RESUMEN
Driver oncogenes are investigated upfront at diagnosis using multi-CDx systems with next-generation sequencing techniques or multiplex reverse-transcriptase polymerase chain reaction assays. Additionally, from 2019, comprehensive genomic profiling (CGP) assays have been available in Japan for patients with advanced solid tumors who had completed or were expected to complete standard chemotherapy. These assays are expected to comprehensively detect the driver oncogenes, especially for patients with non-small cell lung cancer (NSCLC). However, there are no reports of nationwide research on the detection of driver oncogenes in patients with advanced NSCLC who undergo CGP assays, especially in those with undetected driver oncogenes at diagnosis. In this study, we investigated the proportion of driver oncogenes detected in patients with advanced NSCLC with undetectable driver oncogenes at initial diagnosis and in all patients with advanced NSCLC who underwent CGP assays. We retrospectively analyzed data from 986 patients with advanced NSCLC who underwent CGP assays between August 2019 and March 2022, using the Center for Cancer Genomics and Advanced Therapeutics database. The proportion of driver oncogenes newly detected in patients with NSCLC who tested negative for driver oncogenes at diagnosis and in all patients with NSCLC were investigated. Driver oncogenes were detected in 451 patients (45.7%). EGFR was the most common (16.5%), followed by KRAS (14.5%). Among the 330 patients with undetected EGFR, ALK, ROS1, and BRAF V600E mutations at diagnosis, 81 patients (24.5%) had newly identified driver oncogenes. CGP assays could be useful to identify driver oncogenes in patients with advanced NSCLC, including those initially undetected, facilitating personalized treatment.
Asunto(s)
Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Oncogenes , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Femenino , Anciano , Oncogenes/genética , Persona de Mediana Edad , Quinasa de Linfoma Anaplásico/genética , Estudios Retrospectivos , Japón , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Receptores ErbB/genética , Anciano de 80 o más Años , Adulto , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas/genética , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
Lazertinib, a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), demonstrates marked efficacy in EGFR-mutant lung cancer. However, resistance commonly develops, prompting consideration of therapeutic strategies to overcome initial drug resistance mechanisms. This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells.
RESUMEN
BACKGROUND: Recent therapeutic strategies for KRAS-mutated cancers that inhibit the MAPK pathway have attracted considerable attention. The RAF/MEK clamp avutometinib (VS-6766/CH5126766/RO5126766/CKI27) is promising for patients with KRAS-mutated cancers. Although avutometinib monotherapy has shown clinical activity in patients with KRAS-mutated cancers, effective combination strategies will be important to develop. METHODS: Using a phosphorylation kinase array kit, we explored the feedback mechanism of avutometinib in KRAS-mutated NSCLC cells, and investigated the efficacy of combining avutometinib with inhibitors of the feedback signal using in vitro and in vivo experiments. Moreover, we searched for a biomarker for the efficacy of combination therapy through an in vitro study and analysis using the The Cancer Genome Atlas Programme dataset. RESULTS: Focal adhesion kinase (FAK) phosphorylation/activation was increased after avutometinib treatment and synergy between avutometinib and FAK inhibitor, defactinib, was observed in KRAS-mutated NSCLC cells with an epithelial rather than mesenchymal phenotype. Combination therapy with avutometinib and defactinib induced apoptosis with upregulation of Bim in cancer cells with an epithelial phenotype in an in vitro and in vivo study. CONCLUSIONS: These results demonstrate that the epithelial-mesenchymal transition status may be a promising biomarker for the efficacy of combination therapy with avutometinib and defactinib in KRAS-mutated NSCLC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Ratones , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Fosforilación , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Femenino , Benzamidas , Pirazinas , SulfonamidasRESUMEN
BACKGROUND: A history of pre-administration of immune checkpoint inhibitors has been reported to be associated with good outcomes of ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC). However, existing knowledge on the clinical significance of RAM and DOC following combined chemoimmunotherapy is limited. Therefore, we evaluated the efficacy and safety of RAM plus DOC therapy after combined chemoimmunotherapy and attempted to identify the predictors of its outcomes. PATIENTS AND METHODS: This multicenter, prospective study investigated the efficacy and safety of RAM plus DOC after combined chemoimmunotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. An exploratory analysis measured serum cytokine levels at the start of treatment. RESULTS: Overall, 44 patients were enrolled from 10 Japanese institutions between April 2020 and June 2022. The median PFS and OS were 6.3 and 22.6 months, respectively. Furthermore, the ORR and DCR were 36.4% and 72.7%, respectively. The high vascular endothelial growth factor D (VEGF-D) group had a significantly shorter PFS and OS. A combination of high VEGF-A and low VEGF-D levels was associated with a longer PFS. CONCLUSION: Our results showed that RAM plus DOC after combined chemoimmunotherapy might be an effective and relatively feasible second-line treatment for patients with advanced NSCLC in a real-world setting.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Docetaxel , Neoplasias Pulmonares , Ramucirumab , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Docetaxel/administración & dosificación , Docetaxel/uso terapéutico , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Femenino , Estudios Prospectivos , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Inmunoterapia/métodos , AdultoRESUMEN
INTRODUCTION: The risk of thromboembolic events developing limits the dose of antiangiogenic agents, thereby reducing their efficacy. This retrospective study therefore sought to identify predictors for the development of antiangiogenic agent-induced thromboembolic events and to elucidate whether differences in the likelihood of thromboembolic events exist between different antiangiogenic agents or cancer types, to guide future strategies for optimizing safety, efficacy, and quality of life in patients receiving chemotherapy. METHODS: This study retrospectively investigated 468 cancer patients who received chemotherapy with bevacizumab, ramucirumab, or aflibercept at our outpatient chemotherapy center between December 2016 and April 2022. Variables related to the development of thromboembolic events were extracted from the medical records, and multivariate logistic regression analysis was performed to identify predictors for the development of thromboembolic events. The Wilcoxon/Kruskal-Wallis test was used to detect significant differences between groups. RESULTS: Significant factors included serum albumin level (odds ratio [OR] = 0.363, 95% confidence interval [CI] = 0.193-0.685; p = 0.0017) and diabetes mellitus (OR = 5.356, 95% CI = 1.711-16.769; p = 0.0039). Renin-angiotensin system inhibitors (OR = 0.307) had low OR, although it was not significant. No difference in the development of thromboembolic events was evident between cancer types (p = 0.0781), but differences were identified between the three antiangiogenic agents (p = 0.0132). Ramucirumab was associated with a lower likelihood of thromboembolic events. CONCLUSION: Serum albumin level and diabetes mellitus were identified as significant predictors for the development of antiangiogenic agent-induced thromboembolic events. In addition, the likelihood of thromboembolic events did not differ between cancer types but differed between antiangiogenic agents.
Asunto(s)
Inhibidores de la Angiogénesis , Anticuerpos Monoclonales Humanizados , Bevacizumab , Neoplasias , Ramucirumab , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Tromboembolia , Humanos , Bevacizumab/efectos adversos , Bevacizumab/administración & dosificación , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Tromboembolia/inducido químicamente , Tromboembolia/epidemiología , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/administración & dosificación , Adulto , Anciano de 80 o más Años , Factores de RiesgoRESUMEN
Histrionicotoxin (HTX) alkaloids, which are isolated from Colombian poison dart frogs, are analgesic neurotoxins that modulate nicotinic acetylcholine receptors (nAChRs) as antagonists. Perhydrohistrionicotoxin (pHTX) is the potent synthetic analogue of HTX and possesses a 1-azaspiro[5.5]undecane skeleton common to the HTX family. Here, we show for the first time the divergent nine-step synthesis of pHTX and its three stereoisomers from the known aldehyde through a one-step construction of the 1-azaspiro[5.5]undecane framework from a linear amino ynone substrate. Surprisingly, some pHTX diastereomers exhibited antagonistic activities on the chicken α4ß2-neuronal nAChRs that were more potent than pHTX.
Asunto(s)
Venenos de Anfibios , Pollos , Receptores Nicotínicos , Animales , AlcanosRESUMEN
Universal screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on admission is reportedly beneficial in preventing nosocomial infections. However, some issues remain, including low positivity rate, cost, and time required for testing. We describe SARS-CoV-2 reverse transcription polymerase chain reaction (PCR) for universal screening in asymptomatic patients on planned admissions. In total, 14,574 patients were included between October 12, 2020, and June 23, 2022. The PCR-positive rate for the period was 0.44 % (64/14,574). The PCR positivity for the epidemic period by strain was 0.28 % (95 % confidence interval [CI] 0.12-0.56 %), 0.16 % (95 % CI 0.05-0.37 %), 0.21 % (95 % CI 0.09-0.41 %), and 0.9 % (95 % CI 0.65-1.2 %) for the wild-type strain, Alpha, Delta, and Omicron variants, respectively. The proportion of Ct values < 30 was higher in the first half of the epidemic (first vs. second, 29.4 % [95 % CI 16.9-44.8 %] vs. 16.7 % [95 % CI 6.0-28.5 %]), whereas that of Ct values ≥ 35 increased significantly in the second half (first vs. second, 32.4 % [95 % CI 19.3-47.8 %] vs. 70.0 % [95 % CI 53.5-83.4 %]). Of all positives, 50 % (32/64) had a coronavirus disease (COVID-19) history before PCR screening, with a median of 28 days (10-105) from COVID-19 onset or positive to PCR screening. PCR screening may help detect positives with high viral loads early in the epidemic for each mutant strain, with an increasing proportion of positives with low viral loads later in the epidemic. PCR testing may be unnecessary for recently diagnosed cases and patients in whom reinfection is unlikely.
Asunto(s)
Infecciones Asintomáticas , Prueba de Ácido Nucleico para COVID-19 , COVID-19 , Tamizaje Masivo , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/virología , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , Tamizaje Masivo/métodos , Persona de Mediana Edad , Masculino , Prueba de Ácido Nucleico para COVID-19/métodos , Prueba de Ácido Nucleico para COVID-19/estadística & datos numéricos , Femenino , Infecciones Asintomáticas/epidemiología , Adulto , Anciano , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Anciano de 80 o más AñosRESUMEN
What is this summary about? This is a plain language summary of a clinical research study. The study was looking the effects of a drug called anamorelin for Japanese people with advanced non-small cell lung cancer (often shortened to NSCLC) who also had a condition called cachexia. People with cachexia have a loss of appetite, severe weight loss, loss of body fat and loss of muscle mass (called muscle wasting). Cachexia is common in many chronic (long term) diseases, such as cancer and can lead to a decrease in a person's ability to do everyday tasks (called functional strength). Cachexia can negatively affect a person's quality of life and increases the risk of serious side effects during chemotherapy.Anamorelin is a drug that has been shown in previous research studies to improve appetite and increase lean body mass (the total weight of the body, not counting fat) and overall body weight. In this study, participants were given anamorelin (100 mg daily) for 12 weeks.What did the researchers find out? Participants who took anamorelin had an increase in their lean body mass and body weight, and had an improvement in their appetite. Their overall body condition improved but no improvement was seen in how well their muscles worked.The researchers found that anamorelin did not cause a large number of significant or severe side effects.What do the results mean? The study showed that anamorelin can help people with advanced NSCLC and cachexia to substantially increase their lean body mass, improve their nutritional status, and increase their appetite. Since January 2021, anamorelin for cachexia has been approved for use in Japanese people with NSCLC.
RESUMEN
What is this summary about? This is a plain language summary of a clinical research study. The study investigated the effects of a drug called anamorelin for people in Japan with advanced gastrointestinal cancer (colon, rectum, stomach or pancreas) who also had a condition called cachexia.People with cachexia have a loss of appetite, severe weight loss, loss of body fat, and loss of muscle. Anamorelin has been shown in previous research studies to improve appetite and increase lean body mass (the total weight of the body, not counting fat) and overall body weight. In this study, participants were given anamorelin (100 mg daily) for 12 weeks.What did the researchers find out? 31 out of 49 participants (63%) had an increase in their lean body mass, with an average increase of almost 2 kg, which was seen from week 3 of the study. Participants also experienced an improvement in their appetite and overall body weight. The researchers found that anamorelin did not cause a large number of serious side effects.What do the results mean? This study found that anamorelin can help people with advanced gastrointestinal cancer and cachexia to increase their lean body mass and overall body weight, regain their appetite and improve their nutritional status. Since this study was done, the use of anamorelin for cachexia in people with gastrointestinal cancer has been approved for use in Japan.
RESUMEN
BACKGROUND: Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. METHODS: This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. RESULTS: This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). CONCLUSION: The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.
Asunto(s)
Caquexia , Hidrazinas , Neoplasias , Vigilancia de Productos Comercializados , Humanos , Caquexia/tratamiento farmacológico , Caquexia/etiología , Masculino , Femenino , Anciano , Estudios Prospectivos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Japón , Persona de Mediana Edad , Hiperglucemia/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Oligopéptidos/efectos adversos , Resultado del Tratamiento , Adulto , Apetito/efectos de los fármacosRESUMEN
BACKGROUND: Combination therapy with docetaxel (DTX) and ramucirumab (RAM) has been used as a second-line treatment for advanced or recurrent lung cancer. However, there is insufficient evidence regarding the safety of angiogenesis inhibitors in older patients. OBJECTIVE: This multicenter retrospective study aimed to investigate the efficacy and safety of second-line treatment regimens in older patients with advanced or recurrent non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively analyzed 145 patients aged ≥ 70 years with advanced or recurrent NSCLC treated with second-line chemotherapy after platinum-based therapy between April 1, 2016, and March 31, 2021. Patients were subdivided into the DTX + RAM (n = 38) and single-agent (n = 107) groups. RESULTS: The median time to treatment failure was 6.3 months (95% confidence interval [CI] 3.6-9.6) in the DTX + RAM group and 2.3 months (95% CI 1.7-3.0) in the single-agent group (p < 0.01). The median overall survival was 15.9 months (95% CI 12.3-Not Achieved) in the DTX + RAM group and 9.4 months (95% CI 6.9-15.1) in the single-agent group (p = 0.01). Grade ≥ 3 adverse events frequency was not significantly different between the two groups, except for edema. Patients in the DTX + RAM group who did not discontinue treatment owing to adverse events exhibited the most favorable prognosis. CONCLUSIONS: These findings suggest that the DTX + RAM combination is an effective second-line therapy for older patients with advanced or recurrent NSCLC, offering favorable efficacy without treatment discontinuation owing to adverse events.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Docetaxel , Neoplasias Pulmonares , Ramucirumab , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Docetaxel/uso terapéutico , Docetaxel/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Masculino , Anciano , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Anciano de 80 o más Años , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
BACKGROUND: In advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations, those with impaired performance status (PS) treated with EGFR-tyrosine kinase inhibitors (TKIs) have demonstrated comparable activities to good-PS patients. Due to the limited sample size and inclusion of older adult patients with good PS, these findings may not accurately depict the efficacy of EGFR-TKI in poor-PS patients. We investigated the benefit of EGFR-TKIs in this population and identified relevant prognostic factors. PATIENTS AND METHODS: This nationwide prospective registry study included 9872 patients with local or advanced NSCLC. Outcomes were compared between poor- and good-PS patients treated with EGFR-mutated lung cancer therapies. RESULTS: Of 9872 NSCLC patients, 1965 (19.9%) had EGFR mutations, with 1846 (93.9%) presenting common EGFR mutations. Poor PS (PS score ≥ 3) was noted in 171 patients (8.7%) and identified as an independent prognostic factor; those with poor PS had a significantly lower 1-year survival rate. The median overall survival (OS) for EGFR-TKI-treated good-PS patients was 31.5 (95% confidence interval, 29.6-33.4) months. Among poor-PS patients with EGFR mutations, 135 (78.9%) of whom were treated with EGFR-TKI had an OS of 15.5 (12.7-18.3) months, while those receiving only supportive care had an OS of 2.5 (1.4-3.6) months (P < .001). Hypoalbuminemia (< 3.5 g/dL), liver metastasis, and uncommon EGFR mutations were associated with poor prognosis. CONCLUSION: Poor PS at diagnosis was rare and associated with limited EGFR-TKI efficacy and a dismal prognosis. Liver metastasis and hypoalbuminemia may reduce EGFR-TKI efficacy in these patients.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Sistema de Registros , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Femenino , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Persona de Mediana Edad , Japón , Pronóstico , Estudios Prospectivos , Anciano de 80 o más Años , Adulto , Tasa de Supervivencia , Metástasis de la Neoplasia , Pueblos del Este de AsiaRESUMEN
Although the coronavirus disease 2019 (COVID-19) pandemic is coming to an end, it still poses a threat to the immunocompromised and others with underlying diseases. Especially in cases of persistent COVID-19, new mutations conferring resistance to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapies have considerable clinical implications. We present a patient who independently acquired a T21I mutation in the 3CL protease after nirmatrelvir exposure. The T21I mutation in the 3CL protease is one of the most frequent mutations responsible for nirmatrelvir resistance. However, limited reports exist on actual cases of SARS-CoV-2 with T21I and other mutations in the 3CL protease. The patient, a 55 year-old male, had COVID-19 during chemotherapy for multiple myeloma. He was treated with nirmatrelvir early in the course of the disease but relapsed, and SARS-CoV-2 with a T21I mutation in the 3CL protease was detected in nasopharyngeal swab fluid. The patient had temporary respiratory failure but later recovered well. During treatment with remdesivir and dexamethasone, viruses with the T21I mutation in the 3CL protease showed a decreasing trend during disease progression while increasing during improvement. The impact of drug-resistant SARS-CoV-2 on the clinical course, including its severity, remains unknown. Our study is important for examining the clinical impact of nirmatrelvir resistance in COVID-19.
Asunto(s)
Antivirales , COVID-19 , Farmacorresistencia Viral , Huésped Inmunocomprometido , SARS-CoV-2 , Humanos , Persona de Mediana Edad , Masculino , SARS-CoV-2/genética , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Farmacorresistencia Viral/genética , Antivirales/uso terapéutico , Antivirales/farmacología , COVID-19/inmunología , COVID-19/virología , Mutación , Mieloma Múltiple/tratamiento farmacológico , Proteasas 3C de Coronavirus/genética , Tratamiento Farmacológico de COVID-19 , Alanina/análogos & derivados , Alanina/uso terapéuticoRESUMEN
We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.
Asunto(s)
Acrilamidas , Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Tirosina Quinasa del Receptor Axl , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas , Pirimidinas , Proteínas Tirosina Quinasas Receptoras , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Ensayos Antitumor por Modelo de Xenoinjerto , Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Línea Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pirimidinas/farmacología , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones , Apoptosis/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/administración & dosificación , Femenino , Ratones Endogámicos BALB C , Supervivencia Celular/efectos de los fármacos , Piperazinas/farmacología , Benzocicloheptenos , Indoles , TriazolesRESUMEN
BACKGROUND: Advances in anticancer drugs for lung cancer (LC) have improved the prognosis of LC. Chronic pulmonary aspergillosis (CPA) is a progressive and often exacerbating respiratory disease with a poor prognosis. To date, the prognosis of LC complicated by CPA has not been elucidated. This study investigated the clinical implications of concomitant CPA in patients with LC undergoing anticancer drug treatment. METHODS: Between January 2010 and May 2020, we consecutively enrolled patients with LC complicated with CPA at five different institutions in Japan. We analyzed patients with LC complicated by CPA who received anticancer drug treatment. RESULTS: A total of 10 patients with LC complicated by CPA received anticancer drug treatment. The median overall survival (OS) was 14.57 months (95% confidence interval [CI]: 5.37-21.67). The cause of death in all patients was LC. Six of the seven patients with LC did not show worsening pulmonary aspergillosis lesions during the anticancer drug treatment. Although two patients discontinued anticancer drug treatment due to pneumonitis, CPA complications did not interfere with the continuation of anticancer drug treatment. In univariate analyses, squamous histology (p = 0.01) and body mass index (<18.5 kg/m2) (p = 0.0008) were significantly associated with poorer OS. CONCLUSIONS: This study demonstrated that the cause of death in LC patients with concomitant CPA who received anticancer drug treatments and effective antifungal treatment was LC progression. Further large-scale studies are needed to identify the effect of CPA in patients with LC.
RESUMEN
With the spread of resistance to long-established insecticides targeting Anopheles malaria vectors, understanding the actions of compounds newly identified for vector control is essential. With new commercial vector-control products containing neonicotinoids under development, we investigate the actions of 6 neonicotinoids (imidacloprid, thiacloprid, clothianidin, dinotefuran, nitenpyram and acetamiprid) on 13 Anopheles gambiae nicotinic acetylcholine receptor (nAChR) subtypes produced by expression of combinations of the Agα1, Agα2, Agα3, Agα8 and Agß1 subunits in Xenopus laevis oocytes, the Drosophila melanogaster orthologues of which we have previously shown to be important in neonicotinoid actions. The presence of the Agα2 subunit reduces neonicotinoid affinity for the mosquito nAChRs, whereas the Agα3 subunit increases it. Crystal structures of the acetylcholine binding protein (AChBP), an established surrogate for the ligand-binding domain, with dinotefuran bound, shows a unique target site interaction through hydrogen bond formation and CH-N interaction at the tetrahydrofuran ring. This is of interest as dinotefuran is also under trial as the toxic element in baited traps. Multiple regression analyses show a correlation between the efficacy of neonicotinoids for the Agα1/Agα2/Agα8/Agß1 nAChR, their hydrophobicity and their rate of knockdown of adult female An. gambiae, providing new insights into neonicotinoid features important for malaria vector control.
Asunto(s)
Anopheles , Guanidinas , Insecticidas , Mosquitos Vectores , Neonicotinoides , Nitrocompuestos , Receptores Nicotínicos , Animales , Anopheles/metabolismo , Anopheles/genética , Anopheles/efectos de los fármacos , Neonicotinoides/farmacología , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/química , Insecticidas/farmacología , Insecticidas/química , Nitrocompuestos/farmacología , Nitrocompuestos/química , Guanidinas/farmacología , Mosquitos Vectores/efectos de los fármacos , Mosquitos Vectores/genética , Xenopus laevis , Ligandos , Piridinas/farmacología , Malaria/transmisión , Malaria/parasitología , Tiazoles/farmacología , Tiazoles/química , Tiazoles/metabolismo , Tiazinas/farmacología , Tiazinas/química , Oocitos/metabolismo , Oocitos/efectos de los fármacos , Femenino , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Proteínas de Insectos/química , Imidazoles/farmacología , Imidazoles/químicaRESUMEN
Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.
Asunto(s)
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/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal , Apoptosis , Respuesta Patológica Completa , MutaciónRESUMEN
Introduction: Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1-predictive markers for response to various immune checkpoint inhibitors in NSCLC-have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear. Methods: In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients. Results: The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival. Conclusions: In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.
RESUMEN
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: The efficacy of second-line immune checkpoint inhibitor (ICI) therapy is limited in non-small cell lung cancer (NSCLC) patients with ≤ 49% PD-L1 expression. Although chemoimmunotherapy is a promising strategy, platinum-based chemotherapy followed by ICI monotherapy is often used to avoid synergistic adverse events. However, predictors of the efficacy of ICI monotherapy after platinum-based chemotherapy in NSCLC with ≤ 49% PD-L1 expression remain scarce. Methods: This multicenter retrospective study evaluated 54 advanced or recurrent NSCLC patients with ≤ 49% PD-L1 expression who were treated with second-line ICI monotherapy following disease progression on first-line platinum-based chemotherapy at nine hospitals in Japan. The impact of response to platinum-based chemotherapy on the efficacy of subsequent ICI monotherapy was investigated. Results: The response to first-line platinum-based chemotherapy was divided into two groups: the non-progressive disease (PD) group, which included patients who did not experience disease progression after four cycles of chemotherapy, and the PD group, which included patients who showed initial PD or could not maintain disease control during the four cycles of chemotherapy and switched to second-line ICI monotherapy. Among the 54 patients, 32 and 22 were classified into the non-PD and PD groups, respectively. The non-PD group showed better response rates (p = 0.038) and longer overall survival (OS) with ICI monotherapy (p = 0.023) than the PD group. Multivariate analysis identified that maintaining a non-PD status after four cycles of chemotherapy was an independent prognostic factor for ICI monotherapy (p = 0.046). Moreover, patients with a modified Glasgow Prognostic Score (mGPS) of 0 showed a tendency for longer OS with ICI monotherapy (p = 0.079), and there was a significant correlation between maintaining non-PD after four cycles of chemotherapy and an mGPS of 0 (p = 0.045). Conclusion: Maintaining a non-PD status after four cycles of platinum-based chemotherapy was a predictor of OS after second-line ICI monotherapy. These findings will help physicians select the most suitable treatment option for NSCLC patients who were treated with platinum-based chemotherapy and switched to second-line treatment. Those who experienced early PD during platinum-based chemotherapy should not be treated with ICI monotherapy in the second-line setting.