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BACKGROUND: The risk and survival of patients with non-small cell lung cancer (NSCLC) with pre-existing autoimmune disorders (AIDs) receiving immune checkpoint blockade (ICB) therapy have not been clearly established. PATIENTS AND METHODS: This multi-institutional, retrospective cohort study was conducted in collaboration with 20 centers in Japan. RESULTS: In total, 229 patients with advanced or recurrent NSCLC and pre-existing AID, with or without ICB treatment from January 2010-February 2020, were included and analyzed. Among 69 patients who received ICB, 2 received two lines of ICBs with a total of 71 ICB treatments; 57 (80.3 %) and 14 (19.7 %) patients received ICB monotherapy and combination therapy, respectively. AID flares were observed in 18 patients (25.4 %, 95 % confidence interval [CI], 15.8-37.1 %) receiving ICB. AID exacerbations were more likely when NSCLC was diagnosed less than 1 year after the AID diagnosis (odds ratio 5.26 [95 % CI, 1.40-21.61]; P = 0.016). Immune-related adverse events were observed in 32 patients (45.1 %, 95 % CI, 33.2-57.3 %); 17 had grade 3 or higher. The safety profile of combination immunotherapy was not significantly different from that of the monotherapy. After inverse probability weighting, the use of ICB prolonged survival (hazard ratio 0.43 [95 % CI, 0.26-0.70]; P = 0.0006). CONCLUSIONS: These findings revealed a novel risk factor for AID flares following ICB treatment, that is the diagnosis of NSCLC within 1 year of AID diagnosis, and showed that ICBs may improve survival in this population. These results support the utilization of ICB in patients with NSCLC and pre-existing AID.
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Enfermedades Autoinmunes , Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Estudios Retrospectivos , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Anciano , Enfermedades Autoinmunes/mortalidad , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/complicaciones , Persona de Mediana Edad , Análisis de Supervivencia , Japón/epidemiología , Anciano de 80 o más Años , Tasa de Supervivencia , AdultoRESUMEN
Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.
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Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.
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BACKGROUND/AIM: Osimertinib is currently used as a first-line treatment for EGFR-mutated non-small cell lung cancer, and the emergence of drug resistance poses a substantial challenge. Liquid biopsy with a multi-gene panel can examine both the molecular mechanisms and possibility of early resistance diagnosis. PATIENTS AND METHODS: We used a molecular barcode library construction kit (Archer® LiquidPlex™) that allowed the analysis of multiple cancer-related genes using cell-free DNA from the plasma samples of patients. We collected plasma from 17 consecutive patients with lung adenocarcinoma at our hospital at various time points and cell-free DNA was extracted and subjected to LiquidPlex analysis. RESULTS: Plasma DNA concentration was not associated with the presence or absence of resistance to osimertinib. The pathological mutations detected using next-generation sequencing in the resistant specimens were in MAP2K1, PIK3CA, TP53, BRAF, and EGFR. Among the recurrent cases, EGFR mutations identified at the initial diagnosis were detected within 6 months before relapse confirmation in four cases (average 88 days). Many of the recurrent cases without detection of known EGFR mutations in the liquid biopsy showed a longer interval between the detection of relapse and the last blood draw for the liquid biopsy (average 255 days). CONCLUSION: Frequent liquid biopsies are useful for identifying known EGFR mutations as markers for early detection of relapse. Several cancer driver mutations were observed, suggesting a variety of mechanisms of resistance in first-line osimertinib-treated lung adenocarcinoma.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Recurrencia Local de Neoplasia , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Biopsia Líquida , Recurrencia , Receptores ErbB/genéticaRESUMEN
Osimertinib is a standard treatment for patients with EGFR-mutated non-small cell lung carcinoma (NSCLC). We evaluated the relationship between plasma osimertinib concentrations and treatment outcome in patients with NSCLC for this cohort study. The plasma levels of osimertinib and its metabolite AZ5104 were measured a week after the start of treatment (P1). The primary endpoint was to evaluate the correlation between plasma concentration and adverse events (AEs). The correlation with treatment efficacy was one of the secondary endpoints. In patients with CNS metastases, the concentration in the cerebrospinal fluid was also measured. Forty-one patients were enrolled. The frequency of AEs was highest for rash, followed by anorexia and thrombocytopenia. Thirty-eight cases provided measurements for P1. The median plasma concentration of osimertinib was 227 ng/mL, and that of AZ5104 was 16.5 ng/mL. The mean CNS penetration rate of two cases was 3.8%. The P1 in the group with anorexia was significantly higher than that in the group without anorexia (385.0 ng/mL vs. 231.5 ng/mL, p = 0.009). Divided into quartiles by P1 trough level, Q2 + Q3 (164-338 ng/mL) had longer PFS, while Q1 and Q4 had shorter PFS. An appropriate plasma level of osimertinib may avoid some adverse events and induce long PFS. Further large-scale trials are warranted.
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BACKGROUND: Osimertinib was first approved for the treatment of non-small cell lung cancer (NSCLC) in patients who have developed the epidermal growth factor receptor (EGFR) T790M mutation after treatment with EGFR tyrosine kinase inhibitors (TKIs). We routinely evaluated the plasma of NSCLC patients with the T790M mutation to more rapidly detect an increase in disease activity and resistance to treatment. METHODS: Eligible patients received osimertinib after resistance to the first- or second-generation of EGFR-TKIs in NSCLC harboring T790M mutation detectable in tumor tissue or plasma. Plasma samples were collected every 8 weeks during osimertinib treatment. The plasma analysis was performed using an improved PNA-LNA PCR clamp method. We tested samples for a resistance mechanism, including EGFR-activating, T790M, and C797S mutations, and assessed the association between the mutations and osimertinib treatment. RESULTS: Of the 60 patients enrolled in the study, 58 were eligible for this analysis. In plasma collected before osimertinib treatment, activating mutations were detected in 47 of 58 patients (81.0%) and T790M was detected in 44 patients (75.9%). Activating mutations were cleared in 60.9% (28/46) and T790M was cleared in 93.0% (40/43). Of these, 71.4% (20/28) of activating mutations and 87.5% (35/40) of T790M mutation were cleared within 8 weeks of treatment. The total response rate (RR) was 53.4% (31/58). The median duration of treatment was 259 days, with a trend toward longer treatment duration in patients who experienced the clearance of activating mutations with osimertinib. At the time of disease progression during osimertinib treatment, C797S was detected in 3 of 37 patients (8.1%). CONCLUSION: Plasma EGFR mutation analysis was effective in predicting the effect of osimertinib treatment.
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Teleost oocytes are surrounded by a structure called chorion or egg envelopes, which is composed of zona pellucida (ZP) proteins. As a result of the gene duplication in teleost, the expression site of the zp genes, coding the major component protein of egg envelopes, changed from the ovary to the maternal liver. In Euteleostei, there are three liver-expressed zp genes, named choriogenin (chg) h, chg hm, and chg l, and the composition of the egg envelope is mostly made up of these Chgs. In addition, ovary-expressed zp genes are also conserved in the medaka genomes, and their proteins have also been found to be minor components of the egg envelopes. However, the specific role of liver-expressed versus ovary-expressed zp genes was unclear. In the present study, we showed that ovary-synthesized ZP proteins first form the base layer of the egg envelope and then Chgs polymerize inwardly to thicken the egg envelope. To analyze the effects of dysfunction of the chg gene, we generated some chg knockout medaka. All knockout females failed to produce normally fertilized eggs by the natural spawning. The egg envelopes lacking Chgs were significantly thinner, but layers formed by ZP proteins synthesized in the ovary were found in the thin egg envelope of knockout as well as wildtype eggs. These results suggest that the ovary-expressed zp gene is well conserved in all teleosts, including those species in which liver-derived ZP proteins are the major component, because it is essential for the initiation of egg envelope formation.
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Proteínas de Peces , Hígado , Oryzias , Ovario , Glicoproteínas de la Zona Pelúcida , Animales , Femenino , Secuencia de Aminoácidos , Hígado/metabolismo , Oryzias/genética , Oryzias/metabolismo , Ovario/anatomía & histología , Ovario/metabolismo , Zona Pelúcida/química , Zona Pelúcida/metabolismo , Glicoproteínas de la Zona Pelúcida/genética , Glicoproteínas de la Zona Pelúcida/metabolismo , Técnicas de Inactivación de Genes , Expresión Génica , Óvulo/citología , Óvulo/metabolismoRESUMEN
OBJECTIVE: Cochlear implantation (CI) for the treatment of single-sided deafness (SSD) is a relatively new treatment modality. Although comparing the effectiveness of CI and contralateral routing of signal (CROS) hearing aids (HAs) is important, very few reports on this topic exist. In this study, objective assessments and subjective assessments were conducted to determine which SSD individuals would prefer CI or CROS HAs. MATERIALS AND METHODS: Objective assessments (speech perception and sound localization) and subjective assessments (Hearing Handicap Inventory for Adults (HHIA), Abbreviated Profile of Hearing Aid Benefit (APHAB), MOS Short-Form 36-Item Health Survey version 2 (SF-36v2)) were performed on 87 SSD patients. Of the 87 SSD patients, 33 patients hoped for CROS HAs, and 17 patients hoped for CI. The CI group underwent subjective and objective assessments at 6 and 12 months postoperatively. The CROS HAs group underwent objective assessments at 1 month after wearing CROS HAs. RESULTS: After the intervention, the localization ability was significantly improved in the CI group (p < 0.05) with no significant improvement in that of the CROS HAs group (p = 0.48). No significant improvement in speech perception in noise was observed in the CROS (Signal-to-Noise ratio + 10, p = 0.08; SN + 0, p = 0.17); however, a significant improvement in the CI group was observed at 12 months postoperatively. The APHAB subscale "background noise" and SF-36v2 health concepts of role-physical, general health, vitality, role-emotional, and mental health were significantly higher in the CI group. CONCLUSION: CI was superior to CROS HAs in speech perception in terms of noise and sound localization. Patients with postlingual acute-onset hearing loss and more handicaps and a more positive view of their hearing loss possibly tend to choose CI.
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Implantación Coclear , Implantes Cocleares , Sordera , Audífonos , Pérdida Auditiva Unilateral , Pérdida Auditiva , Localización de Sonidos , Percepción del Habla , Adulto , Humanos , Estudios Prospectivos , Sordera/cirugía , Sordera/rehabilitación , Pérdida Auditiva Unilateral/cirugía , Resultado del TratamientoRESUMEN
Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.
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We conducted a multicenter phase II trial to evaluate the efficacy and safety of S-1 and irinotecan combination therapy in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Epidermal growth factor receptor-mutated non-small-cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors and platinum-based chemotherapy received 80 mg/m2 S-1 on days 1-14 and 70 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. The primary endpoint was disease control rate 8 weeks after enrollment. The secondary endpoints were progression-free survival, overall response rate, and safety. We enrolled 25 patients from five hospitals. The patients underwent a median of four cycles. The disease control rate, 8 weeks after enrollment, was 84% (95% confidence interval 63.9-95.5%). Progression-free survival and overall survival were 5.0 and 17.1 months, respectively. The overall response rate was 52.0%. Grade ≥ 3 adverse events were reported in 56.0% of patients: hematological toxicities of leukopenia (44%), neutropenia (52%), anemia (20%), thrombocytopenia (20%), and febrile neutropenia (16%). Non-hematological toxicities of grade ≥ 3 included elevated alanine aminotransferase (4%), anorexia (8%), nausea (4%), diarrhea (16%), and pulmonary embolism (4%). None developed grade 5 toxicities. Combination therapy with S-1 and irinotecan in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors and platinum-based chemotherapy demonstrated high effectiveness with tolerable toxicities. Future phase III studies are needed to evaluate the role of this treatment in such patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Supervivencia sin Enfermedad , Receptores ErbB , Humanos , Irinotecán/uso terapéutico , Japón , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized, open-label, phase III NEJ009 study, gefitinib plus chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) compared with gefitinib-alone in patients with untreated non-small-cell lung cancer harboring mutations in epidermal growth factor receptor. Herein, we report the updated survival outcome and long-term tolerability. Patients were randomly assigned to gefitinib (gefitinib 250 mg orally, once daily) and gefitinib combined with carboplatin plus pemetrexed (GCP in a 3-week cycle for six cycles followed by concurrent gefitinib and pemetrexed maintenance) groups. At the data cutoff (May 22, 2020), GCP demonstrated significantly better PFS2 (hazard ratio, 0.77; 95% CI, 0.62 to 0.97; P = .027) than gefitinib. However, the updated median OS was 38.5 months (95% CI, 31.1 to 47.1) and 49.0 months (95% CI, 41.8 to 56.7) in the gefitinib and GCP groups, respectively (hazard ratio, 0.82; 95% CI, 0.64 to 1.06; P = .127). The OS in both groups was similar for the overall patient population. No severe adverse events occurred since the first report. This updated analysis revealed that the GCP regimen improved PFS and PFS2 with an acceptable safety profile compared with gefitinib-alone. GCP is more efficient than gefitinib monotherapy as a first-line treatment for non-small-cell lung cancer with epidermal growth factor receptor mutations.
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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 , Gefitinib/uso terapéutico , Pemetrexed , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptores ErbB/genética , MutaciónRESUMEN
For the evaluation of novel therapeutic agents for diabetic kidney disease (DKD), it is desirable to examine their efficacy in animal models by using the glomerular filtration rate (GFR) as an index. For this purpose, animal models that demonstrate a short-term GFR decline because of disease progression are required. Therefore, we aimed to develop such an animal model of DKD by using obese type 2 diabetic spontaneously diabetic Torii (SDT) fatty rats treated with salt loading by drinking water containing sodium chloride with or without unilateral nephrectomy. As a result, we have found that 0.3% salt loading with unilateral nephrectomy or 0.8% salt loading alone caused a rapid GFR decline, hypertension and rapid development of tubulointerstitial fibrosis. Moreover, the addition of losartan to a mixed diet suppressed the GFR decline in SDT fatty rats treated with 0.3% salt loading with unilateral nephrectomy. These results suggest that the model of SDT fatty rats treated with 0.3% salt loading and unilateral nephrectomy could be used as a hypertensive DKD model for evaluating therapeutic agents based on suppression of GFR decline.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Hipertensión , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/cirugía , Nefropatías Diabéticas/etiología , Modelos Animales de Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/complicaciones , Hipertensión/cirugía , Masculino , Nefrectomía/efectos adversos , Obesidad/complicaciones , Obesidad/cirugía , Ratas , Cloruro de Sodio , Cloruro de Sodio DietéticoRESUMEN
BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become the gold standard for EGFR-mutated non-small cell lung cancer (NSCLC) treatment. Immune checkpoint inhibitors (ICIs) have been developed for the treatment of several malignancies, including lung cancer. However, it is known that ICIs have poorer efficacy in EGFR-mutated NSCLC. METHODS: We collected data for patients with EGFR-mutated NSCLC receiving monotherapy with ICIs after EGFR-TKIs between December 2015 and March 2020 in three institutions, and retrospectively analyzed the association between patient characteristics and efficacy of ICIs. RESULTS: A total of 25 patients were included in this study. We defined responders as patients undergoing 90 days or longer of ICI treatment. Comparing characteristics between responders and non-responders, more tumors with L858R EGFR mutation were observed in responders than in non-responders (L858R: 66.7% and 25.0%, respectively, p < 0.05). There was no difference in incidence of T790M resistance mutation before ICI treatment. The PD-L1 positive rate was slightly higher in responders but not statistically significant (22.2% and 12.5%, respectively). Median duration of EGFR-TKI pretreatment was shorter in ICI responders compared with nonresponders (13.3 and 19.9 months, respectively). The survival of patients with L858R tumors was significantly longer than that of patients with exon 19 deletion (HR: 0.35, 95% CI: 0.13-0.93, p = 0.026). CONCLUSIONS: ICI treatment tends to have better efficacy in patients with L858R-mutated tumors. This study suggests that patients with L858R-mutated NSCLC are candidates for ICI treatment after EGFR-TKI treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , 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 , Receptores ErbB , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/efectos adversosAsunto(s)
COVID-19 , Virosis , Atención a la Salud , Instituciones de Salud , Humanos , Japón/epidemiología , SARS-CoV-2RESUMEN
BACKGROUND: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life. METHODS: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47). INTERPRETATION: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression. FUNDING: Chugai Pharmaceutical.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , 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 , Supervivencia sin Enfermedad , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Humanos , Japón , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Calidad de Vida , Análisis de SupervivenciaRESUMEN
Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Transformación Celular Neoplásica/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas Receptoras/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 15/genética , Humanos , Lactamas/farmacología , Lactamas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Desnudos , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
CLN6 (Ceroid Lipofuscinosis, Neuronal, 6) is a 311-amino acid protein spanning the endoplasmic reticulum membrane. Mutations in CLN6 are linked to CLN6 disease, a hereditary neurodegenerative disorder categorized into the neuronal ceroid lipofuscinoses. CLN6 disease is an autosomal recessive disorder and individuals affected with this disease have two identical (homozygous) or two distinct (compound heterozygous) CLN6 mutant alleles. Little has been known about CLN6's physiological roles and the disease mechanism. We recently found that CLN6 prevents protein aggregate formation, pointing to impaired CLN6's anti-aggregate activity as a cause for the disease. To comprehensively understand the pathomechanism, overall anti-aggregate activity derived from two different CLN6 mutants needs to be investigated, considering patients compound heterozygous for CLN6 alleles. We focused on mutant combinations involving the S132CfsX18 (132fsX) prematurely terminated protein, produced from the most frequent mutation in CLN6. The 132fsX mutant nullified anti-aggregate activity of the P299L CLN6 missense mutant but not of wild-type CLN6. Wild-type CLN6's resistance to the 132fsX mutant was abolished by replacement of amino acids 297-301, including Pro297 and Pro299, with five alanine residues. Given that removal of CLN6's C-terminal fifteen amino acids 297-311 (luminal tail) did not affect the resistance, we suggested that CLN6's luminal tail, when unleashed from Pro297/299-mediated conformational constraints, is improperly positioned by the 132fsX mutant, thereby blocking the induction of anti- aggregate activity. We here reveal a novel mechanism for dissipating CLN6 mutants' residual functions, providing an explanation for the compound heterozygosity-driven pathogenesis.
Asunto(s)
Lipofuscinosis Ceroideas Neuronales , Retículo Endoplásmico , Humanos , Proteínas de la Membrana/genética , Mutación , Lipofuscinosis Ceroideas Neuronales/genéticaRESUMEN
BACKGROUND: Osimertinib is now a standard treatment for patients with previously untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC). We here investigated whether the combination of osimertinib with cytotoxic chemotherapy might hold additive efficacy, as well as tolerability. PATIENTS AND METHODS: We conducted an open-label randomised phase 2 study to evaluate osimertinib and carboplatin-pemetrexed combination in comparison with osimertinib monotherapy in EGFR mutation-positive NSCLC patients who experienced disease progression associated with the emergence of the T790M resistance mutation of EGFR during first-line EGFR-TKI therapy. The primary endpoint was PFS, with secondary endpoints, including OS, response, and safety. Given that osimertinib was approved as a first-line treatment during the study, patient accrual was discontinued, and a final analysis was performed for the 62 enrolled patients. RESULTS: Median PFS was 15.8 months for the osimertinib monotherapy group and 14.6 months for the combination therapy group (hazard ratio of 1.09, with a 95% confidence interval of 0.51-2.32; P = .83). Median OS was not reached in either group. The overall response rate was 71.4% in the osimertinib monotherapy group and 53.6% in the combination group. The frequency or severity of known adverse events in the combination group was comparable to those with carboplatin and pemetrexed previously reported, and novel adverse events were not observed in this study. CONCLUSION: This is the first randomised study to investigate the efficacy and safety of the combination of osimertinib and cytotoxic chemotherapy for EGFR-mutated NSCLC. The addition of chemotherapy to osimertinib as a second-line treatment did not prolong survival, while it was found to be generally tolerable. This combination strategy will be further validated in the first-line setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) identifier: jRCTs071180062.