RESUMEN
OBJECTIVES: Small cell lung cancer (SCLC) responds well to chemoradiotherapy but frequently relapses. Here, we evaluate activity and safety of the poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor olaparib as maintenance treatment for patients with chemoresponsive SCLC. MATERIALS AND METHODS: Eligible patients had complete or partial response to first line chemotherapy or chemoradiotherapy for SCLC. Patients were randomised 2:2:1:1 to olaparib 300 mg twice a day (BD), olaparib 200 mg three times a day (TDS), placebo BD or placebo TDS. The primary outcome was progression-free survival time (PFS). The trial design had 80% power to detect a 3-month difference in median PFS based on a one-sided 5% significance level. Secondary outcome measures included overall survival time (OS), adverse events and quality of life. ISRCTN 73164486, EudraCT 2010-021165-76. RESULTS: 220 patients were randomised: 74 placebo, 73 olaparib BD, 73 olaparib TDS. Median PFS (90% confidence interval (CI)) was 2·5 (1·8, 3·7), 3·7 (3·1, 4·6) and 3·6 (2·8, 4·7) months in the placebo, olaparib BD and TDS arms, respectively. There was no significant difference in PFS between olaparib and placebo for either BD (Hazard Ratio (HR) (90%CI) 0·76 (0·57, 1·02), P = 0·125 or TDS 0·86, (0·64, 1·15), P = 0·402. Common adverse events on olaparib were fatigue, nausea, anaemia, vomiting and anorexia. Of 214 patients who discontinued treatment before 24 months, toxicity was the reason cited for 66 (18 placebo, 24 olaparib BD, 24 olaparib TDS). CONCLUSION: This trial does not provide sufficient evidence that either the BD or TDS regimen for maintenance olaparib monotherapy improves PFS or OS in an unselected SCLC population to warrant further research. Toxicity for olaparib was similar to other studies.
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Neoplasias Ováricas , Carcinoma Pulmonar de Células Pequeñas , Antineoplásicos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/inducido químicamente , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas , Piperazinas , Calidad de Vida , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
BACKGROUND: Genomic sequencing is necessary for first-line advanced non-small cell lung cancer (aNSCLC) treatment decision-making. Tissue next generation sequencing (NGS) is standard but tissue quantity, quality, and time-to-results remains problematic. Here, we compare upfront cell-free-DNA (cfDNA) NGS clinical utility against routine tissue testing in patients with aNSCLC. METHODS: cfDNA-NGS was performed in consecutive, newly identified aNSCLC patients between December 2019-October 2021 alongside routine tissue genotyping. Variants were interpreted using AMP/ASCO/CAP guidelines. The primary endpoint was tier-1 variants detected on cfDNA-NGS. cfDNA-NGS results were compared to tissue results. RESULTS: Of 311 patients, 282 (91%) had an informative cfDNA-NGS test; 118 (38%) patients had a tier-1 variant identified by cfDNA-NGS. Of 243 patients with paired tissue-cfDNA tests, 122 (50%) tissue tests were informative; 85 (35%) tissue tests identified a tier-1 variant. cfDNA-NGS detected 39 additional tier-1 variants compared to tissue alone, increasing the tier-1 detection rate by 46% (from 85 to 124). The sensitivity of cfDNA-NGS relative to tissue was 75% (25% tissue tier-1 variants were not detected on cfDNA-NGS); 33% of cfDNA tier-1 variants were not identified on tissue tests. Median time from request-to-report was shorter for cfDNA-NGS versus tissue (8 versus 22 days; p < 0.0001). A total of 245 (79%) patients received first-line systemic-therapy: 49 (20%) with cfDNA-NGS results alone. Median time from sampling-to-commencement of first-line treatment was shorter for cfDNA-NGS blood draw versus first tissue biopsy (16 versus 35 days; p < 0.0001). CONCLUSIONS: cfDNA-NGS increased the tier-1 variant detection rate with high concordance with tissue, and halves time-to-treatment. 'Plasma-first' upfront cfDNA-NGS use should be considered routinely for aNSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Ácidos Nucleicos Libres de Células/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Reino UnidoRESUMEN
BACKGROUND: Concurrent chemoradiotherapy is a standard therapy for patients with stage III non-small-cell lung cancer (NSCLC). Durvalumab is an approved treatment option following concurrent chemoradiotherapy in the absence of disease progression. The multicenter, phase III, randomized, placebo- and active-controlled, double-blind KEYLYNK-012 study evaluates whether initiation of immunotherapy with pembrolizumab concurrently with chemoradiotherapy, followed by post-chemoradiotherapy pembrolizumab with or without olaparib improves outcomes for participants with stage III NSCLC. (ClinicalTrials.gov: NCT04380636) METHODS: Eligible participants are aged ≥18 years with previously untreated, pathologically confirmed, stages IIIA-C, squamous or nonsquamous NSCLC not suitable for surgery with curative intent. Participants will be randomized 1:1:1 to platinum-doublet chemotherapy plus radiotherapy with pembrolizumab (Groups A and B) or concurrent chemoradiotherapy alone (Group C) for 3 cycles. In the absence of disease progression, participants will receive pembrolizumab plus olaparib placebo (Group A), pembrolizumab plus olaparib (Group B), or durvalumab monotherapy (Group C). Dual primary endpoints are progression-free survival per RECIST version 1.1 by independent central review and overall survival. RESULTS: Enrollment began on July 6, 2020, and is ongoing at approximately 190 sites. CONCLUSION: KEYLYNK-012 will provide important information on the efficacy and safety of pembrolizumab combined with concurrent chemoradiotherapy and subsequent pembrolizumab with or without olaparib in participants with unresectable stage III NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quimioradioterapia , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ftalazinas , PiperazinasRESUMEN
Pneumonitis is a well-described, potentially life-threatening adverse effect of immune checkpoint inhibitors (ICI) and thoracic radiotherapy. It can require additional investigations, treatment, and interruption of cancer therapy. It is important for clinicians to have an awareness of its incidence and severity, however real-world data are lacking and do not always correlate with findings from clinical trials. Similarly, there is a dearth of information on cost impact of symptomatic pneumonitis. Informatics approaches are increasingly being applied to healthcare data for their ability to identify specific patient cohorts efficiently, at scale. We developed a Structured Query Language (SQL)-based informatics algorithm which we applied to CT report text to identify cases of ICI and radiotherapy pneumonitis between 1/1/2015 and 31/12/2020. Further data on severity, investigations, medical management were also acquired from the electronic health record. We identified 248 cases of pneumonitis attributable to ICI and/or radiotherapy, of which 139 were symptomatic with CTCAE severity grade 2 or more. The grade ≥2 ICI pneumonitis incidence in our cohort is 5.43%, greater than the all-grade 1.3-2.7% incidence reported in the literature. Time to onset of ICI pneumonitis was also longer in our cohort (mean 4.5 months, range 4 days-21 months), compared to the median 2.7 months (range 9 days-19.2 months) described in the literature. The estimated average healthcare cost of symptomatic pneumonitis is £3932.33 per patient. In this study we use an informatics approach to present new real-world data on the incidence, severity, management, and resource burden of ICI and radiotherapy pneumonitis. To our knowledge, this is the first study to look at real-world incidence and healthcare resource utilisation at the per-patient level in a UK cancer hospital. Improved management of pneumonitis may facilitate prompt continuation of cancer therapy, and improved outcomes for this not insubstantial cohort of patients.
RESUMEN
AIM: We explore HER3 expression in lung adenocarcinoma (adeno-NSCLC) and identify potential mechanisms of HER3 expression. MATERIALS & METHODS: Tumor samples from 45 patients with adeno-NSCLC were analyzed. HER3 and HER2 expression were identified using immunohistochemistry and bioinformatic interrogation of The Cancer Genome Atlas (TCGA). RESULTS: HER3 was highly expressed in 42.2% of cases. ERBB3 copy number did not account for HER3 overexpression. Bioinformatic analysis of TCGA demonstrated that MEK activity score (a surrogate of functional signaling) did not correlate with HER3 ligands. ERBB3 RNA expression levels were significantly correlated with MEK activity after adjusting for EGFR expression. CONCLUSION: HER3 expression is common and is a potential therapeutic target by virtue of frequent overexpression and functional downstream signaling.
RESUMEN
Durvalumab is the first approved adjuvant immunotherapy agent for patients with stage III NSCLC treated with concurrent chemoradiotherapy and is associated with improved overall survival. In order to minimise the number of hospital visits for patients receiving durvalumab during the COVID-19 pandemic we implemented 4-weekly (20 mg/kg) durvalumab in place of 2-weekly infusions at The Royal Marsden Hospital. We assessed the potential impact of the safety of a 4-weekly schedule in patients receiving adjuvant durvalumab. We carried out a retrospective study of 40 patients treated with 2-weekly and 4-weekly infusions of durvalumab prior to and during the COVID-19 pandemic. Clinical documentation was analysed from 216 consultations across 40 patients receiving 2-weekly durvalumab and 66 consultations of 14 patients who switched from 2-weekly to 4-weekly durvalumab during the COVID-19 pandemic. In patients receiving 2-weekly durvalumab, the rate of grade 3 and 4 toxicities was 15 % compared to 7% in patients receiving 4-weekly durvalumab. Pre-existing autoimmune disease was considered a risk factor for the development of grade 3 or 4 toxicities. We did not observe any difference in the rate of grade 1 and 2 toxicities between the two groups. Our findings support the use of 4-weekly durvalumab during the COVID-19 pandemic and beyond, obviating the need for 2-weekly face-to-face consultations and blood tests, relevant given the current pandemic and the need to re-structure cancer services to minimise patient hospital visits and exposure to SARS-CoV-2.
Asunto(s)
COVID-19 , Neoplasias Pulmonares , Anticuerpos Monoclonales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Pandemias , Estudios Retrospectivos , SARS-CoV-2RESUMEN
BACKGROUND: UK COVID-19 mortality rates are amongst the highest globally. Controversy exists on the vulnerability of thoracic cancer patients. We describe the characteristics and sequelae of patients with thoracic cancer treated at a UK cancer centre infected with COVID-19. METHODS: Patients undergoing care for thoracic cancer diagnosed with COVID-19 (RT-PCR/radiology/clinically) between March-June 2020 were included. Data were extracted from patient records. RESULTS: Thirty-two patients were included: 14 (43%) diagnosed by RT-PCR, 18 (57%) by radiology and/or convincing symptoms. 88% had advanced thoracic malignancies. Eleven of 14 (79%) patients diagnosed by RT-PCR and 12 of 18 (56%) patients diagnosed by radiology/clinically were hospitalised, of which four (29%) and 2 (11%) patients required high-dependency/intensive care respectively. Three (21%) patients diagnosed by RT-PCR and 2 (11%) patients diagnosed by radiology/clinically required non-invasive ventilation; none were intubated. Complications included pneumonia and sepsis (43% and 14% respectively in patients diagnosed by RT-PCR; 17% and 11% respectively in patients diagnosed by radiology/clinically). In patients receiving active cancer treatment, therapy was delayed/ceased in 10/12 (83%) and 7/11 (64%) patients diagnosed by RT-PCR and radiology/clinically respectively. Nine (28%) patients died; all were smokers. Median time from symptom onset to death was 7 days (range 3-37). CONCLUSIONS: The immediate morbidity from COVID-19 is high in thoracic cancer patients. Hospitalisation and treatment interruption rates were high. Improved risk-stratification models for UK cancer patients are urgently needed to guide safe cancer-care delivery without compromising efficacy.
Asunto(s)
COVID-19/epidemiología , SARS-CoV-2/patogenicidad , Neoplasias Torácicas/epidemiología , Adulto , COVID-19/complicaciones , COVID-19/virología , Cuidados Críticos , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Torácicas/complicaciones , Neoplasias Torácicas/virología , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: In light of the coronavirus disease 2019 (COVID-19) pandemic, cancer centres in the United Kingdom and Europe re-organised their services at an unprecedented pace, and many patients with cancer have had their treatments severely disrupted. Patients with cancer were considered at high risk on sparse evidence, and despite a small number of emerging observational studies, the true incidence and impact of COVID-19 in the 'at-risk' population of patients with cancer is yet to be defined. METHODS: Epidemiological and clinical data were collected prospectively for patients attending the Royal Marsden Hospital and three network hospitals between March 1st and April 30th 2020 that were confirmed to have Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Significance of clinical and pathological characteristics was assessed using the Fisher's exact test and Wilcoxon rank sum test, whilst univariate and multivariate logistic regression models were used to further assess risk. The number of patients attending in March/April 2020 for face-to-face attendances was also extracted. FINDINGS: During the 2-month study period, 867 of 13,489 (6.4%) patients met the criteria leading to swab testing. Of the total at-risk population, only 113 of 13,489 (0.84%) were swab positive, 101 of 13,489 (0.75%) required hospital admission and 29 of 13,489 (0.21%) died of COVID-19. Of the patients that attended the hospital to receive cytotoxic chemotherapy alone or in combination with other therapy, 59 of 2001 (2.9%) were admitted to the hospital for COVID-19-related issues and 20 of 2001 (1%) died. Of the patients that collected targeted treatments, 16 of 1126 (1.4%) were admitted and 1 of 1126 (0.1%) died. Of the 11 patients that had received radiotherapy, 6 of 1042 (0.6%) required inpatient admission and 2 of 1042 (0.2%) died. INTERPRETATIONS: Administration of systemic anticancer therapy appears to be associated with a modest risk of severe COVID-19 infection. Based on this snapshot taken as the first wave of COVID-19 hit our practice, we conclude that continuation of active cancer treatment, even in the palliative setting, is appropriate.
Asunto(s)
Antineoplásicos/uso terapéutico , Infecciones por Coronavirus/epidemiología , Hospitalización/estadística & datos numéricos , Neoplasias/epidemiología , Neumonía Viral/epidemiología , Radioterapia/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/mortalidad , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Humanos , Incidencia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Mortalidad , Análisis Multivariante , Neoplasias/terapia , Pandemias , Neumonía Viral/mortalidad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Factores de Riesgo , SARS-CoV-2 , Reino Unido/epidemiología , Adulto JovenRESUMEN
Brain metastases (BrMs) are associated with significant morbidity and are found in up to 50% of patients with advanced non-small cell lung cancer (NSCLC). Most of the literature focuses on symptomatic BrMs, with a lack of baseline brain imaging in asymptomatic patients. Unfortunately, much of the data on local treatments with or without systemic treatment is retrospective. Clinical trials of systemic treatments largely exclude patients with BrMs. Chemotherapy is an active treatment for BrM with response rates in the brain similar to other sites of disease. Targeted systemic treatments in patients with driver mutations (EGFR and ALK-MET to date) have impressive central nervous system (CNS) penetrance and response rates. Unfortunately, no prospective data can currently guide the timings or modality of local therapies with systemic treatments in these patients who have a high incidence of CNS disease, but retrospective data suggest that early local therapies may give better intracranial progression-free survival (ICPFS). Recent immunotherapy trials have included patients with BrMs. These patients have largely been pre-treated with local therapies and are asymptomatic. Thus, the current standard is becoming, early local therapies before or in conjunction with immunotherapy agents. The approach seems to be safe. Prospective studies are needed in NSCLC BrMs patients to make sure any benefit from local therapies on the ICPFS and quality of life is not overlooked. Here we report what we think are reasonable conclusions from the available data and make suggestions for future clinical trials in the management of NSCLC BrMs.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patología , PronósticoRESUMEN
OBJECTIVES: Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity. MATERIAL AND METHODS: Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities. RESULTS: Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities. CONCLUSION: On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short.
Asunto(s)
Biomarcadores/sangre , Depresión/etiología , Homocisteína/sangre , Pemetrexed/efectos adversos , Vitaminas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Suplementos Dietéticos , Femenino , Ácido Fólico/administración & dosificación , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/tratamiento farmacológico , Mesotelioma/mortalidad , Mesotelioma/patología , Mesotelioma Maligno , Persona de Mediana Edad , Pemetrexed/uso terapéutico , Estudios Prospectivos , Resultado del Tratamiento , Vitamina B 12/administración & dosificaciónRESUMEN
INTRODUCTION: Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562). METHODS: Patients with stage IIIB-IV NSCLC (squamous or nonsquamous) received durvalumab 10 mg/kg every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. Primary objectives were safety and antitumor activity. Tumoral PD-L1 expression was assessed using the VENTANA SP263 Assay. Responses were assessed by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1). Adverse events were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (v4.03). RESULTS: Of 304 patients, 79.0% were previously treated. Confirmed objective response rate was 21.8% in patients with greater than or equal to 25% PD-L1 expression and 6.4% in those with less than 25%; 25.9% in first-line patients and 12.7% in previously treated patients; and 14.0% in squamous and 16.7% in nonsquamous disease. Median overall survival was 12.4 months and median progression-free survival was 1.7 months; both were numerically longer in the PD-L1 greater than or equal to 25% group than in the PD-L1 less than 25% group (overall survival 16.4 versus 7.6 months, respectively; progression-free survival 2.6 versus 1.4 months, respectively). Treatment-related adverse events occurred in 57.2%, were grade 3/4 in 10.2%, and led to discontinuation in 5.6%. One patient (0.3%) died of treatment-related pneumonia with underlying pneumonitis. CONCLUSIONS: Durvalumab was clinically active irrespective of histology in this mostly pretreated population, with a manageable safety profile. Response rates and survival appeared to be enhanced in patients with greater tumoral PD-L1 expression.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos Inmunológicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Distribución TisularRESUMEN
PURPOSE: Afatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy. METHODS: As part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin plus paclitaxel (A/C/P). Starting doses: afatinib 20 mg/day, carboplatin AUC6 (A/C) with paclitaxel 175 mg/m2 (A/C/P) (chemotherapy: Day 1 of 21-day cycles). The primary objective was to determine the MTDs; safety, pharmacokinetics and antitumor activity were also evaluated. RESULTS: Thirty-eight patients received A/C (n = 12) or A/C/P (n = 26). No dose-limiting toxicities (DLTs) were reported with A(20 mg)/C(AUC6). One patient experienced DLT in the A(40 mg)/C(AUC6) cohort (grade 3 acneiform rash); A(40 mg)/C(AUC6) was determined as the recommended phase II dose (RP2D) for A/C. Two patients each had DLTs with A(20 mg/day)/C(AUC6)/P(175 mg/m2): fatigue, infection, diarrhea, small intestine hemorrhage, dehydration, renal impairment, neutropenic sepsis (n = 1), mucositis (n = 1); A(40 mg)/C(AUC5)/P(175 mg/m2): febrile neutropenia (n = 1), mucositis, fatigue (n = 1); and A(30 mg)/C(AUC5)/P(175 mg/m2): stomatitis (n = 1), mucositis (n = 1). No DLT was observed with A(20 mg)/C(AUC5)/P(175 mg/m2), determined as the RP2D for A/C/P. The most frequent drug-related adverse events were (A/C; A/C/P): rash (75%; 73%), fatigue (67%; 69%), and diarrhea (58%; 88%). Drug plasma concentrations were similar between cycles, suggesting no drug-drug interactions. Objective response rates in these heavily pretreated patients were A/C, 3/12 (25%); A/C/P, 5/26 (19%). CONCLUSIONS: Afatinib 40 mg/day (approved monotherapy dose) with carboplatin AUC6, and afatinib 20 mg/day with carboplatin AUC5 and paclitaxel 175 mg/m2 demonstrated manageable safety and antitumor activity. Afatinib > 20 mg/day in the triple combination was not well tolerated.
Asunto(s)
Afatinib/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carboplatino/administración & dosificación , Neoplasias/tratamiento farmacológico , Paclitaxel/administración & dosificación , Afatinib/efectos adversos , Afatinib/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Resultado del TratamientoRESUMEN
INTRODUCTION: In the era of biomarker-driven systemic therapy for advanced NSCLC, the role of routine repeated biopsies for decision making outside EGFR-mutant disease remains unproven. We report our center's experience of safety and adequacy for molecular retesting of tumor material obtained from image-guided lung rebiopsies in NSCLC. METHODS: We performed a retrospective case note analysis of patients undergoing image-guided lung rebiopsies at a single cancer center between 2011 and 2014. The primary objective was to determine the pathological success rate. Secondary and exploratory objectives were to determine technical success rate, histological concordance, molecular adequacy, genotypes identified, and complication rate. RESULTS: In all, 103 patients underwent transthoracic image-guided procedures. A total of 66 rebiopsies in NSCLC were identified and analyzed. The pathological success rate was 87.1%. A high histological discordance rate was observed (12 of 52 evaluable cases [23.1%]). Pretest molecular adequacy as determined by the lung pathologist was 78.8% (52 of 66). Of 52 adequate samples 51 were sent for molecular analysis, with a total of 209 genes analyzed (including EGFR, ALK receptor tyrosine kinase gene [ALK], KRAS, BRAF, dicoidin domain receptor tyrosine kinase 2 gene [DDR2], NRAS, ROS1, and rearranged during transfection proto-oncogene gene [RET]). The rate of postgenotyping molecular adequacy was 87.1% (182 of 209). Overall, 20 new potentially actionable mutations were identified, with 13 of 66 patients (19.7%) starting to receive new targeted treatment as a result. Overall, rebiopsies informed clinical decision making in 63.6% of cases. The rates of complications were 15% for pneumothorax, 3% for pneumothorax requiring chest drain, and 8% for hemoptysis. CONCLUSIONS: We have validated the pathological and molecular adequacy rates of rebiopsies and demonstrated clinical utility in routine decision making.
Asunto(s)
Adenocarcinoma/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Técnicas de Apoyo para la Decisión , Receptores ErbB/genética , Biopsia Guiada por Imagen/métodos , Neoplasias Pulmonares/patología , Adenocarcinoma/genética , Adenocarcinoma/cirugía , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/cirugía , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Proto-Oncogenes Mas , Estudios RetrospectivosRESUMEN
We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected with NFAT-luciferase was used to study if changes in PD-L1 expression in cancer cell lines were functionally relevant. Five KRAS mutant cell lines with high PD-L1 expression (H441, H2291, H23, H2030 and A549) were exposed to GI50 inhibitor concentrations of a MEK inhibitor (trametinib) and an AKT inhibitor (AZD5363) for 3 weeks. Only 3/5 (H23, H2030 and A549) and 2/5 cell lines (H441 and H23) showed functionally significant increases in PD-L1 expression when exposed to trametinib or AZD5363 respectively. PD-L1 overexpression is not consistent and is unlikely to be an early mechanism of resistance to KRAS mutant adeno-NSCLC treated with MEK or AKT inhibitors.
Asunto(s)
Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Genes ras , Neoplasias Pulmonares/metabolismo , Mutación , 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 , Línea Celular Tumoral , Técnicas de Cocultivo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologíaRESUMEN
OBJECTIVES: Despite advances in novel drug development for patients with advanced non-small cell lung cancer (NSCLC), there are still only a limited number of approved treatments. We therefore evaluated the clinical outcomes of patients with advanced NSCLC referred to a dedicated phase I clinical trials unit assessed baseline clinical factors associated with successful enrollment onto phase I trials. MATERIAL AND METHODS: We conducted a retrospective study involving patients with advanced NSCLC referred to the Drug Development Unit at the RMH between January 2005 and December 2013. RESULTS: 257 patients with advanced NSCLC were referred for consideration of phase I trials, of which only 89 (35%) patients successfully commenced phase I trials. The commonest reasons for not entering study included poor ECOG performance status and rapid disease progression. A multivariate analysis identified that ECOG performance status (0-1) and RMH prognostic score (0-1) were associated with successful enrollment onto phase I trials (p<0.001). Single agent therapies included novel agents against the phosphatidylinositol-3 kinase pathway, insulin growth factor-1 receptor and pan-HER family tyrosine kinases. These trial therapies were well tolerated and mainly associated with grade 1-2 adverse events, with a minority experiencing grade 3 toxicities. Nine (10%) patients, 4 with known EGFR or KRAS mutations, achieved RECIST partial responses. Median time to progression was 2.6 months and median overall survival was 8.1 months for patients enrolled. CONCLUSIONS: Phase I trial therapies were generally well tolerated with potential antitumor benefit for patients with advanced NSCLC. Early referral to drug development units at time of disease progression should be considered to enhance the odds of patient participation in these studies.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Clasificación del Tumor , Estadificación de Neoplasias , Oportunidad Relativa , Retratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: We have previously reported a prognostic score for patients in phase I trials in the Drug Development Unit, treated at the Royal Marsden Hospital (RPS). The RPS is an objective tool used in patient selection for phase I trials based on albumin, number of disease sites and LDH. Patients with mesothelioma are often selected for phase I trials as the disease remains localised for long periods of time. We have now reviewed the clinical outcomes of patients with relapsed malignant mesothelioma (MM) and propose a specific mesothelioma prognostic score (m-RPS) that can help identify patients who are most likely to benefit from early referral. METHODS: Patients who participated in 38 phase I trials between September 2003 and November 2015 were included in the analysis. Efficacy was assessed by response rate, median overall survival (OS) and progression-free survival (PFS). Univariate (UVA) and multivariate analyses (MVA) were carried out to develop the m-RPS. RESULTS: A total of 65 patients with advanced MM were included in this retrospective study. The PFS was 2.5 months (95% confidence interval [CI] 2.0-3.1 months) and OS was 8 months (95% CI 5.6-9.8 months). A total of four (6%) patients had RECIST partial responses, whereas 26 (40%) patients had RECIST stable disease >3 months. The m-RPS was developed comprising of three different prognostic factors: a neutrophil: lymphocyte ratio greater than 3, the presence of more than two disease sites (including lymph nodes as a single site of disease) and albumin levels less than 35 from the MVA. Patients each received a score of 1 for the presence of each factor. Patients in group A (m-RPS 0-1; n = 35) had a median OS of 13.4 months (95% CI 8.5-21.6), whereas those in group B (m-RPS 2-3; n = 30) had a median OS of 4.0 months (95% CI 2.9-7.1, P < 0.0001). A total of 56 (86%) patients experienced G1-2 toxicities, whereas reversible G3-4 toxicities were observed in 18 (28%) patients. Only 10 (15%) patients discontinued phase I trials due to toxicity. CONCLUSIONS: Phase I clinical trial therapies were well tolerated with early signals of antitumour activity in advanced MM patients. The m-RPS is a useful tool to assess MM patient suitability for phase I trials and should now be prospectively validated.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mesotelioma/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Adulto , Anciano , Ensayos Clínicos Fase I como Asunto , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Mesotelioma/mortalidad , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias Peritoneales/mortalidad , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias Pleurales/mortalidad , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Small cell lung cancer (SCLC) is a smoking-induced malignancy with multiple toxin-associated mutations, which accounts for 15% of all lung cancers. It remains a clinical challenge with a rapid doubling time, early dissemination and poor prognosis. Despite multiple clinical trials in SCLC, platinum-based chemotherapy remains the mainstay of treatment in the first line advanced disease setting; good initial responses are nevertheless inevitably followed by disease relapse and survival ultimately remains poor. There are currently no molecularly targeted agents licenced for use in SCLC. Advances in sequencing the cancer genome and other high-throughput profiling technologies have identified aberrant pathways and mechanisms implicated in SCLC development and progression. Novel anti-tumour therapeutics that impact these putative targets are now being developed and investigated in SCLC. In this review, we discuss novel anti-tumour agents assessed in SCLC with reference to the complex molecular mechanisms implicated in SCLC development and progression. We focus on novel DNA damage response inhibitors, immune checkpoint modulators and antibody-drug conjugates that have shown promise in SCLC, and which may potentially transform treatment strategies in this disease. Finally, we envision the future management of SCLC and propose a biomarker-driven translational treatment paradigm for SCLC that incorporates next generation sequencing studies with patient tumours, circulating plasma DNA and functional imaging. Such modern strategies have the potential to transform the management and improve patient outcomes in SCLC.
Asunto(s)
Inmunoterapia/métodos , Neoplasias Pulmonares/terapia , Terapia Molecular Dirigida/métodos , Carcinoma Pulmonar de Células Pequeñas/terapia , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Comunicación Celular/efectos de los fármacos , Comunicación Celular/inmunología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Daño del ADN/efectos de los fármacos , Daño del ADN/inmunología , Reparación del ADN/efectos de los fármacos , Reparación del ADN/inmunología , Descubrimiento de Drogas , Humanos , Sistema Inmunológico/efectos de los fármacos , Medicina de Precisión/métodosRESUMEN
OBJECTIVES: We hypothesised that it was possible to quantify phosphorylation of important nodes in the phosphatidylinositol 3-kinase (PI3K) pathway in cancer cells isolated from pleural effusions of patients with non-small cell lung cancer (NSCLC) and study their correlation to somatic mutations and clinical outcomes. MATERIALS AND METHODS: Cells were immunomagnetically separated from samples of pleural effusion in patients with NSCLC. p-AKT, p-S6K and p-GSK3ß levels were quantified by ELISA; targeted next-generation sequencing was used to characterise mutations in 26 genes. RESULTS: It was possible to quantify phosphoproteins in cells isolated from 38/43 pleural effusions. There was a significant correlation between p-AKT and p-S6K levels [r = 0.85 (95% confidence interval 0.73-0.92), p < 0.0001], but not p-AKT and p-GSK3ß levels [r = 0.19 (95% confidence interval -0.16 to 0.5), p = 0.3]. A wide range of mutations was described and p-S6K was higher in samples that harboured at least one mutation compared to those that did not (p = 0.03). On multivariate analysis, p-S6K levels were significantly associated with poor survival (p < 0.01). CONCLUSION: Our study has shown a correlation between p-AKT levels and p-S6K, but not GSK3ß, suggesting differences in regulation of the distal PI3K pathway by AKT. Higher p-S6K levels were associated with adverse survival, making it a critically important target in NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Derrame Pleural Maligno/patología , Transducción de Señal , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Células Neoplásicas Circulantes/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismoRESUMEN
PURPOSE: Erlotinib is active in advanced non-small cell lung cancer (aNSCLC) particularly in patients with EGFR-sensitizing mutations. The thymidylate synthase inhibitors are active in NSCLC, but capecitabine is not well studied. This study explored the safety and activity of this oral combination. METHODS: This phase Ib trial used a 3 + 3 escalation design with a combination of erlotinib (100 mg daily) with increasing doses of capecitabine (500, 750 and 1000 mg/m(2) BD, 14/21 days), in first- and second-line aNSCLC of adenocarcinoma histology. The DLT was any drug-induced toxicity ≥grade (G)2 causing dose interruption or dose delay during the first 2 cycles. RESULTS: Forty patients were recruited, and 1 patient had an EGFR mutation. Dose escalation stopped at capecitabine 1000 mg/m(2) with expansion to 6 patients due to unpredicted DLTs in 2/6 patients: G2 creatinine rise, G2 anaemia, G3 atrial fibrillation and G3 pneumonia. MTD was capecitabine 750 mg/m(2). First-line dose escalation at the MTD led to unpredicted DLTs in 3/4 patients (G3 troponin rise, G2 rash and G2 hyperbilirubinaemia). MTD expansion in the second-line setting was well tolerated. The most common drug toxicities were gastrointestinal (35 %), followed by skin disorders (28 %). The response rate was 3 % with a disease control rate of 34 %. Median progressive-free survival was 1.6 months (95 % CI 1.4-3.5), and median overall survival was 6.1 months (95 % CI 5.1-10.1). CONCLUSION: The MTD for the combination of capecitabine and erlotinib is 750 mg/m(2) BD, 14/21 days, and 100 mg daily, respectively, which is lower than predicted. Capecitabine did not improve the efficacy of erlotinib in aNSCLC unselected for EGFR mutation.
Asunto(s)
Capecitabina , Carcinoma de Pulmón de Células no Pequeñas , Clorhidrato de Erlotinib , Neoplasias Pulmonares , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina/administración & dosificación , Capecitabina/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/patología , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Receptores ErbB/genética , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
BACKGROUND: There is an urgent need to identify molecular signatures in small cell lung cancer (SCLC) that may select patients who are likely to respond to molecularly targeted therapies. In this study, we investigate the feasibility of undertaking focused molecular analyses on routine diagnostic biopsies in patients with SCLC. METHODS: A series of histopathologically confirmed formalin-fixed, paraffin-embedded SCLC specimens were analysed for epidermal growth factor receptors (EGFR), KRAS, NRAS and BRAF mutations, ALK gene rearrangements and MET amplification. EGFR and KRAS mutation testing was evaluated using real time polymerase chain reaction (RT-PCR cobas(®)), BRAF and NRAS mutations using multiplex PCR and capillary electrophoresis-single strand conformation analysis, and ALK and MET aberrations with fluorescent in situ hybridization. All genetic aberrations detected were validated independently. RESULTS: A total of 105 patients diagnosed with SCLC between July 1990 and September 2006 were included. 60 (57 %) patients had suitable tumour tissue for molecular testing. 25 patients were successfully evaluated for all six pre-defined molecular aberrations. Eleven patients failed all molecular analysis. No mutations in EGFR, KRAS and NRAS were detected, and no ALK gene rearrangements or MET gene amplifications were identified. A V600E substitution in BRAF was detected in a Caucasian male smoker diagnosed with SCLC with squamoid and glandular features. CONCLUSION: The paucity of patients with sufficient tumour tissue, quality of DNA extracted and low frequency of aberrations detected indicate that alternative molecular characterisation approaches are necessary, such as the use of circulating plasma DNA in patients with SCLC.