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In this work, we conceived and developed antibody-drug conjugates (ADCs) that could efficiently release the drug after enzymatic cleavage of the linker moiety by tumoral proteases. The antibody-drug linkers we used are the result of a rational optimization of a previously reported PEGylated linker, PUREBRIGHT® MA-P12-PS, which showed excellent drug loading capacities but lacked an inbuilt drug discharge mechanism, thus limiting the potency of the resulting ADCs. To address this limitation, we chose to incorporate a protease-sensitive trigger into the linker to favor the release of a "PEGless" drug inside the tumor cells and, therefore, obtain potent ADCs. Currently, most marketed ADCs are based on the Val-Cit dipeptide followed by a self-immolative spacer for releasing the drug in its unmodified form. Here, we selected two untraditional peptide sequences, a Phe-Gly dipeptide and a Val-Ala-Gly tripeptide and placed one or the other in between the drug on one side (N-terminus) and the rest of the linker, including the PEG moiety, on the other side (C-terminus), without a self-immolative group. We found that both linkers responded to cathepsin B, a reference lysosomal enzyme, and liberated a PEG-free drug catabolite, as desired. We then used the two linkers to generate ADCs based on trastuzumab (a HER2-targeting antibody) and DM1 (a microtubule-targeted cytotoxic agent) with an average drug-to-antibody ratio (DAR) of 4 or 8. The ADCs showed restored cytotoxicity in vitro, which was proportional to the DM1 loading and generally higher for the ADCs bearing Val-Ala-Gly in their structure. In an ovarian cancer model in mice, the DAR 8 ADC based on Val-Ala-Gly behaved better than Kadcyla® (an approved ADC of DAR 3.5 used as control throughout this study), leading to a higher tumor volume reduction and more prolonged median survival. Taken together, our results depict a successful linker optimization process and encourage the application of the Val-Ala-Gly tripeptide as an alternative to other existing protease-sensitive triggers for ADCs.
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BACKGROUND: Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM). MATERIALS AND METHODS: Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints. RESULTS: OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity. CONCLUSIONS: A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , 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 , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Gemcitabina , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Cisplatino/uso terapéutico , Cisplatino/farmacología , Cisplatino/efectos adversos , Anciano de 80 o más AñosRESUMEN
Histiocytic sarcoma is a malignant proliferation of cells that exhibit morphological and immunophenotypic features of mature histiocytes. Owing to its rarity, its clinical features and standard treatment have not yet been established. This report describes a case of histiocytic sarcoma of the palate that developed in a 76-year-old man, the first report of an intraoral histiocytic sarcoma. An extended resection was performed; however, establishing the excision line was extremely difficult because assessing the tumour boundary on imaging was challenging and the tumour underwent dynamic gross morphological changes following biopsy. Complete resection is required to obtain a favourable prognosis for high-grade tumours with indistinct borders. In this case, an intraoperative rapid examination with frozen section analysis was performed along the planned excision line to completely resect the tumours exhibiting such behaviour. At 28 months postoperatively, the patient demonstrated no recurrence or metastasis; however, he is under careful monitoring.
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Sarcoma Histiocítico , Masculino , Humanos , Anciano , Sarcoma Histiocítico/diagnóstico por imagen , Sarcoma Histiocítico/cirugía , Histiocitos/patología , Diagnóstico por Imagen , Biopsia , Hueso PaladarRESUMEN
BACKGROUND: Mature progression-free survival (PFS) data from the phase III J-ALEX study showed superiority for alectinib versus crizotinib [hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.26-0.52; median PFS 34.1 versus 10.2 months, respectively] in advanced ALK (anaplastic lymphoma kinase)-positive non-small-cell lung cancer (NSCLC). Overall survival (OS) data were immature (HR 0.80, 99.8799% CI 0.35-1.82) at the time of data cut-off (30 June 2018). We report final OS data after ≥5 years of follow-up. PATIENTS AND METHODS: ALK inhibitor naive Japanese patients who were chemotherapy naive or had received one prior chemotherapy regimen were enrolled. Patients were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was independent review facility-assessed PFS, with OS (not fully powered) as a secondary endpoint. RESULTS: Median duration of OS follow-up was 68.6 months with alectinib and 68.0 months with crizotinib. Treatment with alectinib did not prolong OS relative to crizotinib (HR 1.03, 95.0405% CI 0.67-1.58; P = 0.9105). Five-year OS rates were 60.9% (95% CI 51.4-70.3) with alectinib and 64.1% (95% CI 54.9-73.4) with crizotinib. In total, 91.3% (n = 95/104) of crizotinib-treated patients and 46.6% (n = 48/103) of alectinib-treated patients received at least one subsequent anticancer therapy. After study drug discontinuation, 78.8% of patients in the crizotinib arm switched to alectinib, while 10.7% of patients in the alectinib arm switched to crizotinib as a first subsequent anticancer therapy. Patients randomized to crizotinib tended to switch treatment earlier than those randomized to alectinib. CONCLUSION: Final OS analysis from J-ALEX did not show superiority of alectinib to crizotinib; this result was most likely confounded by treatment crossover. Alectinib remains a standard of care for the treatment of patients with advanced ALK-positive NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carbazoles , Crizotinib , Humanos , Japón , Piperidinas , Inhibidores de Proteínas Quinasas , Análisis de SupervivenciaRESUMEN
AIMS: A novel bladder preservation therapy, the OMC (Osaka Medical College) regimen, which combines radiation therapy with balloon-occluded arterial infusion of anticancer agents, is a treatment option for patients with muscle-invasive bladder cancer (MIBC). We retrospectively analysed the effects of changes in radiation dose and irradiation field on treatment efficacy and adverse events.The purpose of this study is to use the results of this study to help determine a course of radiation therapy for bladder preservation therapy of cT2N0M0 MIBC. MATERIALS AND METHODS: We examined 352 patients with clinical stage T2N0M0 (cT2N0M0) MIBC classified into the following groups based on the irradiation method: group A, the whole pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group B, the small pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group C, the whole pelvis (40 Gy/20 fractions) + local bladder (10 Gy/5 fractions). RESULTS: The complete response rate, 3-year overall survival and progression-free survival rates in group A were 92.9%, 94.9% and 82.1%, respectively; in group B were 87.2%, 86.7% and 76.7%, respectively; and in group C were 95.2%, 92.6% and 71.1%, respectively. No significant differences between the groups were noted. The incidence of ≥grade 3 urinary tract and gastrointestinal toxicities were not significantly different among the groups (group A: 7.8%, 1.7%; B, 11.1%, 0%; C, 7.1%, 1.8%, respectively). The 3-year progression-free rates of the common iliac lymph node (CILN) region in patients who received whole-pelvis and small-pelvis irradiation were 99.0 and 89.0% (P < 0.01), respectively, with the latter group having significantly high lymph node recurrence in the CILN region. CONCLUSIONS: Our findings showed that the optimal radiation therapy for patients with cT2N0M0 MIBC undergoing the OMC regimen is whole-pelvis irradiation including the CILN region, with a total dose of 50 Gy/25 fractions.
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Antineoplásicos , Oclusión con Balón , Neoplasias de la Vejiga Urinaria , Antineoplásicos/uso terapéutico , Cisplatino , Terapia Combinada , Desoxicitidina , Supervivencia sin Enfermedad , Humanos , Estudios Retrospectivos , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Antibody-drug conjugates (ADCs) are an established therapeutic entity in which potent cytotoxic drugs are conjugated to a monoclonal antibody. In parallel with the great emphasis put on novel site-specific bioconjugation technologies, future advancements in this field also rely on exploring novel linker-drug architectures that improve the efficacy and stability of ADCs. In this context, the use of hydrophilic linkers represents a valid strategy to mask or reduce the inherent hydrophobicity of the most used cytotoxic drugs and positively impact the physical stability and in vivo performance of ADCs. Here, we describe the use of linkers containing monodisperse poly(ethylene glycol) (PEG) moieties for the construction of highly-loaded lysine-conjugated ADCs. The studied ADCs differ in the positioning of PEG (linear or pendant), the bonding type with the antibody (amide or carbamate), and the drug-to-antibody ratio (DAR). These ADCs were first evaluated for their stability in solution under thermal stress, showing that both the drug-linker-polymer design and the nature of the antibody-linker bonding are of great importance for their physical and chemical stability. Amide-coupled ADCs bearing two pendant 12-unit poly(ethylene glycol) chains within the drug-linker structure were the best performing conjugates, distancing themselves from the ADCs obtained with a conventional linear 24-unit PEG oligomer or the linker of Kadcyla®. The pharmacokinetic profiles of amide-linked ADCs, with a linear or pendant configuration of the PEG, were tested in mice in comparison to Kadcyla®. Total antibody pharmacokinetics paralleled the trends in aggregation tendency, with slower clearance rates for the ADCs based on the pendant drug-linker format. The above-mentioned findings have provided important clues on the drug-linker design and revealed that the positioning and configuration of a PEG unit have to be carefully tuned to achieve ADCs with improved stability and pharmacokinetics.
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Antineoplásicos , Inmunoconjugados , Animales , Anticuerpos Monoclonales , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , PolietilenglicolesRESUMEN
BACKGROUND: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. PATIENTS AND METHODS: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. RESULTS: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). CONCLUSIONS: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Acrilamidas , Afatinib/uso terapéutico , Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios de Cohortes , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Estudios ProspectivosRESUMEN
BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/administración & dosificación , Docetaxel/administración & dosificación , Gefitinib/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Docetaxel/efectos adversos , Receptores ErbB/genética , Femenino , Gefitinib/efectos adversos , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del TratamientoAsunto(s)
Carboxiliasas/genética , Eccema/genética , Hipohidrosis/genética , Miopatías Estructurales Congénitas/diagnóstico , Proteína ORAI1/genética , Biopsia , Preescolar , Análisis Mutacional de ADN , Dermoscopía , Eccema/patología , Humanos , Hipohidrosis/patología , Masculino , Músculo Esquelético/patología , Miopatías Estructurales Congénitas/complicaciones , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Piel/diagnóstico por imagen , Piel/patología , Glándulas Sudoríparas/patologíaAsunto(s)
Antígenos CD/metabolismo , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/patología , Cadenas alfa de Integrinas/metabolismo , Neoplasias Cutáneas/patología , Linfocitos T Reguladores/metabolismo , Carcinoma Basocelular/inmunología , Carcinoma de Células Escamosas/inmunología , Humanos , Memoria Inmunológica , Piel/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Microambiente TumoralAsunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Interleucina-17/metabolismo , Psoriasis/inmunología , Piel/patología , Linfocitos T CD8-positivos/metabolismo , Separación Celular , Células Cultivadas , Citometría de Flujo , Humanos , Interferón gamma/metabolismo , Interleucina-17/inmunología , Cultivo Primario de Células , Psoriasis/patología , Piel/citología , Piel/inmunología , Factores de TiempoAsunto(s)
Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Esclerodermia Sistémica/inmunología , Piel/inmunología , Antígenos CD/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Humanos , Cadenas alfa de Integrinas/metabolismo , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/patología , Piel/citología , Piel/patologíaAsunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Neoplasias de la Conjuntiva/tratamiento farmacológico , Granuloma/inducido químicamente , Melanoma/tratamiento farmacológico , Nivolumab/efectos adversos , Enfermedades de la Piel/inducido químicamente , Neoplasias de la Conjuntiva/patología , Células Epitelioides/patología , Femenino , Granuloma/patología , Humanos , Melanoma/secundario , Persona de Mediana Edad , Enfermedades de la Piel/patologíaRESUMEN
AIM: To investigate the usefulness of high-resolution 3 T magnetic resonance imaging (MRI) for the evaluation of traumatic and degenerative triangular fibrocartilage complex (TFCC) abnormalities among three groups: patients presenting with wrist pain who were (a) younger than age 50 years or (b) age 50 or older (PT<50 and PT≥50, respectively), and (c) asymptomatic controls who were younger than age 50 years (AC). MATERIALS AND METHODS: High-resolution 3 T MRI was evaluated retrospectively in 96 patients, including 47 PT<50, 38 PT≥50, and 11 AC. Two board-certified radiologists reviewed the MRI images independently. MRI features of TFCC injury were analysed according to the Palmer classification, and cartilage degeneration around the TFCC was evaluated using the Outerbridge classification. Differences in MRI findings among these groups were detected using chi-square test. Cohen's kappa was calculated to assess interobserver and intra-observer reliability. RESULTS: The incidence of Palmer class 1A, 1C and 1D traumatic TFCC injury was significantly (p<0.05) higher in PT≥50 than in PT<50 (class 1A: 47.4% versus 27.7%, class 1C: 31.6% versus 12.8%, and class 1D: 21.1% versus 2.1%). Likewise, MRI findings of TFCC degeneration were observed more frequently in PT≥50 than in PT<50 (p<0.01). Outerbridge grade 2 or higher cartilage degeneration was significantly (p<0.01) more frequently seen in PT≥50 than in PT<50 (55.3% versus 17% in the lunate, 28.9% versus 4.3% in the triquetrum, 73.7% versus 12.8% in the ulna). CONCLUSION: High-resolution wrist MRI at 3 T enables detailed evaluation of TFCC traumatic injury and degenerative changes using the Palmer and Outerbridge classifications, with good or excellent interobserver and intra-observer reliability.
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Enfermedades de los Cartílagos/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Fibrocartílago Triangular/diagnóstico por imagen , Adulto , Factores de Edad , Anciano , Enfermedades de los Cartílagos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Fibrocartílago Triangular/lesiones , Fibrocartílago Triangular/patología , Traumatismos de la Muñeca/diagnóstico por imagen , Traumatismos de la Muñeca/patología , Articulación de la Muñeca/patología , Adulto JovenAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Estudios de Cohortes , Femenino , Humanos , Neoplasias Pulmonares/radioterapia , Masculino , Nivolumab , Estudios RetrospectivosRESUMEN
BACKGROUND: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR. PATIENTS AND METHODS: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B). RESULTS: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. CONCLUSION: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Receptores ErbB/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Nivolumab , Selección de Paciente , Fenotipo , Medicina de Precisión , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration: NCT01207011 (ClinicalTrials.gov).
Asunto(s)
Antraciclinas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Taxoides/uso terapéutico , Anciano , Antraciclinas/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Docetaxel , Resistencia a Antineoplásicos , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
Autoantibodies to melanoma differentiation-associated protein 5 (MDA5) are associated with a subset of patients with dermatomyositis (DM) who have rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis. Intensive immunosuppressive therapy is initiated before irreversible lung damage can occur; however, there are few lines of evidence for the treatment of RP-ILD. Here, we report three cases of anti-MDA5 antibody-associated DM with RP-ILD in which the patients were treated with combined-modality therapy, including high-dose prednisolone, tacrolimus, intravenous cyclophosphamide and intravenous immunoglobulin (IVIG). In all three cases, serum ferritin levels, which are known to represent the disease activity of RP-ILD, were decreased after IVIG administration. IVIG might contribute to the control of the disease activity of anti-MDA5 antibody-positive DM. Moreover, palmar violaceous macules/papules around the interphalangeal joints, which was observed in all three cases in the incipient stage, might be a useful sign in suggesting a diagnosis of anti-MDA5 antibody-associated DM.
Asunto(s)
Dermatomiositis/prevención & control , Dermatosis de la Mano/prevención & control , Inmunoglobulinas Intravenosas/uso terapéutico , Helicasa Inducida por Interferón IFIH1/inmunología , Enfermedades Pulmonares Intersticiales/prevención & control , Anciano , Antiinflamatorios/administración & dosificación , Autoanticuerpos/sangre , Terapia Combinada , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificación , Tacrolimus/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. PATIENTS AND METHODS: In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. RESULT: ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. CONCLUSIONS: Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. REGISTRATION NUMBER: JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carbazoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Fusión Oncogénica/metabolismo , Piperidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/metabolismo , Adenocarcinoma/enzimología , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). METHODS: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. RESULTS: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). CONCLUSIONS: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR. TRIAL REGISTRATION NUMBER: NCT01377376.