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Background: Apolipoprotein B mRNA editing catalytic polypeptide (APOBEC), an endogenous mutator, induces DNA damage and activates the ataxia telangiectasia and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) pathway. Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer (MIBC), it has a poor survival rate. Therefore, this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B (APOBEC3B) expressing MIBC. Methods: Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC. The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis. Western blot analysis was performed to confirm differences in phosphorylated Chk1 (pChk1) expression according to the APOBEC3B expression. Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin. Conclusion: There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC. Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels. Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression. Compared to cisplatin single treatment, combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression. Conclusion: Our study shows that APOBEC3B's higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition. This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.
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Protéines mutées dans l'ataxie-télangiectasie , Cisplatine , Cytidine deaminase , Antigènes mineurs d'histocompatibilité , Tumeurs de la vessie urinaire , Humains , Tumeurs de la vessie urinaire/traitement médicamenteux , Tumeurs de la vessie urinaire/anatomopathologie , Tumeurs de la vessie urinaire/génétique , Tumeurs de la vessie urinaire/métabolisme , Protéines mutées dans l'ataxie-télangiectasie/métabolisme , Protéines mutées dans l'ataxie-télangiectasie/antagonistes et inhibiteurs , Cisplatine/pharmacologie , Cisplatine/usage thérapeutique , Cytidine deaminase/génétique , Cytidine deaminase/métabolisme , Lignée cellulaire tumorale , Mâle , Antigènes mineurs d'histocompatibilité/métabolisme , Antigènes mineurs d'histocompatibilité/génétique , Adulte d'âge moyen , Femelle , Checkpoint kinase 1/métabolisme , Checkpoint kinase 1/antagonistes et inhibiteurs , Checkpoint kinase 1/génétique , Apoptose , Sujet âgé , Invasion tumorale , Prolifération cellulaire , Survie cellulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
PURPOSE: In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. MATERIALS AND METHODS: We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). RESULTS: A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm. CONCLUSION: To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.
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Anticorps monoclonaux humanisés , Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Humains , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Bévacizumab , Carboplatine , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Antigène CD274/usage thérapeutique , Pémétrexed/usage thérapeutique , Récepteurs ErbB/génétique , Récepteurs à activité tyrosine kinase/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirablesRÉSUMÉ
PURPOSE: This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment-related AEs occurred with lazertinib than gefitinib. CONCLUSION: Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.
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Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Morpholines , Pyrazoles , Pyrimidines , Humains , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Géfitinib/usage thérapeutique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Quinazolines , Récepteurs ErbB/génétique , Récepteurs ErbB/métabolisme , République de Corée , Mutation , Inhibiteurs de protéines kinases/effets indésirablesRÉSUMÉ
The role of upfront primary tumor resection (PTR) in patients with unresectable metastatic colorectal cancer without severe symptoms remains controversial. We retrospectively analyzed the role of PTR in overall survival (OS) in this population. Among the 205 patients who enrolled, the PTR group (n = 42) showed better performance (p = 0.061), had higher frequencies of right-sided origin (p = 0.058), the T4 stage (p = 0.003), the M1a stage (p = 0.012), and <2 organ metastases (p = 0.002), and received fewer targeted agents (p = 0.011) than the chemotherapy group (n = 163). The PTR group showed a trend for longer OS (20.5 versus 16.0 months, p = 0.064) but was not related to OS in Cox regression multivariate analysis (p = 0.220). The male sex (p = 0.061), a good performance status (p = 0.078), the T3 stage (p = 0.060), the M1a stage (p = 0.042), <2 organ metastases (p = 0.035), an RAS wild tumor (p = 0.054), and the administration of targeted agents (p = 0.037), especially bevacizumab (p = 0.067), seemed to be related to PTR benefits. Upfront PTR could be considered beneficial in some subgroups, but these findings require larger studies to verify.
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INTRODUCTION: Increased DNA damage triggered through poly (ADP-ribose) polymerase inhibition may modify tumor immunogenicity, sensitizing tumors to immunotherapy. ORION (NCT03775486) evaluated the combination of olaparib with durvalumab as maintenance therapy in patients with metastatic NSCLC. METHODS: ORION is a phase 2, randomized, multicenter, double-blind, international study. Patients with metastatic NSCLC (without activating EGFR or ALK aberrations) and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to receive initial therapy with durvalumab (1500 mg intravenously; every 3 wk) plus platinum-based chemotherapy for four cycles. Patients without disease progression were then randomized (1:1) to maintenance durvalumab (1500 mg; every 4 wk) plus either olaparib (300 mg orally) or placebo (both twice daily); randomization was stratified by objective response during initial therapy and tumor histologic type. The primary end point was investigator-assessed progression-free survival (PFS) (Response Evaluation Criteria in Solid Tumors version 1.1). RESULTS: Between January 2019 and February 2020, 269 of 401 patients who received initial therapy were randomized. As of January 11, 2021 (median follow-up: 9.6 mo), median PFS was 7.2 months (95% confidence interval: 5.3-7.9) with durvalumab plus olaparib versus 5.3 months (3.7-5.8) with durvalumab plus placebo (hazard ratio = 0.76, 95% confidence interval: 0.57-1.02, p = 0.074). Safety findings were consistent with the known profiles of durvalumab and olaparib. Anemia was the most common adverse event (AE) with durvalumab plus olaparib (26.1% versus 8.2% with durvalumab plus placebo). The incidence of grade 3 or 4 AEs (34.3% versus 17.9%) and AEs leading to treatment discontinuation (10.4% versus 4.5%) was numerically higher with durvalumab plus olaparib versus durvalumab plus placebo. CONCLUSIONS: Maintenance therapy with durvalumab in combination with olaparib was not associated with a statistically significant improvement in PFS versus durvalumab alone, although numerical improvement was observed.
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Protocoles de polychimiothérapie antinéoplasique , Tumeurs du poumon , Humains , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Tumeurs du poumon/étiologie , Anticorps monoclonaux/effets indésirables , Phtalazines/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Salivary duct carcinoma (SDC) is uncommon but is the most aggressive subtype of salivary gland carcinomas. The high positivity rate for human epidermal growth factor receptor 2 (HER2) led to an investigation of the efficacy of HER2-targeted agents. Docetaxel-PM (polymeric micelle) is a low-molecular-weight, nontoxic, biodegradable, and docetaxel-loaded micellar formulation. Trastuzumab-pkrb is a biosimilar to trastuzumab. METHODS: This was a multicenter, single-arm, open-label phase 2 study. Patients with HER2-positive (immunohistochemistry [IHC] score of ≥2+ and/or HER2/chromosome enumeration probe 17 [CEP17] ratio of ≥2.0) advanced SDCs were enrolled. Patients received docetaxel-PM (75 mg/m2 ) and trastuzumab-pkrb (8 mg/kg in the first cycle and 6 mg/kg in subsequent cycles) every 3 weeks. Primary end point was objective response rate (ORR). RESULTS: A total of 43 patients were enrolled. The best objective responses were partial response in 30 (69.8%) patients and stable disease in 10 (23.3%) patients, leading to an ORR of 69.8% (95% confidence interval [CI], 53.9-82.8) and a disease control rate of 93.0% (80.9-98.5). Median progression-free survival, duration of response, and overall survival were 7.9 (6.3-9.5), 6.7 (5.1-8.4), and 23.3 (19.9-26.7) months, respectively. Patients with HER2 IHC score of 3+ or HER2/CEP17 ratio ≥2.0 demonstrated better efficacies compared to those with HER2 IHC score of 2+. Thirty-eight (88.4%) patients experienced treatment-related adverse events (TRAE). Because of TRAE, nine (20.9%), 14 (32.6%), and 19 (44.2%) patients required temporary discontinuation, permanent discontinuation, or dose reduction, respectively. CONCLUSIONS: The combination of docetaxel-PM and trastuzumab-pkrb demonstrated promising antitumor activity with a manageable toxicity profile in HER2-positive advanced SDC. PLAIN LANGUAGE SUMMARY: Salivary duct carcinoma (SDC) is uncommon but is the most aggressive subtype of salivary gland carcinomas. SDC shares morphological and histological similarities with invasive ductal carcinoma of breast, which led to an investigation of hormonal receptor and human epidermal growth factor receptor 2 (HER2)/neu expression status in SDC. In this study, patients with HER2-positive SDC were enrolled and treated with combination of docetaxel-polymeric micelle and trastuzumab-pkrb. Promising antitumor activities were shown with objective response rate of 69.8%, disease control rate of 93.0%, median progression-free survival of 7.9 months, median duration of response of 6.7 months, and median overall survival of 23.3 months.
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Tumeurs du sein , Carcinome canalaire , Humains , Femelle , Docetaxel/usage thérapeutique , Micelles , Anticorps monoclonaux humanisés/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Trastuzumab/usage thérapeutique , Récepteur ErbB-2/génétique , Récepteur ErbB-2/métabolisme , Glandes salivaires/métabolisme , Tumeurs du sein/traitement médicamenteuxRÉSUMÉ
PURPOSE: Oxaliplatin, a component of the capecitabine plus oxaliplatin (XELOX) regimen, has a more favorable toxicity profile than cisplatin in patients with advanced gastric cancer (GC). However, oxaliplatin can induce sensory neuropathy and cumulative, dose-related toxicities. Thus, the capecitabine maintenance regimen may achieve the maximum treatment effect while reducing the cumulative neurotoxicity of oxaliplatin. This study aimed to compare the survival of patients with advanced GC between capecitabine maintenance and observation after 1st line XELOX chemotherapy. MATERIALS AND METHODS: Sixty-three patients treated with six cycles of XELOX for advanced GC in six hospitals of the Catholic University of Korea were randomized 1:1 to receive capecitabine maintenance or observation. The primary endpoint was progression-free survival (PFS), analyzed using a two-sided log-rank test stratified at a 5% significance level. RESULTS: Between 2015 and 2020, 32 and 31 patients were randomized into the maintenance and observation groups, respectively. After randomization, the median number of capecitabine maintenance cycles was 6. The PFS was significantly higher in the maintenance group than the observation group (6.3 vs. 4.1 months, P=0.010). Overall survival was not significantly different between the 2 groups (18.2 vs. 16.5 months, P=0.624). Toxicities, such as hand-foot syndrome, were reported in some maintenance group patients. Maintenance treatment was a significant factor associated with PFS in multivariate analysis (hazard ratio, 0.472; 95% confidence interval, 0.250-0.890; P=0.020). CONCLUSIONS: After 6 cycles of XELOX chemotherapy, capecitabine maintenance significantly prolonged PFS compared with observation, and toxicity was manageable. Maintenance treatment was a significant prognostic factor associated with PFS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02289547.
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BACKGROUND: Factors involved in inflammation and cancer interact in various ways with each other, and biomarkers of systemic inflammation may have a prognostic value in cancer. Glucose transporter 1 (GLUT1) plays a pivotal role in glucose transport and metabolism and it is aberrantly expressed in various cancer types. We evaluated the differential expression of GLUT1, along with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in non-small-cell lung cancer (NSCLC), and then analyzed their prognostic significance. METHODS: A total of 163 patients with resectable NSCLC were included in this study. Tumor sections were immunohistochemically stained for GLUT1 and GLUT3. Maximum standardized uptake value (SUVmax) was measured by preoperative FDG-PET, and neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) were derived from pretreatment blood count. RESULTS: GLUT1 and GLUT3 was positively expressed in 74.8% and 6.1% of the NSCLC tissues, respectively. GLUT1 expression was significantly correlated with squamous cell carcinoma histology, poor differentiation, high pathologic stage, old age, male, smoking, and high SUVmax (>7) (all p < 0.05). The squamous cell carcinoma and smoker group also showed significantly higher SUVmax (both p < 0.001). Systemic inflammation markers, including NLR, PLR, and LMR, were positively correlated with high SUVmax (all p < 0.05). High GLUT1 expression, high SUVmax, high NLR, and low LMR, were significantly associated with poor overall survival in patients with NSCLC. However, in the multivariate survival analysis, LMR was an independent prognostic factor overall (HR 1.86, 95% CI 1.05-3.3) and for the stage I/II cohort (HR 2.3, 95% CI 1.24-4.3) (all p < 0.05). CONCLUSIONS: Systemic inflammatory markers-NLR, PLR, and LMR are strongly correlated with the SUVmax and are indicators of aggressive tumor behavior. Specifically, LMR is a promising prognostic biomarker in NSCLC patients.
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Background: The clinical utility of plasma tumor mutational burden (pTMB) requires further validation. Herein, the pTMB and genetic alterations were investigated as predictive biomarkers for anti-PD-1 monotherapy outcome in metastatic non-small cell lung cancer (NSCLC). Methods: The GuardantOMNI panel (Guardant Health) was used to identify pTMB and genetic alterations. Data from 99 patients with metastatic NSCLC treated with pembrolizumab or nivolumab in first-, second-, or third-line settings between June 2016 and December 2020 were collected. Associations between pTMB and clinical benefit rate (CBR, stable disease ⩾6 months or partial response), progression-free survival (PFS), and overall survival (OS) were assessed. Results: Median pTMB in 84 patients was 10.8 mutations/megabase (mut/Mb). Histological analyses revealed that 61 and 36% of the patients had adenocarcinomas and squamous NSCLC, respectively. Most patients were treated with nivolumab (74%) and most anti-PD-1 agents were administered as second-line treatment (70%). The median follow-up duration was of 10.9 months (range, 0.2-40.7). Patients with high pTMB (⩾19 mut/Mb) had a higher CBR (69%) compared with low pTMB patients (33%; p = 0.01). ARID1A (p = 0.007) and either ERBB2 or KIT mutations (p = 0.012) were positive and negative determinants, respectively, for clinical benefit. Multivariate analysis further showed that high pTMB was an independent predictive biomarker for both PFS [hazard ratio (HR) = 0.44, 95% confidence interval (CI): 0.22-0.88, p = 0.02] and OS (HR = 0.37, 95% CI: 0.18-0.76, p = 0.007). Conclusion: High pTMB (⩾19 mut/Mb) is significantly associated with CBR in patients with NSCLC treated with anti-PD-1 agents.
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Studies have been actively conducted to identify actionable mutations and incorporate them into clinical practice in pancreatic ductal adenocarcinoma (PDAC), which is known to have a poor prognosis with traditional cytotoxic chemotherapy. A BRAF point mutation in V600E is commonly reported in KRAS wild-type PDAC, and targeting BRAF_V600E is already being applied to various carcinomas, including PDAC. Accumulated evidence also shows that not only BRAF_V600E but also short in-frame deletions of BRAF have an oncogenic function. Here, we report that a patient with BRAF N486_P490 deletion initiated on dabrafenib or trametinib, a BRAF inhibitor, and a MEK inhibitor, respectively, after cytotoxic chemotherapy failure. The patient then presented with a partial response.
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Purpose: This regulatory post-marketing surveillance (PMS) study was performed to evaluate the safety and effectiveness of regorafenib on Korean patients with colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (HCC) in a real-world clinical setting. Methods: This PMS was conducted as a multi-center, prospective, observational study at 34 centers in Korea from August 2013 to August 2019. The primary objective was to evaluate the safety of regorafenib in real-world practice, with the secondary objective to investigate its effectiveness, including its overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In total, 301 patients were included in the analysis (254 patients with CRC, 14 patients with GIST, and 33 patients with HCC). The incidence rates of adverse events (AEs) were 85.0%, 78.6%, and 81.8% in patients with CRC, GIST, and HCC, respectively. The most frequent AE related to regorafenib in the three cancer types was palmar-plantar erythrodysesthesia syndrome (PPES). The ORRs of patients with CRC, GIST, and HCC were 4.7%, 0%, and 41.4%, respectively. The median PFS and OS were 2.1 and 6.1 months for CRC, respectively; 9.2 and 16.4 months for GIST, respectively; and 5.5 months and not estimated (NE) for HCC, respectively. Patients who experienced a dose modification or discontinuation of regorafenib showed significantly shorter median PFS and OS (2.2 vs. 2.6 months, respectively, P = 0.0335 for PFS; 5.3 vs. 8.5 months, respectively, P = 0.0010 for OS). Conclusion: This PMS study, which is the largest surveillance study of CRC in Korea, found no newly identified safety concerns for patients who received regorafenib in the real-world setting. Additionally, the results of this study were consisted with those previously reported in phase III trials.
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Temporal muscle thickness (TMT) has recently been suggested as a novel biomarker of sarcopenia in head and neck malignancies. However, few studies have evaluated TMT as a prognostic marker in patients with brain metastasis. This study investigated the association of TMT with overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastasis. The records of all NSCLC patients with brain metastasis between 2009 and 2018 at St. Vincent's Hospital were reviewed retrospectively. A total of 221 patients met our eligibility criteria. In the group with TMT thicker than the median, OS was longer than the group with TMT thinner than the median (240 days versus 139 days, p = 0.014). In multivariate analysis, the thicker TMT group had longer survival (HR 0.73 CI 0.56−0.96, p = 0.024). Male (HR 1.58 CI 1.19−2.09, p = 0.002) and older age (≥65 years) (HR 2.05 CI 1.53−2.74, p < 0.001) also showed statistical significance. We also performed subgroup analysis in older patients (≥65 years). In this subgroup of 107 patients, the thicker TMT group also showed longer OS than the thinner TMT group (209 days versus 82 days, p = 0.009). Our findings suggest that TMT can be a useful biomarker for OS in NSCLC patients with brain metastasis.
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Tumeurs du cerveau , Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Sujet âgé , Tumeurs du cerveau/secondaire , Carcinome pulmonaire non à petites cellules/anatomopathologie , Humains , Tumeurs du poumon/anatomopathologie , Mâle , Pronostic , Études rétrospectives , Muscle temporal/anatomopathologieRÉSUMÉ
Background: Irrespective of the first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor chosen, acquired resistance to therapy is inevitable. Therefore, a key consideration when assessing therapeutic choices is the availability of subsequent treatment options following disease progression. We assessed clinical outcomes in patients who received first-line afatinib treatment with various second-line treatments including osimertinib for patients acquiring the T790M mutation. Methods: A total of 737 EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) patients receiving first-line afatinib treatment were categorized by second-line treatment: T790M+ sequentially treated with osimertinib (cohort A, n=116); T790M- given chemotherapy or others (cohort B, n=143); patients with unknown T790M status (cohort C, n=111); and patients who were undergoing afatinib treatment at the time of data collection, were dead, had discontinued afatinib treatment due to serious adverse events or were lost to follow-up (cohort D, n=367). The primary outcomes were total time on treatment (TOT) and TOT for first-line (TOT-1) and second-line treatments (TOT-2). Secondary outcomes were objective response rates (ORR), overall survival (OS), and central nervous system (CNS) efficacy. Results: Median total TOT in cohorts A, B, C, and D were 35.10 months [95% confidence interval (CI): 30.09-43.53 months], 18.80 months (95% CI: 16.92-20.20 months), 12.00 months (95% CI: 10.22-14.98 months), and 42.60 months (95% CI: 30.95-59.23 months), respectively. The ORR of patients given afatinib was 75.7%. In patients with initial brain metastasis without local treatment, the CNS response rate was 67.0% and CNS progression-free survival was 24.70 months (95% CI: 19.84-33.15 months). Conclusions: This study showed that sequential approach of afatinib followed by second line treatment is an effective therapeutic strategy for EGFR M+ NSCLC patients.
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BACKGROUND: KEYNOTE-063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second-line therapy in Asian patients with advanced programmed death ligand 1 (PD-L1)-positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer. METHODS: This randomized, open-label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m2 of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression-free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety. RESULTS: Between February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE-061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4-10 months) with pembrolizumab versus 8 months (95% CI, 5-11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63-1.54). Median PFS was 2 months (95% CI, 1-3 months) with pembrolizumab versus 4 months (95% CI, 3-6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04-2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any-grade treatment-related adverse events occurred in 28 pembrolizumab-treated patients (60%) and 42 paclitaxel-treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively. CONCLUSIONS: Definitive conclusions about the efficacy of second-line pembrolizumab in Asian patients with advanced PD-L1-positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE-061 trial.
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Anticorps monoclonaux humanisés , Tumeurs de l'oesophage , Paclitaxel , Tumeurs de l'estomac , Anticorps monoclonaux humanisés/effets indésirables , Chine , Tumeurs de l'oesophage/traitement médicamenteux , Tumeurs de l'oesophage/anatomopathologie , Jonction oesogastrique/anatomopathologie , Humains , Paclitaxel/effets indésirables , Tumeurs de l'estomac/traitement médicamenteux , Tumeurs de l'estomac/anatomopathologieRÉSUMÉ
INTRODUCTION: This integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy. METHODS: Adults with EGFR mutation-positive NSCLC that progressed after prior EGFR-directed TKIs received once daily oral lazertinib 240 mg continuously until disease progression. Prior TKIs to treat T790M-positive NSCLC were prohibited. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival, and intracranial ORR. RESULTS: A total of 78 patients received lazertinib 240 mg at 17 centers in South Korea. Among patients with T790M-positive tumors at baseline (N = 76), one (1.3%) had a complete response and 41 (53.9%) had partial responses, giving an ORR of 55.3% (95% confidence interval [CI]: 44.1-66.4). Median progression-free survival was 11.1 months (95% CI: 5.5-16.4). Median overall survival was not reached (median follow-up = 22.0 mo). In patients with measurable intracranial lesions (n = 7), one (14.3%) had a complete intracranial response and five (71.4%) had partial responses, giving an intracranial ORR of 85.7% (95% CI: 59.8%-100.0%). The most common treatment-emergent adverse events were rash (37.2%), pruritus (34.6%), and paresthesia (33.3%); most were mild to moderate in severity. Serious drug-related adverse events occurred in three patients (gastritis, pneumonia, pneumonitis). The major mechanism of resistance was EGFR T790M loss. CONCLUSIONS: Lazertinib 240 mg/d has a manageable safety profile with durable antitumor efficacy, including brain metastases, in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy.
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Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Adulte , Carcinome pulmonaire non à petites cellules/induit chimiquement , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Récepteurs ErbB/génétique , Humains , Tumeurs du poumon/induit chimiquement , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Morpholines , Mutation , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Pyrazoles , PyrimidinesRÉSUMÉ
Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel-Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL-HIF-VEGF/VEGFR pathway, which involves the von Hippel-Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL-HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL-HIF pathway.
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Néphrocarcinome/génétique , Facteur de croissance endothéliale vasculaire de type A/génétique , Récepteur-1 au facteur croissance endothéliale vasculaire/génétique , Protéine Von Hippel-Lindau supresseur de tumeur/génétique , Néphrocarcinome/anatomopathologie , Régulation de l'expression des gènes tumoraux , Gènes suppresseurs de tumeur , Humains , Sous-unité alpha du facteur-1 induit par l'hypoxie/génétique , Transduction du signalRÉSUMÉ
PURPOSE: Evaluation of symptoms and signs for the management of neuropathic cancer pain (NCP) is challenging. This study aimed to identify clinical predictors of NCP and symptoms and signs most relevant of those in Korean patients. METHODS: This nationwide, descriptive, cross-sectional, multicenter, observational study included 2,003 cancer patients aged ≥20 years who reported a visual analog scale (VAS) score ≥1 for pain and provided informed consent for participation. The Douleur Neuropathic (DN4) questionnaire (score ≥4) was used to determine symptoms and signs as well as the presence of NCP. RESULTS: The prevalence of NCP was associated with age <65 years [OR, 1.57; 95% CI, 1.270-1.934], disease duration >6 months (OR, 1.57; 95% CI, 1.232-2.012), stage IV cancer (OR, 0.75; 95% CI, 0.593-0.955), history of chemotherapy (OR, 1.74; 95% CI, 1.225-2.472), and moderate-to-severe cancer pain (OR, 2.05; 95% CI, 1.671-2.524) after multivariate analysis. The most common descriptive symptoms of NCP were tingling, electric shock, and pins and needles. For NCP patients in the presence or absence of the clinical predictors, pins and needles (p = 0.001) and painful cold (p<0.001) symptoms were significantly frequent in patients with moderate-to-severe pain. Tingling, numbness, and touch hypoesthesia (p = 0.022, 0.033, 0.024, respectively) were more frequent in those with longer cancer duration and hyperesthesia (p = 0.024) was more frequent in young patients. CONCLUSION: Age <65 years, disease duration >6 months, stage IV cancer, history of chemotherapy, and moderate-to-severe cancer pain, were identified as predictors of NCP. Some symptoms and signs of NCP were associated with these predictors. Further studies are warranted on the pathogenesis and management of NCP with respect to the symptoms and signs, and factors associated with pain severity in Korean patients.
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Douleur cancéreuse , Tumeurs , Névralgie , Mesure de la douleur , Enquêtes et questionnaires , Facteurs âges , Sujet âgé , Douleur cancéreuse/diagnostic , Douleur cancéreuse/épidémiologie , Douleur cancéreuse/physiopathologie , Femelle , Humains , Mâle , Adulte d'âge moyen , Tumeurs/traitement médicamenteux , Tumeurs/épidémiologie , Tumeurs/physiopathologie , Névralgie/diagnostic , Névralgie/épidémiologie , Névralgie/physiopathologie , PrévalenceRÉSUMÉ
BACKGROUND: Body composition, including sarcopenia and fat parameters, has received much attention as a prognostic factor in breast cancer. METHODS: A total of 479 breast cancer patients who underwent surgery and received adjuvant chemotherapy were enrolled in this study. Body composition, including the index and density of skeletal muscle, visceral fat, subcutaneous fat, and intermuscular fat calculated by CT scan, was used as a prognostic factor. The endpoints were breast cancer-specific survival (BCSS) and overall survival (OS). RESULTS: The number of patients with stages I, II, and III was 146 (30.5%), 237 (49.5%), and 96 (20%), respectively. Sarcopenia and muscle density were not significant prognostic factors for BCSS and OS. A high visceral fat index (VFI) was an independent prognostic factor for BCSS (HR, 2.55; 95% CI 1.10-5.95, p = 0.03) and OS (HR 2.55, 95% CI 1.26-5.16, p = 0.01). In addition, high intermuscular fat density (IMFD) was also a significant prognostic factor for BCSS (HR, 2.95; 95% CI 1.34-6.46, p = 0.007) and OS (HR 2.28, 95% CI 1.22-4.26, p = 0.01) in multivariate analysis. CONCLUSION: VFI and IMFD were significant prognostic factors for BCSS and OS in breast cancer patients treated with adjuvant chemotherapy.
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Tumeurs du sein , Sarcopénie , Composition corporelle , Tumeurs du sein/traitement médicamenteux , Traitement médicamenteux adjuvant , Femelle , Humains , Pronostic , Sarcopénie/étiologieRÉSUMÉ
PURPOSE: Although immune-checkpoint inhibitors have become a new therapeutic option for recurrent/metastatic non-small cell lung cancers (R/M-NSCLC), its clinical benefit in the real-world is still unclear. METHODS: We investigated 1181 Korean patients with programmed death-1 ligand 1 (PD-L1)-positive [tumor proportion score (TPS) ≥ 10% by the SP263 assay or ≥ 50% by the 22C3 assay] R/M-NSCLC treated with pembrolizumab or nivolumab after failure of platinum-based chemotherapy. RESULTS: The median age was 67 years, 13% of patients had ECOG-PS ≥ 2, and 27% were never-smokers. Adenocarcinoma was predominant (61%) and 18.1% harbored an EGFR activating mutation or ALK rearrangement. Pembrolizumab and nivolumab were administered to 51.3% and 48.7, respectively, and 42% received them beyond the third-line chemotherapy. Objective response rate (ORR) was 28.6%. Pembrolizumab group showed numerically higher ORR (30.7%) than the nivolumab group (26.4%), but it was comparable with that of the nivolumab group having PD-L1 TPS ≥ 50% (32.4%). Median progression-free survival (PFS) and overall survival (OS) were 2.9 (95% CI 0-27.9) and 10.7 months (95% CI 0-28.2), respectively. In multivariable analysis, concordance of TPS ≥ 50% in both PD-L1 assays and the development of immune-related adverse events (irAEs) were two significant predictors of better ORR, PFS, and OS. EGFR mutation could also predict significantly worse OS outcomes. CONCLUSION: The real-world benefit of later-line anti-PD1 antibodies was comparable to clinical trials in patients with R/M-NSCLC, although patients generally were more heavily pretreated and had poorer ECOG-PS. Concordantly high PD-L1 TPS ≥ 50% and development of irAE could independently predict better treatment outcomes, while EGFR mutation negatively affected OS.
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Antinéoplasiques immunologiques/usage thérapeutique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Cisplatine/usage thérapeutique , Résistance aux médicaments antinéoplasiques , Tumeurs du poumon/traitement médicamenteux , Récepteur-1 de mort cellulaire programmée/immunologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Anticorps monoclonaux/usage thérapeutique , Anticorps monoclonaux humanisés/usage thérapeutique , Antigène CD274/génétique , Antigène CD274/métabolisme , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/mortalité , Carcinome pulmonaire non à petites cellules/anatomopathologie , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Femelle , Humains , Tumeurs du poumon/génétique , Tumeurs du poumon/mortalité , Tumeurs du poumon/anatomopathologie , Mâle , Adulte d'âge moyen , Métastase tumorale , Récidive tumorale locale/diagnostic , Récidive tumorale locale/génétique , Récidive tumorale locale/métabolisme , Nivolumab/usage thérapeutique , Pronostic , République de Corée/épidémiologie , Analyse de survie , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. RESULTS: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. CONCLUSIONS: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.