Imunoterapie checkpoint inhibitory prokázala pozoruhodný přínos v léčbě řady onkologických diagnóz včetně karcinomu plic. Standardně je indikována léčba inhibitory receptoru programované buněčné smrti 1 / ligandu programované buněčné smrti 1 (programmed cell death protein 1 / programmed cell death-ligand 1, PD-1/PD-LI) v monoterapii, jako kombinovaná imunoterapie s inhibitory cytotoxického antigenu 4 asociovaného s T lymfocyty (cytotoxic T-lymphocyte antigen 4, CTLA-4) nebo v kombinaci s jinými léčebnými modalitami, např. chemoterapií či radioterapií. Tento článek si klade za cíl představit aktuální možnosti léčby karcinomu plic durvalumabem - pětiletá data studie PACIFIC a tříletá data studie CASPIAN.

Immunotherapy with checkpoint inhibitors has demonstrated remarkable therapeutic benefits in many oncological diagnoses, including lung cancer. Treatment with programmed cell death protein 1 / programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors can be indicated in various ways: as monotherapy, combination immunotherapy with cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors or in combination with other treatment modalities as chemotherapy or radiotherapy. This article aims to present current treatment options of lung cancer with durvalumab - the five-year data of the PACIFIC trial and the three-year data of the CASPIAN trial.

• Klíčová slova
• durvalumab,
• MeSH
• analýza přežití MeSH
• imunoterapie MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• monoklonální protilátky aplikace a dávkování   ekonomika   MeSH
• multicentrické studie jako téma MeSH
• nádory plic * farmakoterapie   radioterapie   MeSH
• protinádorové látky imunologicky aktivní * aplikace a dávkování   ekonomika   MeSH
• randomizované kontrolované studie jako téma MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

Malobuněčný karcinom plic patří k nejagresivnějším zhoubným nádorům s nepříznivou prognózou. Základem léčby je systémová chemoterapie platinovým derivátem a etoposidem. Imunoterapie checkpoint inhibitory prokázala pozoruhodný přínos v léčbě řady onkologických diagnóz včetně karcinomu plic. Durvalumab prokázal léčebný benefit v rámci studie CASPIAN.

Small cell lung cancer is one of the most aggressive cancers. The prognosis of the disease is not favorable. The basis of treatment is systemic chemotherapy with a platinum derivative and etopo- side. Immunotherapy with check-point inhibitors has shown remarkable benefit in the treatment of a number of oncological diagnoses, including lung cancer. Durvalumab demonstrated therapeutic benefit in the CASPIAN trial.

• Klíčová slova
• durvalumab,
• MeSH
• etoposid terapeutické užití   MeSH
• imunoterapie * metody   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• malobuněčný karcinom plic terapie   MeSH
• platina terapeutické užití   MeSH
• protinádorové látky imunologicky aktivní MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• přehledy MeSH

• Klíčová slova
• durvalumab, studie PACIFIC, studie CASPIAN,
• MeSH
• analýza přežití MeSH
• doba přežití bez progrese choroby MeSH
• dvojitá slepá metoda MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• monoklonální protilátky * farmakologie   terapeutické užití   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   radioterapie   MeSH
• protinádorové látky imunologicky aktivní * farmakologie   terapeutické užití   MeSH
• protokoly protinádorové léčby MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC. METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. FUNDING: AstraZeneca.

• MeSH
• cisplatina aplikace a dávkování   škodlivé účinky   MeSH
• doba přežití bez progrese choroby MeSH
• etoposid aplikace a dávkování   škodlivé účinky   MeSH
• fytogenní protinádorové látky aplikace a dávkování   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   MeSH
• karboplatina aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malobuněčný karcinom plic farmakoterapie   mortalita   MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• nádory plic farmakoterapie   mortalita   MeSH
• protinádorové látky imunologicky aktivní aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum-etoposide) showed a significant improvement in overall survival versus platinum-etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone. METHODS: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or platinum-etoposide alone. In all groups, patients received etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m2 on day 1 of each cycle. Patients in the platinum-etoposide group received up to six cycles of platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum-etoposide versus platinum-etoposide and for durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. FINDINGS: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not associated with a significant improvement in overall survival versus platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months (9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus 10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum-etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and thrombocytopenia [n=1 each]). INTERPRETATION: First-line durvalumab plus platinum-etoposide showed sustained overall survival improvement versus platinum-etoposide but the addition of tremelimumab to durvalumab plus platinum-etoposide did not significantly improve outcomes versus platinum-etoposide. These results support the use of durvalumab plus platinum-etoposide as a new standard of care for the first-line treatment of ES-SCLC. FUNDING: AstraZeneca.

• MeSH
• časové faktory MeSH
• cisplatina aplikace a dávkování   škodlivé účinky   MeSH
• doba přežití bez progrese choroby MeSH
• etoposid aplikace a dávkování   škodlivé účinky   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• karboplatina aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malobuněčný karcinom plic farmakoterapie   mortalita   patologie   MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• nádory plic farmakoterapie   mortalita   patologie   MeSH
• progrese nemoci MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

• Klíčová slova
• cytopenie,
• MeSH
• analýza přežití MeSH
• chimerické antigenní receptory * imunologie   terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom terapie   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• nežádoucí účinky léčiv * MeSH
• statistika jako téma MeSH
• T-lymfocyty imunologie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH

Durvalumab představuje monoklonální protilátku, která stimuluje imunitní systém v rozpoznávání a usmrcování nádorových buněk. Durvalumab prokázal svoji účinnost i bezpečnost v léčbě lokálně pokročilého neresekabilního nemalobuněčného plicního karcinomu po kurativní chemoradioterapii jako udržovací léčba na základě výsledků klinické studie PACIFIC, jejíž aktualizovaná data byla publikována v tomto roce. Současně získal durvalumab registraci pro léčbu generalizovaného malobuněčného plicního karcinomu s chemoterapií a následně jako monoterapie na základě studie CASPIAN, jejíž aktualizovaná data jsou opět předmětem tohoto sdělení. Úhrada z veřejného zdravotního pojištění v této druhé indikaci v tuto chvíli bohužel chybí. Současně jsou prezentovány povzbudivé výsledky pacienta s malobuněčným plicním karcinomem léčeného durvalumabem v našem komplexním onkologickém centru.

Durvalumab represents a monoclonal antibody which stimulates the immune system in the detection and killing of the tumor cells. Durvalumab has proven safety and effectivity in the treatment of the locally advanced non-resectable non-small cell lung cancer after curative chemoradiotherapy as maintenance therapy based on the results of the clinical trial PACIFIC. The updated results of this trial were published this year. At the same time durvalumab gained registration for the treatment of the metastatic small cell lung cancer with chemotherapy and as maintenance therapy based on the results of the CASPIAN trial, which updated results are again presented in this paper. Unfortunately the health insurance reimbursement for the second mentioned indication is missing so far. There is also presented very promising case report with patient with small cell lung cancer treated with durvalumab.

• Klíčová slova
• durvalumab, studie PACIFIC, studie CASPIAN,
• MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• malobuněčný karcinom plic diagnostické zobrazování   diagnóza   farmakoterapie   MeSH
• monoklonální protilátky * terapeutické užití   MeSH
• nemalobuněčný karcinom plic * diagnostické zobrazování   diagnóza   farmakoterapie   MeSH
• počítačová rentgenová tomografie MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH

Introduction: In the phase 3 study involving the use of durvalumab with or without tremelimumab in combination with platinum-based chemotherapy in untreated extensive-stage SCLC (CASPIAN study), first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone (p = 0.0047). We report exploratory subgroup analyses of treatment patterns and outcomes according to the presence of baseline brain or central nervous system metastases. Methods: Patients (WHO performance status 0 or 1), including those with asymptomatic or treated-and-stable brain metastases, were randomized to four cycles of durvalumab plus EP followed by maintenance durvalumab until progression or up to six cycles of EP and optional prophylactic cranial irradiation. Prespecified analyses of OS and progression-free survival (PFS) in subgroups with or without brain metastases used unstratified-Cox proportional hazards models. The data cutoff was on January 27, 2020. Results: At baseline, 28 out of 268 patients (10.4%) in the durvalumab plus EP arm and 27 out of 269 patients (10.0%) in the EP arm had known brain metastases, of whom 3 of 28 (10.7%) and 4 of 27 (14.8%) had previous brain radiotherapy, respectively. Durvalumab plus EP (versus EP alone) prolonged OS (hazard ratio, 95% confidence interval) in patients with (0.79, 0.44-1.41) or without (0.76, 0.62-0.92) brain metastases, with similar PFS results (0.73, 0.42-1.29 and 0.80, 0.66-0.97, respectively). Among patients without brain metastases, similar proportions in each arm developed new brain lesions as part of their first progression (8.8% and 9.5%), although 8.3% in the EP arm received prophylactic cranial irradiation. Similar proportions in each arm received subsequent brain radiotherapy (20.5% and 21.2%), although more common in patients with than without baseline brain metastases (45.5% and 18.0%). Conclusions: The OS and PFS benefit with first-line durvalumab plus EP were maintained irrespective of the presence of brain metastases, further supporting its standard-of-care use.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: In the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab plus tremelimumab plus EP numerically improved OS versus EP, but did not reach statistical significance. Here we report updated OS in censored patients after median follow-up of >3 years. PATIENTS AND METHODS: 805 patients with treatment-naïve ES-SCLC were randomized 1 : 1 : 1 to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP. The two primary endpoints were OS for durvalumab plus EP versus EP and for durvalumab plus tremelimumab plus EP versus EP. RESULTS: As of 22 March 2021 (median follow-up 39.4 months, 86% maturity), durvalumab plus EP continued to demonstrate improved OS versus EP: hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.60-0.86; nominal P = 0.0003]; median OS was 12.9 versus 10.5 months, and 36-month OS rate was 17.6% versus 5.8%. Durvalumab plus tremelimumab plus EP continued to numerically improve OS versus EP: HR 0.81 (95% CI: 0.67-0.97; nominal P = 0.0200); median OS was 10.4 months, and 36-month OS rate was 15.3%. Twenty-seven and nineteen patients in the durvalumab plus EP and durvalumab plus tremelimumab plus EP arms, respectively, remained on durvalumab treatment at data cut-off. CONCLUSIONS: Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus EP versus EP, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus EP as first-line standard of care for ES-SCLC.

• MeSH
• etoposid terapeutické užití   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• malobuněčný karcinom plic * farmakoterapie   MeSH
• monoklonální protilátky MeSH
• nádory plic * farmakoterapie   MeSH
• platina terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

OBJECTIVES: In the phase III CASPIAN study, first-line durvalumab plus etoposide in combination with either cisplatin or carboplatin (EP) significantly improved overall survival (primary endpoint) versus EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) at the interim analysis. Here we report patient-reported outcomes (PROs). MATERIALS AND METHODS: Treatment-naïve patients with ES-SCLC received 4 cycles of durvalumab plus EP every 3 weeks followed by maintenance durvalumab every 4 weeks until progression, or up to 6 cycles of EP every 3 weeks. PROs, assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), were prespecified secondary endpoints. Changes from baseline to disease progression or 12 months in prespecified key disease-related symptoms (cough, dyspnea, chest pain, fatigue, appetite loss) were analyzed with a mixed model for repeated measures. Time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization was analyzed. RESULTS: In the durvalumab plus EP and EP arms, 261 and 260 patients were PRO-evaluable. Patients in both arms experienced numerically reduced symptom burden over 12 months or until progression for key symptoms. For the improvements from baseline in appetite loss, the between-arm difference was statistically significant, favoring durvalumab plus EP (difference, -4.5; 99% CI: -9.04, -0.04; nominal p = 0.009). Patients experienced longer TTD with durvalumab plus EP versus EP for all symptoms (hazard ratio [95% CI] for key symptoms: cough 0.78 [0.600‒1.026]; dyspnea 0.79 [0.625‒1.006]; chest pain 0.76 [0.575‒0.996]; fatigue 0.82 [0.653‒1.027]; appetite loss 0.70 [0.542‒0.899]), functioning, and global health status/QoL. CONCLUSION: Addition of durvalumab to first-line EP maintained QoL and delayed worsening of patient-reported symptoms, functioning, and global health status/QoL compared with EP.

• MeSH
• cisplatina terapeutické užití   MeSH
• etoposid terapeutické užití   MeSH
• hodnocení výsledků péče pacientem MeSH
• kvalita života MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• nádory plic * farmakoterapie   MeSH
• platina terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH