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INTRODUCTION: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients. METHODS: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point. RESULTS: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%). CONCLUSIONS: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1/metabolismo , Carcinogénesis , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Perforación Intestinal/etiología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/mortalidad , Masculino , Metástasis de la Neoplasia , Estadificación de Neoplasias , Insuficiencia Respiratoria/etiología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVES: Early clinical trials showed promising outcomes with immune-checkpoint inhibitors (ICI) in a subset of patients with relapsed small-cell lung carcinoma (SCLC). The aim of this retrospective analysis was to assess the efficacy and safety of ICI for relapsed SCLC in a real-world patient population. METHODS: Nine cancer centres in Switzerland contributed data to this cohort. Responses were assessed by the local investigators using standard RECIST v1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were analysed by the Kaplan-Meier method. Associations between potential predictive markers and survival endpoints were probed by Cox proportional hazards. RESULTS: Forty-five patients were included in the analysis. Median age was 63 years, 73% were males and 18% had an ECOG performance status (PS) ≥ 2. ICIs were given as second-line treatment in 60%. Twenty-four patients (53%) received ipilimumab with nivolumab. Twenty-eight patients (62%) had undergone irradiation (RT) prior to or during ICI. Overall response rate (ORR) was 29% and median PFS and OS were 2.3 and 6.5 months, respectively. Median duration of response was 9 months (95% CI 2.8-NA). Five patients maintained their response for > 6 months, all of them receiving combination treatment. There were no new safety signals. CONCLUSION: This is the first report of "real-world" data on ICI in relapsed SCLC also including patients with poor PS. Promising durable responses were observed. No biological prognostic marker could be identified.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia/mortalidad , Neoplasias Pulmonares/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Biomarcadores de Tumor/análisis , Femenino , Estudios de Seguimiento , Humanos , Ipilimumab/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Nivolumab/administración & dosificación , Pronóstico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de Supervivencia , SuizaRESUMEN
Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical practice and highlighting the potential of this new class of targeted therapies. This review summarizes the pharmacological and molecular background of the main drug conjugation systems, namely antibody drug conjugates (ADCs), immunotoxins and immunoliposomes. All these compounds combine the specific targeting moiety of an antibody or similar construct with the efficacy of a toxic drug. The aim of this strategy is to target tumor cells specifically while sparing normal tissue, thus resulting in high efficacy and low toxicity. Recently, several strategies have been investigated in phase I clinical trials and some have entered phase III clinical development. This review provides a detailed overview of various strategies and critically discusses the most relevant achievements. Examples of the most advanced compounds include T-DM1 and brentuximab vedotin. However, additional promising strategies such as immunotoxins and immunoliposmes are already in clinical development. In summary, targeted drug delivery by drug conjugates is a new emerging class of anti-cancer therapy that may play a major role in the future.
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Anticuerpos Monoclonales Humanizados , Antineoplásicos , Inmunoconjugados , Inmunotoxinas , Liposomas , Maitansina/análogos & derivados , Neoplasias , Ado-Trastuzumab Emtansina , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/inmunología , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Brentuximab Vedotina , Humanos , Inmunoconjugados/inmunología , Inmunoconjugados/farmacocinética , Inmunoconjugados/uso terapéutico , Inmunotoxinas/inmunología , Inmunotoxinas/farmacocinética , Inmunotoxinas/uso terapéutico , Liposomas/inmunología , Liposomas/farmacocinética , Liposomas/uso terapéutico , Maitansina/inmunología , Maitansina/farmacocinética , Maitansina/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , TrastuzumabRESUMEN
INTRODUCTION: Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy. METHODS: Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients. These consisted of immune-inflammatory indexes (neutrophil-lymphocyte ratio [NLR], systemic immune-inflammatory index [SII], lactate dehydrogenase [LDH]) along with other already known prognostic baseline characteristics and laboratory values. Cut-offs were chosen independently of outcome. Based on Cox multivariable analysis for PFS in the whole cohort, a risk factor model was built to illustrate the prognostic stratification of patients by the combination of the derived independent prognostic factors, taking into account the EORTC score, a validated prognostic score in MPM. All models were stratified by histology and adjusted by treatment. RESULTS: In the stratified multivariable analysis in the whole cohort, high SII (hazard ratio (HR) 2.06; 95%CI 1.39-3.05) and low haemoglobin (HR 1.62; 95%CI 1.06-2.50) were associated with worse PFS. Based on these two prognostic factors, a mesothelioma risk score (MRS) was constructed with three PFS risk prognosis categories: favourable, intermediate and poor with 0, 1 and 2 risk factors, respectively (corresponding percent of cohort: 24%, 34% and 42% and median PFS: 5.8, 4.2 and 2.1 months). The derived MRS stratified the prognosis for PFS and OS, overall and within each of the EORTC groups. No significant predictors of treatment benefit were identified. CONCLUSIONS: The proposed MRS is prognostic of patient outcome and it fine-tunes the prognosis of patients with pre-treated MPM alone or when used with the already established EORTC score.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Inmunoterapia , Neoplasias Pulmonares/patología , Mesotelioma/patología , Neoplasias Pleurales/patología , Pronóstico , Estudios RetrospectivosRESUMEN
PURPOSE: For patients with resectable stage IIIA(N2) non-small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab. METHODS: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m2 and docetaxel 85 mg/m2 once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%. RESULTS: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related. CONCLUSION: The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%.
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Neoadyuvante , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioterapia Adyuvante , Cisplatino/uso terapéutico , Docetaxel/uso terapéutico , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/mortalidad , Estadificación de Neoplasias , Neumonectomía , Supervivencia sin Progresión , Suiza , Factores de TiempoRESUMEN
BACKGROUND: Scientific data on the image modality to be used in postcurative treatment surveillance of non-small cell lung cancer patients are scarce. This prospective randomized pilot trial compared the performance of integrated 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) and contrast-enhanced computed tomography (CE-CT). METHODS: After termination of curative-intent treatment, patients were randomly assigned to the PET-CT or the CE-CT group. Imaging was performed every 6 months for 2 years. If suspicious radiologic findings were detected or patients became symptomatic, a diagnostic workup was initiated. Sensitivity, specificity, and positive predictive value for detecting cancer recurrence were calculated for both imaging procedures. RESULTS: The study enrolled 96 patients. In 14 of 50 patients (28%) in the PET-CT group and in 14 of 46 patients (30%) in the CE-CT group, a suspicious radiologic finding was confirmed as cancer recurrence after diagnostic workup. False-positive findings were detected in 11 patients (22%) of the PET-CT group and in 8 patients (17%) of the CE-CT group. The sensitivity, specificity, and positive predictive value for detecting cancer recurrence (95% confidence interval) were 0.88 (0.62 to 0.98), 0.62 (0.42 to 0.79), and 0.56 (0.35 to 0.76) for PET-CT and 0.93 (0.68 to 1.00), 0.72 (0.53 to 0.87), and 0.64 (0.41to 0.83) for CE-CT, respectively. CONCLUSIONS: The results of our study suggest that PET-CT is not superior to CE-CT in detecting cancer recurrence during 2 years after curative-intent treatment of non-small cell lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Fluorodesoxiglucosa F18/farmacología , Neoplasias Pulmonares/diagnóstico , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Radiofármacos/farmacología , Reproducibilidad de los Resultados , Suiza/epidemiologíaRESUMEN
BACKGROUND: Data show that the initial specialist's image interpretation and final multidisciplinary tumor board (MTB) assessment can vary substantially in the pretherapeutic cancer setting. The aim of this post hoc analysis was to investigate the concordance of the specialist's and MTB's image interpretations in patients undergoing systematic posttreatment lung cancer image surveillance. METHODS: In the initial prospective study, lung cancer patients who had received curative-intent treatment were randomly assigned to undergo either contrast-enhanced computed tomography (CE-CT) or integrated 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT). Imaging was performed every 6 months for 2 years, and all imaging studies were finally assessed by our MTB. This post hoc analysis assessed differences between the initial specialist's image interpretation and the final MTB's image interpretation. RESULTS: In 89 patients, 266 imaging studies (129 PET-CT, 137 CE-CT) were analyzed. In 87.2% (88.4, 86.1%) of the studies, complete concordance was found. Out of the 12.8% (11.6, 13.9%) with discordant results, 7.5% (6.9, 8.0%) had implications for alterations in patient management (major disagreements).Twenty major disagreements were detected in 17 study patients. Retrospectively, in eight out of these 17 (47%) patients, in contrast to the MTB's view, the specialist's interpretation was more appropriate, whereas in nine out of 17 patients (53%), the MTB's interpretation was more accurate. CONCLUSIONS: In an experienced MTB, the agreement between imaging specialists and the rest of the MTB with regard to the interpretation of images is high in a setting of posttreatment lung cancer image surveillance. It seems that in cases of disagreements, the rates of more accurate interpretation are well balanced between imaging specialists and the MTB. TRIAL REGISTRATION: ISRCTN16281786, Date 23. February 2017.