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BACKGROUND: Molecular characterization has significantly improved the management of advanced endometrial cancer (EC). It distinguishes four molecular subclasses associated with prognosis and personalized therapeutic strategies. This study assesses the clinical utility of cell-free DNA (cfDNA) profiling in EC to identify targetable alterations. METHODS: Women with metastatic or recurrent EC were prospectively recruited within the framework of the STING trial (NCT04932525), during which cfDNA was analyzed. Genomic alterations were identified with the FoundationOne CDx assay. Each molecular report underwent review by a molecular tumor board. Alterations were categorized via the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT). RESULTS: A total of 61 patients were enrolled. The median age was 66.9 years, with 43% presenting frontline metastatic disease. All histologic subgroups were represented. Notably, 89% of patients yielded informative cfDNA analysis. Six tumors were classified with deficient mismatch repair/microsatellite instability (11%) and 37 as TP53 gene mutant (67%), and 12 had nonspecific molecular profiles (22%). Molecular classification based on liquid biopsy showed 87.5% accuracy in correlating with tissue results. Moreover, 65% of cases exhibited ≥1 actionable alteration, including 25% ESCAT I alterations and 13% ESCAT II alterations. Consequently, 16% of patients received a molecularly matched therapy, and presented with a 56% response rate and median progression-free survival of 7.7 months. CONCLUSIONS: cfDNA sequencing in EC is a feasible approach that produces informative results in 89% of cases and accurately categorizes patients into the main molecular subclasses. It also reveals multiple actionable alterations, which offers the potential for personalized therapeutic strategies.
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Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab-paclitaxel ± durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [nab-paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [nab-paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19-56% and 9-51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Retratamento , Resultado do TratamentoRESUMO
BACKGROUND: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. METHODS: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up. FINDINGS: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group. INTERPRETATION: Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC. FUNDING: Eli Lilly.
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Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Método Duplo-Cego , Receptores ErbB/genética , Cloridrato de Erlotinib , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , RamucirumabRESUMO
BACKGROUND: This randomized phase 2 trial compared the efficacy and safety of second-line nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without the addition of CC-486 (an oral formulation of 5-azacytidine) in patients with advanced-stage, nonsquamous non-small cell lung cancer. METHODS: Patients were randomized to receive either nab-paclitaxel 100 mg/m2 on days 8 and 15 plus CC-486 200 mg daily on days 1 to 14 or single-agent nab-paclitaxel 100 mg/m2 on days 1 and 8, with both regimens administered every 21 days until tumor progression or unacceptable toxicity. The primary endpoint was progression-free survival. Secondary endpoints included the overall response rate, the disease control rate, and overall survival. RESULTS: Between January 2015 and August 2016, 161 patients were randomized (81 to the combination arm and 80 to the single-agent nab-paclitaxel arm). There was no benefit from the addition of CC-486 to nab-paclitaxel. The median progression-free survival was 3.2 months for the combination and 4.2 months for single-agent nab-paclitaxel (hazard ratio, 1.3; 95% confidence interval, 0.9-1.9). The median overall survival was 8.1 months in the combination arm and 17 months in the single-agent nab-paclitaxel arms (hazard ratio, 1.7; 95% confidence interval, 1.08-2.57). Grade 3 or greater treatment-related, emergent adverse events were reported by 40.5% of patients in the combination arm and by 31.6% of those in the single-agent nab-paclitaxel arm. CONCLUSIONS: Single-agent nab-paclitaxel was associated with promising outcomes and a tolerable safety profile as second-line treatment for patients with advanced-stage, nonsquamous non-small cell lung cancer. There was no benefit from the addition of CC-486 to nab-paclitaxel.
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Albuminas/administração & dosagem , Azacitidina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: Erlotinib and gefitinib are both tyrosine kinase inhibitors (TKIs) approved for the treatment of non-small cell lung cancer (NSCLC). Although it is well known that the increase of gastric pH may decrease the solubility of TKIs, there is limited evidence about the clinical repercussion of this fact. The purpose of this study was to determine if the use of gastric acid suppressive therapy (As) concomitantly with TKIs has an adverse impact on progression-free survival (PFS) and to determine whether the type of drug used (proton pump inhibitors/PPIs or histamine-2 receptors antagonists (H2RAs) may influence it. METHODS: In this retrospective observational study included were patients treated for ≥1 week with erlotinib or gefitinib from January 2012 to December 2015. Demographic, diagnostic and therapeutic variables were collected. Patients were divided into two groups (As users and non-As users). For the calculation of the PFS the Kaplan Meier and multivariate Cox regression analysis were used. RESULTS: 163 patients with mean age 70 years were included. 72.397percnt; (n=118) received TKIs and As concomitantly. The mean PFS was 84 days (95% CI, 65-101) and 221 days (95% CI, 125-429; p <0.0001) in As users and non-As users, respectively. Regarding the type of As used, no significant differences were observed. CONCLUSION: Concomitant use of As and TKIs adversely impacted the PFS outcomes in NSCLC patients regardless of the type of As used. Further studies are needed to determine the clinical impact of interactions between antiacids and antineoplastics.
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Ácido Gástrico/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Mutação , Triazinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Feminino , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Triazinas/administração & dosagem , Triazinas/uso terapêutico , Triazinas/efeitos adversos , Adulto , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Idoso de 80 Anos ou mais , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , ImidazóisRESUMO
PURPOSE: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. EXPERIMENTAL DESIGN: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.
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Biomarcadores Tumorais , Perfilação da Expressão Gênica , Imunoterapia , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Transcriptoma , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapia , Biomarcadores Tumorais/genética , Masculino , Feminino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Idoso , Imunoterapia/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do Tratamento , Regulação Neoplásica da Expressão Gênica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , PrognósticoRESUMO
Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Imunoterapia/métodos , Imunoterapia/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
More than half of cancer cases occur in patients aged 65 years or older. The efficacy and safety of antibody drug conjugates (ADCs) in older patients remains an unclear subject as available evidence is limited. Geriatric population is underrepresented in clinical trials. Consequently, most of our knowledge regarding innovative therapeutics was studied on a younger population. In this review of published literature, we report the available information on efficacy, safety and pharmacokinetics of FDA approved ADCs for hematologic malignancies and solid tumors in the geriatric population. We explore the results of clinical trials dedicated for older individuals as well as subgroup analyses of the geriatric population in major trials evaluating these drugs. Available data suggest a similar efficacy in older adults as compared to general population. However, older patients might be prone to a higher rate of adverse events in incidence with a potential impact on quality of life. We lack data to support primary dose reductions or schedule modifications in this category of patients. No pharmacokinetic differences were reported between age groups. It is crucial to encourage the development of clinical trials dedicated to older patients with geriatric parameters (G8 score, G-CODE ) so that results can be more representative of this population outside of clinical trials.
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Imunoconjugados , Humanos , Idoso , Imunoconjugados/efeitos adversos , Qualidade de VidaAssuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Tromboembolia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Rearranjo Gênico , Humanos , Incidência , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Portugal/epidemiologia , Prognóstico , Receptores Proteína Tirosina Quinases/genética , Estudos Retrospectivos , Espanha/epidemiologia , Análise de Sobrevida , Tromboembolia/genética , Adulto JovemRESUMO
Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation. SIGNIFICANCE: In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K-mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR , Classe I de Fosfatidilinositol 3-Quinases , Fosfatidilinositol 3-QuinasesRESUMO
Introduction: We present the results of a phase 2a trial of first-line avelumab (anti-programmed death-ligand 1 antibody) plus cetuximab (anti-EGFR antibody) in patients with advanced squamous NSCLC. Methods: Patients with recurrent or metastatic squamous NSCLC received avelumab 800 mg (d 1 and 8), cetuximab 250 mg/m2 (d 1) and 500 mg/m2 (d 8), cisplatin 75 mg/m2 (d 1), and gemcitabine 1250 mg/m2 (d 1 and 8) for four 3-week cycles, followed by avelumab 800 mg and cetuximab 500 mg/m2 every 2 weeks. The primary end point was the best overall response; the secondary end points were progression-free survival, duration of response, overall survival, and safety. Efficacy analyses were reported from an updated data cutoff. Results: A total of 43 patients were enrolled. The median follow-up was 6.6 months for the primary analyses and 9.2 months for the efficacy analyses. In the efficacy analyses, 15 patients had a confirmed partial response (objective response rate, 34.9% [95% confidence interval: 21.0%-50.9%]), and the median duration of response was 7.1 months (95% confidence interval: 4.2-12.5 mo). The median progression-free survival and overall survival were 6.1 months and 10.0 months, respectively. In the safety analyses (primary analysis), 38 patients (88.4%) had a treatment-related adverse event, of whom 24 (55.8%) had a grade 3 or higher treatment-related adverse event. Conclusions: The combination of avelumab + cetuximab and chemotherapy showed antitumor activity and tolerable safety; however, the ORR was not improved compared with those reported for current standards of care (NCT03717155).
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INTRODUCTION: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. METHODS: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. RESULTS: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1-4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%-55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7-72.1] versus 16.3 mo [12.7-28.8], p < 0.0001). CONCLUSIONS: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.
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Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Resultado do TratamentoRESUMO
INTRODUCTION: SCLC is one of the most lethal malignancies. Classically, staging has been performed using a dual classification distinguishing limited from the extensive stage. This study aimed to evaluate the prognostic value of TNM staging in a real-world population of patients with SCLC. METHODS: Patients were selected from the Surveillance Epidemiology and End Results database. Chi-square bivariate analysis was used for the association of binary qualitative variables. A multivariate Cox regression analysis was performed to determine the impact of these prognostic factors on median overall survival (mOS) and long-term survival. RESULTS: A total of 26,221 patients were included (50.7% men, 55.7% ≥65 y, 82% White). At diagnosis, 18,574 (70.83%) presented metastases, which were more frequent in the liver (n = 11,896, 64%). In the overall population, mOS was 8 (7.86-8.14) months, which decreased according to each increasing category of TNM staging (p < 0.0001). The worse mOS was found among patients with stage IV SCLC (6 mo, 95% confidence interval: 5.83-6.17). Long-term survival decreased according to TNM staging, with patients having stage IV SCLC exhibiting the lowest survival rates at all follow-up time points. Within stage IV, the lowest mOS values were found in patients greater than or equal to 65 years and in those with liver metastases. Among the TNM stages corresponding to the limited stage, stage IB revealed the lowest hazard ratios value for risk of death compared with stage IA (hazard ratio = 1.161, 95% confidence interval: 0.97-1.40, p = 0.114), which increased gradually within the limited-stage SCLC. In the multivariate analysis, TNM staging, male sex, and older age resulted in poor prognostic factors for survival. CONCLUSIONS: TNM staging seems to define prognosis in patients with SCLC in the real-world setting, particularly for those patients with earlier disease.
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INTRODUCTION: Nazartinib, a novel third-generation EGFR-tyrosine kinase inhibitor, previously demonstrated antitumor activity and manageable safety in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) who received ≤ 3 prior lines of systemic therapy. Herein, we report phase 2 efficacy and safety of first-line nazartinib. METHODS: This single-arm, open-label, global study enrolled treatment-naive adult patients with stage IIIB/IV NSCLC harboring EGFR-activating mutations (eg, L858R and/or ex19del). Patients with neurologically stable and controlled brain metastases were also eligible. Patients received oral nazartinib 150 mg once daily. The primary endpoint was Blinded Independent Review Committee (BIRC)-assessed overall response rate (ORR) per RECIST v1.1. RESULTS: Forty-five patients received ≥ 1 dose of nazartinib. The median follow-up time from enrollment to data cutoff (November 1, 2019) was 30 months (range: 25-34). The BIRC-assessed ORR was 69% (95% CI, 53-82). The median progression-free survival (PFS) was 18 months (95% CI, 15-not estimable [NE]). The median overall survival was NE. In patients with baseline brain metastases (n = 18), the ORR and median PFS (95% CIs) were 67% (41-87) and 17 months (11-21). Seventeen of 18 patients had brain metastases as non-target lesions; the CNS lesions were absent/normalized in 9 of 17 (53%). Only 2 of 27 patients without baseline brain metastases developed new brain metastases postbaseline. Most frequent adverse events (≥ 25%, any grade, all-causality) were diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough, and stomatitis (27% each). CONCLUSIONS: First-line nazartinib demonstrated promising efficacy, including clinically meaningful antitumor activity in the brain, and manageable safety in patients with EGFR-mutant NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02108964.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Benzimidazóis , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Nicotina/análogos & derivados , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
BACKGROUND: Tumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed. METHODS: We evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined. RESULTS: Both panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N=55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively. CONCLUSIONS: Both panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.
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Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares/genética , Mutação , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Variações Dependentes do Observador , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: In the phase 3 RELAY trial, ramucirumab/erlotinib demonstrated superior progression-free survival (PFS) over placebo/erlotinib in patients with EGFR-mutated metastatic NSCLC (median PFS 19.4 versus 12.4 months; HR = 0.59, 95% CI = 0.46-0.76; p < .0001). Safety was consistent with established profiles for ramucirumab and erlotinib in NSCLC. Here, we present patient-reported outcomes. METHODS: Patients received oral erlotinib (150 mg daily) plus intravenous ramucirumab (10 mg/kg) or placebo Q2W until progressive disease or unacceptable toxicity. Patients completed the Lung Cancer Symptom Scale (LCSS) and EQ-5D questionnaires at baseline and every other cycle. Analyses included time to deterioration (TtD) for LCSS via Kaplan-Meier method and Cox models and changes from baseline using mixed-model repeated-measures regression analysis. RESULTS: Overall patient compliance for LCSS and EQ-5D was >95%. TtD did not differ between treatment arms for LCSS Total Score (HR = 0.962, 95% CI = 0.690-1.343) and Average Symptom Burden Index (HR = 1.012, 95% CI = 0.732-1.400). TtD of individual LCSS items (appetite loss, fatigue, cough, shortness of breath, pain, symptom distress, difficulties with daily activities, quality of life) indicated no difference between arms; however, patient-reported blood in sputum was worse for ramucirumab/erlotinib (HR = 1.987, 95% CI = 1.206-3.275). Results of LCSS mean changes from baseline were consistent with TtD, indicating no significant differences between treatment arms except for blood in sputum. Mean changes from baseline in EQ-5D index score (p = .94) and visual analogue scale (p = .95) revealed no overall differences in health status between treatment arms. CONCLUSIONS: Patients' overall quality of life and symptom burden did not differ with the addition of ramucirumab to erlotinib compared to placebo/erlotinib. These data support the clinical benefit of ramucirumab/erlotinib in untreated EGFR-mutated metastatic NSCLC.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Medidas de Resultados Relatados pelo Paciente , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Cloridrato de Erlotinib/administração & dosagem , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Qualidade de Vida , RamucirumabRESUMO
Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab-paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC. Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab-paclitaxel 100 mg/m2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety. Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred. Conclusions: The nab-paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted. Clinical Trial Registration: ClinicalTrials.gov registration (NCT02250326). EudraCT number: 2014-001105-41.
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INTRODUCTION: Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK, we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal. METHODS: The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival. RESULTS: A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n = 27) with a median follow-up of 19 months (range: 1-78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47-2.65) p = 0.78. The majority of the events were venous (n = 24; 89%) and occurred in the ambulatory setting (n = 18; 67%). Almost half of the patients (n = 13; 48%) presented the TE in the peri-diagnostic period. CONCLUSIONS: The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs.
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Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Tromboembolia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/complicações , Feminino , Rearranjo Gênico , Humanos , Incidência , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Tromboembolia/epidemiologiaRESUMO
PURPOSE: Anaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with BRAF-wild type disease. As part of a phase I/II study in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor. METHODS: We enrolled patients with locally advanced and/or metastatic anaplastic thyroid carcinoma in a phase II cohort of the study. Patients received 400 mg spartalizumab intravenously, once every 4 weeks. The overall response rate was determined according to RECIST v1.1. RESULTS: Forty-two patients were enrolled. Adverse events were consistent with those previously observed with PD-1 blockade. Most common treatment-related adverse events were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including three patients with a complete response and five with a partial response. Most patients had baseline tumor biopsies positive for PD-L1 expression (n = 28/40 evaluable), and response rates were higher in PD-L1-positive (8/28; 29%) versus PD-L1-negative (0/12; 0%) patients. The highest rate of response was observed in the subset of patients with PD-L1 ≥ 50% (6/17; 35%). Responses were seen in both BRAF-nonmutant and BRAF-mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1-positive population. CONCLUSION: To our knowledge, this is the first clinical trial to show responsiveness of anaplastic thyroid carcinoma to PD-1 blockade.