between MONO and COMBO group. In the MONO group, OS was significantly shorter in patients without smoking history compared to those with smoking history [HR for smoking history against non-smoking history: 0.36 (95% CI: 0.16-0.78), P = 0.010]. In the COMBO group, OS was significantly shorter in patients with PS 1 than those with PS 0 [HR for PS 0 against PS 1: 3.84 (95% CI: 1.44-10.20), P = 0.007] and for patients with squamous cell carcinoma (SQ) compared to non-squamous cell carcinoma (non-SQ) [HR for SQ against non-SQ: 0.17 (95% CI: 0.06-0.44), P < 0.001]. For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-SQ (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383), PFS and OS were significantly longer in the COMBO group. Conclusions: ECOG PS and histological type should be considered when choosing MONO or COMBO treatment in older patients with NSCLC and PD-L1 TPS ≥ 50%.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/patología , Antígeno B7-H1 , Pronóstico , Estudios Retrospectivos , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
Introduction: Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population. Methods: Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching. Results: Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02). Discussion: TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression.
Asunto(s)
Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Masculino , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Estudios Retrospectivos , Anciano , Antígeno B7-H1/metabolismo , Persona de Mediana Edad , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Resultado del Tratamiento , Factor Nuclear Tiroideo 1/metabolismo , Biomarcadores de Tumor , Anciano de 80 o más AñosRESUMEN
A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4-phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6 weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10 mg/kg/day.
Asunto(s)
Anabolizantes/química , Anabolizantes/uso terapéutico , Densidad Ósea/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Tienopiridinas/química , Tienopiridinas/uso terapéutico , Fosfatasa Alcalina/metabolismo , Anabolizantes/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Descubrimiento de Drogas , Femenino , Humanos , Osteoporosis/metabolismo , Ovariectomía , Ratas , Ratas Endogámicas F344 , Relación Estructura-Actividad , Tienopiridinas/farmacologíaRESUMEN
BACKGROUND/AIM: Platinum-doublet chemotherapy plus either programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) checkpoint inhibitors has been reported to improve the survival of patients with advanced non-small cell lung cancer (NSCLC). The IMpower150 study showed significant improvements in progression-free survival and overall survival with atezolizumab in combination with bevacizumab, a humanized anti-VEGF monoclonal antibody, paclitaxel, and carboplatin (ABCP therapy) in chemotherapy-naïve patients with non-squamous NSCLC. We herein report the efficacy and safety of ABCP therapy in Japanese patients with non-squamous NSCLC in clinical practice. PATIENTS AND METHODS: We retrospectively evaluated the efficacy and safety of ABCP therapy in 30 patients treated at our hospital from February 2019 to December 2021. RESULTS: The median age of patients was 69 years, 24 (80.0%) patients were male, 29 (96.7%) patients had a performance status of 0 or 1, 28 (93.3%) patients had adenocarcinoma histology, and 7 (23.3%) patients had epidermal growth factor receptor mutations. Evaluation of the PD-L1 tumor proportion score (TPS) showed that 12 (40.0%), 8 (26.7%), and 6 (20.0%) patients had a TPS of ≥50%, 1% to 49%, and <1%, respectively. The objective response rate of the intention-to-treat wild-type population was 73.9%, and the median progression-free survival was 8.3 months. Immune checkpoint inhibitor (ICI)-induced pneumonitis occurred in one (3.3%) patient. CONCLUSION: ABCP therapy for Japanese non-squamous NSCLC patients in a clinical setting achieved a high response rate with low incidence of ICI-induced pneumonitis equivalent to those observed in IMpower150 study.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Anciano , Femenino , Carcinoma de Pulmón de Células no Pequeñas/patología , Carboplatino , Paclitaxel/uso terapéutico , Bevacizumab/efectos adversos , Antígeno B7-H1 , Neoplasias Pulmonares/patología , Pueblos del Este de Asia , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Importance: Immune checkpoint inhibitor (ICI) monotherapy with pembrolizumab and ICI plus chemotherapy have been approved as first-line treatments for non-small cell lung cancer (NSCLC) for patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of 50% or more, but the choice between these 2 therapeutic options is unclear. Objective: To clarify the association of a history of concurrent medication use with treatment outcomes for ICIs with or without chemotherapy in patients with NSCLC with a high PD-L1 TPS and to determine whether these clinical histories are biomarkers for appropriate treatment selection. Design, Setting, and Participants: This retrospective, multicenter cohort study at 13 hospitals in Japan included patients with advanced NSCLC with a PD-L1 TPS of 50% or more who had received pembrolizumab ICI monotherapy or ICI plus chemotherapy as the initial treatment between March 2017 and December 2020. The median (IQR) follow-up duration was 18.5 (9.2-31.2) months. Data were analyzed from April 2022 through May 2023. Exposure: ICI monotherapy with pembrolizumab or ICI plus chemotherapy as first-line treatment. Main Outcomes and Measures: The primary analysis was the association of treatment outcomes with baseline patient characteristics, including concomitant drug history, after propensity score matching. Cox proportional hazard models were used to determine the associations of patient characteristics with survival outcomes. Logistic regression analysis was used to determine the association of concomitant medication history with treatment outcomes and other patient characteristics. Results: A total of 425 patients with NSCLC were enrolled in the study including 271 patients (median [range] age, 72 [43-90] years; 215 [79%] men) who were treated with pembrolizumab monotherapy as the first-line treatment and 154 patients (median [range] age, 69 [36-86] years; 121 [79%] men) who were treated with ICI plus chemotherapy as the first-line treatment. In multivariable analysis, a history of proton pump inhibitor (PPI) use was independently associated with shorter progression-free survival (PFS) in the pembrolizumab monotherapy group (hazard ratio [HR], 1.38; 95% CI, 1.00-1.91; P = .048), but not in the ICI plus chemotherapy group. In patients with a PPI history, both the median (IQR) PFS (19.3 [9.0 to not reached] months vs 5.7 [2.4 to 15.2] months; HR, 0.38; 95% CI, 0.20-0.72; P = .002) and the median (IQR) overall survival (not reached [9.0 months to not reached) vs 18.4 [10.5 to 50.0] months; HR, 0.43; 95% CI, 0.20-0.92; P = .03) were significantly longer in the ICI plus chemotherapy group than in the pembrolizumab monotherapy group. In patients without a history of PPI use, both the median (IQR) PFS (18.8 months [6.6 months to not reached] vs 10.6 months [2.7 months to not reached]; HR, 0.81; 95% CI, 0.56-1.17; P = .26) and the median (IQR) overall survival (not reached [12.6 months to not reached] vs 29.9 [13.3 to 54.3] months, HR, 0.75; 95% CI, 0.48-1.18; P = .21) did not differ between groups. Conclusions and Relevance: This cohort study found that a history of PPI use could be an important clinical factor in treatment decision-making for patients with NSCLC with a PD-L1 TPS of 50% or more.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Femenino , Humanos , Masculino , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios de Cohortes , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de la Bomba de Protones , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy and ICI plus chemotherapy are approved first-line treatments for patients with non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death-ligand 1 (PD-L1). However, appropriate treatment for patients showing high PD-L1 expression and poor performance status (PS) is not well defined. OBJECTIVE: The aim of this study was to identify a treatment option that is better for these patients in a real-world setting. PATIENTS AND METHODS: A total of 425 patients with NSCLC and high PD-L1 expression were included retrospectively. All patients received either pembrolizumab monotherapy or ICI plus chemotherapy as the first-line treatment. Patients were subdivided into good (PS score 0 or 1; n = 354) and poor PS groups (PS score 2 or 3; n = 71). Early progressive disease (PD) was defined as PD within 3 months of ICI-based therapy initiation. RESULTS: The good PS group had significantly longer progression-free survival (PFS) and overall survival (OS) than the poor PS group upon ICI-based therapy administration. In the poor PS group, no significant difference was observed in PFS and OS between pembrolizumab monotherapy and ICI plus chemotherapy. In the good PS group, pembrolizumab monotherapy, PD-L1 50-89%, and liver metastasis were associated with early PD, as determined using multivariate logistic regression analyses. However, in the poor PS group, the multivariate logistic regression analyses did not show an association between pembrolizumab monotherapy and early PD. CONCLUSIONS: In patients with NSCLC exhibiting poor PS and high PD-L1 expression, ICI plus chemotherapy did not confer PFS or OS benefit compared with pembrolizumab monotherapy.