KEYNOTE Dotaz Zobrazit nápovědu
Asi u 25 % pacientů s renálním karcinomem (RCC) dochází k recidivě po radikálním odstranění nádoru. Po několika desetiletích neúspěšných klinických studií jsme se dočkali významného pokroku a nového standardu adjuvantní léčby pacientů s RCC a vyšším rizikem recidivy. Randomizovaná, dvojitě zaslepená studie KEYNOTE-564 prokázala, že pembrolizumab podávaný po dobu 1 roku významně zlepšuje přežití bez rekurence i celkové přežití. Léčba je plně hrazená a je novým standardem v terapii RCC.
Approximately 25% of patients with renal cell carcinoma (RCC) relapse after radical removal of the tumour. After several decades of unsuccessful clinical trials, significant progress has been achieved recently and a new standard of adjuvant treatment for patients with RCC and a higher risk of recurrence has been established. The randomized, double-blind KEYNOTE-564 trial demonstrated that pembrolizumab administered for 1 year after surgery significantly improved both recurrence-free and overall survival. The treatment is fully reimbursed and is the new standard in RCC therapy.
- Klíčová slova
- pembrolizumab,
- MeSH
- adjuvantní chemoterapie * metody MeSH
- analýza přežití MeSH
- everolimus aplikace a dávkování MeSH
- imunoterapie metody MeSH
- inhibitory tyrosinkinasy terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- nádory ledvin * farmakoterapie terapie MeSH
- randomizované kontrolované studie jako téma MeSH
- riziko MeSH
- sekundární prevence metody MeSH
- TOR serin-threoninkinasy antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
Více než polovina všech případů nádorových onemocnění plic postihuje pacienty ve věku ≥ 65 let, přičemž platí, že starší pacienti mají ve srovnání s mladšími pacienty vyšší mortalitu. Vyšší výskyt nádorů plic u starších osob odráží celosvětový trend stárnutí populace, roli také hraje zvýšená incidence nádorových onemocnění, asociovaná s věkem. Navzdory vysoké incidenci nádorových onemocnění plic u starších osob nebývají tito pacienti dostatečně zastoupeni v klinických studiích. Do studií bývají nejméně často zařazováni pacienti ve věku ≥ 75 let. Zatímco věk sám o sobě nebývá vylučovacím kritériem, vstup starších pacientů do klinických studií je limitován (pacienti nemusejí být schopni léčbu absolvovat, bývají v horším výkonnostním stavu, mívají komorbidity nebo u nich probíhá jiná léčba). Navíc se předpokládá, že s narůstajícím věkem dochází k poklesu funkcí imunitního systému a jeho remodelaci (imunosenescence), což může ovlivňovat účinnost imunoterapie u starších pa cientů. Limitovaná účast starších pacientů ve studiích a nedostatek dat o účinnosti a bezpečnosti protinádorové léčby v této konkrétní populaci pacientů tak u starších pacientů omezuje rozvoj léčebných doporučení založených na důkazech.
- Klíčová slova
- pembrolizumab, KEYNOTE, poolovaná analýza dat,
- MeSH
- analýza přežití MeSH
- humanizované monoklonální protilátky * aplikace a dávkování MeSH
- lidé MeSH
- nemalobuněčný karcinom plic * farmakoterapie MeSH
- protinádorové látky aplikace a dávkování MeSH
- randomizované kontrolované studie jako téma MeSH
- senioři MeSH
- statistika jako téma MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
BACKGROUND: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. FINDINGS: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab. INTERPRETATION: Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy. FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.
- MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- humanizované monoklonální protilátky MeSH
- hypertenze * MeSH
- karcinom z renálních buněk * farmakoterapie chirurgie MeSH
- lidé MeSH
- nádory ledvin * farmakoterapie etiologie chirurgie MeSH
- následné studie MeSH
- nefrektomie škodlivé účinky MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Klíčová slova
- pembrolizumab, studie KEYNOTE-355,
- MeSH
- analýza přežití MeSH
- doba přežití bez progrese choroby MeSH
- humanizované monoklonální protilátky farmakologie terapeutické užití MeSH
- lidé MeSH
- nádory prsu farmakoterapie MeSH
- protinádorové látky imunologicky aktivní farmakologie terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- randomizované kontrolované studie jako téma MeSH
- triple-negativní karcinom prsu * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
BACKGROUND: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC. METHODS: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting. FINDINGS: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo. INTERPRETATION: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
- MeSH
- antigeny CD274 metabolismus MeSH
- humanizované monoklonální protilátky MeSH
- hypertenze * farmakoterapie MeSH
- lidé MeSH
- myokarditida * MeSH
- nádory plic * farmakoterapie metabolismus chirurgie MeSH
- nemalobuněčný karcinom plic * farmakoterapie chirurgie 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
BACKGROUND: In patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results. PATIENTS AND METHODS: In KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score. RESULTS: No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (-2.5; 95% CI -5.2 to 0.1), EORTC QLQ-C30 physical functioning (-0.87; 95% CI -2.7 to 1.0), and FKSI-DRS (-0.7; 95% CI -1.2 to -0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%). CONCLUSIONS: Adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03142334.
- MeSH
- hodnocení výsledků péče pacientem MeSH
- humanizované monoklonální protilátky * MeSH
- karcinom z renálních buněk * farmakoterapie chirurgie MeSH
- kvalita života MeSH
- lidé MeSH
- nádory ledvin * farmakoterapie chirurgie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
