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Pembrolizumab monotherapy or in combination with chemotherapy is approved as first-line treatment in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) based on improved overall survival (OS) versus EXTREME regimen in the KEYNOTE-048 trial. The clinical outcomes of pembrolizumab were compared with other recommended first-line treatments in R/M HNSCC in this study through a Bayesian network meta-analysis. A systematic literature review was conducted in July 2022, from which six trials that matched the KEYNOTE-048 patient eligibility criteria were included in the network. The OS and progression-free survival (PFS) outcomes were compared in the approved pembrolizumab indication (i.e., total population for pembrolizumab in combination with chemotherapy and combined positive score [CPS] ≥ 1 population for pembrolizumab monotherapy). A significant OS improvement was observed for pembrolizumab in combination with chemotherapy and pembrolizumab monotherapy versus EXTREME regimen (hazard ratio, 95% credible interval: 0.72, 0.60-0.86; 0.73, 0.60-0.88), platinum+5- FU (0.58, 0.43-0.76; 0.58, 0.44-0.78), and platinum+paclitaxel (0.53, 0.35-0.79; 0.53, 0.35-0.81), respectively. A non-significant numeric trend in OS improvement was observed versus the TPEx regimen. PFS was comparable with most first-line treatments and was improved versus platinum+5-FU (0.48, 0.36-0.64; 0.59, 0.45-0.79). Additional analyses in higher CPS subgroups also showed consistent results. Overall, our study results showed an improvement in OS outcomes versus alternative first-line treatments, consistent with the findings of the KEYNOTE-048 trial. These data support using pembrolizumab as a suitable firstline treatment option in R/M HNSCC.
Pembrolizumabe em monoterapia ou em combinação com quimioterapia é aprovado como tratamento de primeira linha em carcinoma de células escamosas recorrente/metastático de cabeça e pescoço (CECCP R/M) com base na melhora da sobrevida global (OS), em comparação com o esquema EXTREME no estudo KEYNOTE-048. Esse estudo comparou os resultados clínicos de pembrolizumabe com outros tratamentos recomendados de primeira linha em CECCP R/M por meio de uma metanálise de rede bayesiana. Uma revisão sistemática da literatura foi conduzida em julho de 2022, a partir da qual seis ensaios clínicos que atendiam aos critérios de elegibilidade de pacientes do KEYNOTE-048 foram incluídos na rede. Os desfechos de OS e sobrevida livre de progressão (PFS) foram comparados na indicação de pembrolizumabe (população total para pembrolizumabe em combinação com quimioterapia e população com escore positivo combinado [CPS] ≥ 1 em monoterapia com pembrolizumabe). Foi observada melhora significativa na OS para pembrolizumabe em combinação com quimioterapia e monoterapia com pembrolizumabe versus o esquema EXTREME (razão de risco, intervalo de confiança de 95%: 0,72, 0,60-0,86; 0,73, 0,60-0,88), platina+5-FU (0,58, 0,43-0,76; 0,58, 0,44-0,78) e platina+paclitaxel (0,53, 0,35-0,79; 0,53, 0,35-0,81), respectivamente. Uma tendência numérica não significativa de melhoria na OS foi observada em relação ao esquema TPEx. A PFS foi comparável com a maioria dos tratamentos de primeira linha e melhor em relação à platina+5-FU (0,48, 0,36-0,64; 0,59, 0,45-0,79). Análises adicionais em subgrupos com CPS mais elevado também mostraram resultados consistentes. No geral, os resultados de nosso estudo mostraram melhora nos desfechos de OS em comparação aos tratamentos de primeira linha alternativos, consistentes com os achados do estudo KEYNOTE-048. Esses dados apoiam o uso de pembrolizumabe como opção de tratamento em primeira linha em pacientes com CECCP R/M.
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Tumeurs de l'ovaire , Coûts et analyse des coûts , Santé Complémentaire , Inhibiteurs de poly(ADP-ribose) polymérasesRÉSUMÉ
@#Objective To develop and verify a cation exchange high performance liquid chromatography(CEX-HPLC)method for the detection of charge variants of pembrolizumab.Methods Pembrolizumab was bound to the exchange column matrix by using MabPac SCX-10 column,and the variants with different charges were eluted by gradually increasing the salt concentration of the mobile phase.The specificity,precision,linear range,accuracy and durability of the method were verified,and the charge variants of three batches of pembrolizumab finished products were detected by using the developed method.Results The resolution of the last acidic isomer peak and the first basic isomer peak of pembrolizumab from the main peak were 1.28 and 1.42,respectively.The mobile phase A and preparation buffer had no obvious interference peaks at the peak of the sample;The RSD values of the precision verification were all less than 2.0%;The total peak area,main peak area,acidic isomer peak area and basic isomer peak area of the standard all exhibited good linear relationship with the theoretical dilution concentration with each R~2 of 1.00;The recovery rates of the total peak area and main peak area of the standard at three concentrations were between 96.81% and 106.07%;When pH value of the mobile phase was within the range of 6.30±0.10,the RSD values of the total peak area and main peak area percentage of the standard were1.5% and 1.9%,and when the column temperature was within the range of(35±4) ℃,the RSD values of the total peak area and main peak area percentage of the standard were 0.4% and 0.3%,respectively.The RSD value of the main peak retention time of the three batches of finished products was 0.Conclusion The developed CEX-HPLC method can effectively separate the acidic isomers,main peaks and basic isomers of pembrolizumab with good specificity,precision and accuracy,which can be used for the follow-up research and development of pembrolizumab,the process verification of expanding production and the stability research.
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An elderly female melanoma patient who experienced severe liver injury after treatment with pembrolizumab and axitinib,which improved with glucocorticoid therapy.Through medication analysis and adverse reaction scale evaluated,it was considered that severe liver injury was more closely related to the immune checkpoint inhibitor,pembrolizumab.After a comprehensive analysis of the relationship between liver injury and immunotherapy,as well as the benefits and risks of immunotherapy for patients,immunotherapy was rechallenged 40 days after discontinuation of pembrolizumab.Restarting treatment with pembrolizumab after immune-mediated hepatitis poses a risk of recurrence of hepatotoxicity.After reviewing related literature,it had been found that the incidence of severe hepatotoxicity caused by rechallenging treatment was low,and the overall safety was controllable.Pembrolizumab had brought therapeutic benefits to patients,with no further immune-mediated liver injury of 5 cycles medication.This case can provide a reference for rechallenging immunotherapy after immune-mediated hepatitis.
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Objective:To analyze the safety and efficacy of PD-1 inhibitors versus chemotherapy or ipilimumab in advanced melanoma.Methods:PubMed,CNKI,VIP and Wanfang databases were searched to collect randomised controlled trials of PD-1 inhibi-tors in treatment of advanced melanoma.The search time was from the establishment of the database to May 1,2022.Two reviewers independently screened the literature,extracted data,and assessed risk of bias of included studies.Meta-analysis was performed using RevMan5.4 and STATA16 software.Results:A total of 7 studies were included.Meta-analysis results show that:①Safety:Compared with chemotherapy,PD-1 inhibitor treatment had fewer adverse events,especially in the blood system;compared with ipilimumab alone,PD-1 inhibitor combined with ipilimumab had more adverse events,especially liver function indicators;there was no signifi-cant difference in the incidence of total adverse events between PD-1 inhibitor monotherapy and ipilimumab monotherapy.②Efficacy:The PFS,OS and ORR of PD-1 inhibitor versus chemotherapy or ipilimumab were HR=0.54,95%CI(0.45,0.62),P<0.05,HR= 0.69,95%CI(0.58,0.80),P=0.03 and OR=3.16,95%CI(2.59,3.86),P<0.05,respectively.Conclusion:PD-1 inhibitors have good efficacy in treatment of advanced melanoma,while different combination methods and different control treatments may have different efficacy.Limited by the quantity and quality of included studies,more research evidence is needed to support this.
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Resumen La gastritis inmunomediada es un efecto adverso raro en pacientes bajo tratamiento con inhibidores del punto de control inmunitario; se presenta el caso de una pa ciente con carcinoma de cuello uterino bajo tratamiento con pembrolizumab que ingresa con náuseas, vómitos y pérdida de peso. La endoscopía demostró una lesión ulcerada cubierta por moco en antro y cuerpo gástrico. La biopsia reveló una extensa denudación de la muco sa gástrica con material fibrinoleucocitario. La lámina propia presentó incremento del infiltrado inflamatorio linfocitario y polimorfonuclear. La inmunohistoquímica confirmó positividad para PDL1 (clon SP2630) y un score positivo combinado (CPS) del 35%, con una contribución relativa de células epiteliales de 25% y de células infla matorias de 10%. Luego de tres semanas de tratamiento con 30 mg de meprednisona, la endoscopía constató un estómago con contenido mucoso claro; fundus y cuerpo sin lesiones, antro con mucosa congestiva y múltiples úlceras extensas y superficiales cubiertas por fibrina. Se describen los aspectos diagnósticos y terapéuticos de la gastritis inmunomediada.
Abstract Immune-mediated gastritis is a rare adverse effect in patients treated with immune checkpoint inhibitors. We present a patient with a diagnosis of cervical carcinoma under treatment with pembrolizumab who was admitted with nausea, vomiting and weight loss; an endoscopy revealed a ulcerated lesion covered by mucus in the antrum and gastric body. The biopsy revealed extensive denudation of the gastric mucosa with fibrin leukocyte reaction. Into the lamina propria, an increased lymphocytic and polymorphonuclear inflammatory infiltrate was ob served. Immunohistochemistry confirmed positivity for PDL1 (clone SP2630) and combined positive score of 35%, with a relative contribution of epithelial cells of 25% and inflammatory cells of 10%. After three weeks with 30 mg meprednisone, a new endoscopy revealed a stomach with clear mucus content; fundus and body without lesions, and an antrum with congestive mucosa and multiple su perficial ulcers covered by fibrin. Diagnostic and therapeu tic aspects of immune-mediated gastritis are described.
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Se presenta el caso de un paciente con diagnóstico de adenocarcinoma de pulmón metastásico que, luego de realizar cinco meses de tratamiento con pembrolizumab, presentó neumonitis grado 2, interpretada como toxicidad por pembrolizumab con buena respuesta y resolución de los infiltrados con la suspensión del inmunomodulador y la administración de corticoides(AU)
We present the case of a patient diagnosed with metastatic lung adenocarcinoma who, after five months of treatment with pembrolizumab, presented grade 2 pneumonitis, interpreted as pembrolizumab toxicity, with a good response and resolution of the infiltrates with the suspension of the immunomodulator and the administration of corticosteroids(AU)
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Hormones corticosurrénaliennesRÉSUMÉ
Background: Immunotherapy is a treatment that uses a person’s immune system to fight cancer. Immunotherapy can boost or change how the immune system works so it can find and attack cancer cells. Among several cancers, metastatic cancer causes high mortality, and immunotherapies are expected to be effective in the prevention and treatment of metastatic cancer patients. In Bangladesh, we do have not enough research-based information regarding the role of immunotherapy in treating metastatic cancer patients. This study aimed to assess the role of immunotherapy in treating metastatic cancer patients. Methods: This prospective observational study was conducted in combined military hospital Dhaka, Bangladesh during the period from 26 March 2021 to 21 July 2022. In total 19 patients with metastatic cancer were enrolled in this study as study subjects. Proper written consent was taken from all the participants before data collection. Two (02) different outcomes were studied in this study; progression-free survival (PFS) and side effect percentages. A predesigned questionnaire was used in data collection. All data were processed, analyzed, and disseminated by using MS excel and SPSS version 23 program as per necessity. Results: In using pembrolizumab, side effects, fatigue, nausea, and decreased appetite were found 43%, 22%, and 20% lesser respectively than chemotherapy which was noticeable. In using nivolumab, as a side effect, skin rash was found 66% lesser than chemotherapy. Besides this, itching, face swelling, and apnea was found 33% lesser. On the other hand, in using atezolizumab, as side effects, swelling of arms and constipation were found 66% lesser, and itching, as well as apnea, was found 33% lesser than that in chemotherapy. At the 6-month follow-up we observed that in the nivolumab and atezolizumab treated groups 66% of cases survived separately whereas, in pembrolizumab treated group, 61% survived. Conclusions: In this study in all treatment groups, side effects were found as lesser than that in using chemotherapy. No major complication of any patients was observed in this study. So, can conclude that immune checkpoint inhibitors (ICIs) are better choice for metastatic diseases and ICIs exert lesser side effects than conventional chemotherapies.
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@#Objective To explore the short-term efficacy and safety of pembrolizumab combined with chemotherapy in the neoadjuvant treatment of non-small cell lung cancer. Methods The clinical data of 11 male patients with non-small cell lung cancer who underwent pembrolizumab combined with neoadjuvant chemotherapy in the Department of Thoracic Surgery, the First Affiliated Hospital of Xi'an Jiaotong University from December 2019 to June 2021 were retrospectively analyzed. The average age of the patients was 52.0-79.0 (62.0±6.9) years. The imaging data and pathological changes before and after neoadjuvant treatment were compared, and adverse reactions during neoadjuvant treatment were recorded. Objective remission rate (ORR) and main pathological remission rate (MPR) and pathological complete remission rate (pCR) were the main observation endpoints. Results After preoperative neoadjuvant therapy with pembrolizumab combined with platinum or paclitaxel, all patients successfully underwent thoracoscopic radical resection of lung cancer. The ORR was 72.7%, and the MPR was 81.8%. Among them, 45.5% of patients achieved pCR. The main adverse reactions were hypoalbuminemia, decreased appetite and nausea. The mortality rate within 30 days after surgery was 0, and no tumor metastasis was observed. Conclusion Pembrolizumab combined with neoadjuvant chemotherapy is safe and feasible to treat non-small cell lung cancer, and the short-term efficacy is beneficial.
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OBJECTIVE To evaluate the cost-effectiveness of pembrolizumab combined with chemotherapy versus placebo combined with chemotherapy in the first-line treatment of advanced or unresectable biliary tract carcinoma （BTC） from the perspective of China’s health system. METHODS A partitioned survival model was constructed based on the KEYNOTE-966 study data. The simulation period was 21 days， and the simulation time was the patient’s whole life. Using quality-adjusted life year （QALY） as the output indicator， the cost-utility analysis method was used to evaluate the cost-effectiveness of the two schemes mentioned above. Univariate and probabilistic sensitivity analyses were performed to verify the results of the basic analysis， and to explore the cost-effectiveness under the scenario of drug donation scheme. RESULTS The basic analysis showed that both the cost and effectiveness of the pembrolizumab group were higher than those of the placebo group， and the incremental cost-effectiveness ratio （ICER） was 3 909 359.78 yuan/QALY， which was higher than the willingness-to-pay （WTP） threshold of 3 times 2022 gross domestic product （GDP） per capita （257 094 yuan）， indicating no cost-effectiveness. The results of univariate sensitivity analysis showed that the utility discount rate， the utility value of progression-free survival （PFS） status， the cost discount rate， and the cost of pembrolizumab had a great influence on ICER. Probabilistic sensitivity analysis verified the robustness of the results of basic analysis， and concluded that when the WTP threshold was greater than 1 500 000 yuan/QALY， the pembrolizumab group became cost-effective. The results of the scenario analysis showed that considering the drug donation scheme of pembrolizumab for low-income people， although its treatment cost was significantly reduced， it was still not cost-effective. CONCLUSIONS At the WTP threshold of 3 times China’s GDP per capita in 2022， pembrolizumab combined with chemotherapy is not cost-effective compared with placebo combined with chemotherapy for advanced or unresectable BTC.
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Objective:To analyze the risk factors that affect the prognosis of patients with hypopharyngeal squamous cell carcinoma（HPSCC） and to compare the efficacy of surgical resection followed by adjuvant radiotherapy（SR） with that of neoadjuvant therapy consisting of platinum-based chemotherapy and fluorouracil combined with either cetuximab or nimotuzumab, followed by SR. The study also aimed to evaluate the overall survival（OS） of patients, their postoperative eating function, tracheostomy decannulation rate, and tumor response to the two neoadjuvant chemotherapies. Methods:A retrospective analysis was performed on the medical records of HPSCC patients who received SR or neoadjuvant therapy followed by SR treatment at the Shanghai General Hospital from 2012 to 2019 and had not undergone any prior treatment. The prognostic factors were analyzed, and the survival analysis of patients who underwent SR treatment with two neoadjuvant chemotherapy regimens was performed. Results:A total of 108 patients were included in the study. The results of the univariate analysis showed that gender（P=0.850） had no significant correlation with the survival rate of HPSCC patients who underwent SR. However, age, smoking history, alcohol consumption history, platelet-to-lymphocyte ratio（PLR）, neutrophil-to-lymphocyte ratio（NLR）, T stage, N stage, neoadjuvant therapy with either cetuximab or nimotuzumab combined with platinum-based chemotherapy and fluorouracil, and histological grade were significantly associated with prognosis（P<0.05）. The multivariate analysis revealed that smoking history, histological grade, and neoadjuvant therapy with either cetuximab or nimotuzumab combined with platinum-based chemotherapy and fluorouracil were independent risk factors affecting the prognosis of HPSCC（P<0.05）. Patients who received neoadjuvant therapy had longer OS than those who underwent SR only（P<0.001）. There was no significant difference in tumor response to the two neoadjuvant therapies and in OS（P>0.05）, and there was no significant difference in the rate of oral feeding and tracheostomy decannulation among the three treatment groups（P>0.05）. Conclusion:Univariate analysis showed that age at tumor onset, smoking history, alcohol consumption history, NLR, PLR, T stage, N stage, whether receiving neoadjuvant chemotherapy, and pathological grade were associated with the prognosis of HPSCC patients receiving SR treatment. Multivariate analysis showed that smoking history, pathological grade, and neoadjuvant chemotherapy were independent risk factors affecting the prognosis. Neoadjuvant chemotherapy with cetuximab or nimotuzumab can prolong the OS of patients, providing a certain basis and reference for the treatment of HPSCC.
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Humains , Traitement néoadjuvant , Carcinome épidermoïde de la tête et du cou , Cétuximab/usage thérapeutique , Études rétrospectives , Chine , Pronostic , Fluorouracil , Tumeurs de la tête et du couRÉSUMÉ
Abstract Objective To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. Methods Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. Results Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. Conclusion Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.
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ABSTRACT Background: Glioblastoma, the most common malignant primary brain tumor, remains a lethal disease with few therapeutic options. Immunotherapies, particularly immune checkpoint inhibitors (ICPi), have revolutionized cancer treatment, but their role in glioblastoma is uncertain. Objective: To review the state of immunotherapies in glioblastoma, with an emphasis on recently published ICPi clinical trials. Methods: In this editorial/opinion article, we critically review results of the first generation of trials of ipilimumab, nivolumab and pembrolizumab in glioblastoma, as well as future directions. Results: Expression of PD-L1 is frequent in glioblastoma, ranging from 60-70% of patients. Phase 1 studies of nivolumab with and without ipilimumab, as well as pembrolizumab, showed no new safety concerns in brain tumors, and no neurotoxicity. However, randomized phase 3 trials of nivolumab showed no survival improvements over bevacizumab in recurrent glioblastoma; no role in newly diagnosed disease as a replacement for temozolomide in unmethylated MGMT promoter tumors; and no benefit as an addition to temozolomide in methylated MGMT tumors. However, studies examining post treatment tumor samples have shown signs of increased immunologic response, and occasional long lasting radiographic responses have been seen. A small study of pembrolizumab suggested a potential role as a "neoadjuvant" treatment in resectable recurrent glioblastoma, while other studies are investigating selection of patients with higher mutational burden and novel agents and combinatorial strategies. Conclusion: Despite initial negative trials, immunotherapy remains of high interest in glioblastoma, and many trials are still ongoing. Improving our mechanistic understanding of the immunosuppression and T cell dysfunction induced by both tumor and the CNS microenvironment remains however crucial for the development of successful immunotherapeutic approaches in this disease.
RESUMO Antecedentes: Glioblastoma é o tumor cerebral primário maligno mais comum e continua sendo uma doença letal com poucas opções terapêuticas. As imunoterapias, em especial, os inibidores de checkpoint imunológico (ICPi), revolucionaram o tratamento do câncer, mas seu papel no glioblastoma é incerto. Objetivo: Revisar o estado atual do papel das imunoterapias no glioblastoma, com ênfase nos ensaios clínicos ICPi publicados recentemente. Métodos: Neste artigo de revisão, analisamos criticamente os resultados da primeira geração de estudos de ipilimumab, nivolumab e pembrolizumab em glioblastoma, bem como as perspectivas futuras. Resultados: A expressão de PD-L1 é frequente no glioblastoma, variando de 60-70% dos pacientes. Estudos de fase 1 de nivolumab com e sem ipilimumab, bem como pembrolizumab, não revelaram novas questões de tolerabilidade nem neurotoxicidade. No entanto, ensaios randomizados de fase 3 de nivolumab não apontaram melhorias na sobrevida em relação ao bevacizumab em glioblastoma recorrente, nenhum papel na doença recém-diagnosticada como substituto da temozolomida em tumores promotores de MGMT não metilados e nenhum benefício como adição à temozolomida em tumores MGMT metilados. No entanto, estudos que examinaram amostras de tumores pós-tratamento mostraram sinais de aumento da resposta imunológica, e respostas radiográficas ocasionais de longa duração foram observadas. Um pequeno estudo de pembrolizumab sugeriu um papel potencial como tratamento "neoadjuvante" no glioblastoma recorrente ressecável, ao passo que outros estudos estão investigando a seleção de pacientes com maior carga mutacional e novos agentes e estratégias combinatórias. Conclusão: Apesar dos ensaios iniciais negativos, a imunoterapia continua sendo de grande interesse no glioblastoma, e muitos ensaios ainda estão em andamento. No entanto, melhorar a nossa compreensão dos mecanismos de imunossupressão e disfunção das células T induzidas tanto pelo tumor quanto pelo microambiente do SNC continua sendo crucial para o desenvolvimento de abordagens imunoterapêuticas bem-sucedidas nesta doença.
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BACKGROUND@#The advances in the lung cancer screening methods and therapeutics, together with awareness towards deleterious habits, such as smoking, is increasing the overall survival with better quality of life for the patients. However, lung cancer is still one of the most common and fatal neoplasm with a high incidence and consequently burden to public health worldwide. Thus, based on guidelines and recent phases II and III clinical trials studies, this manuscript summarizes the current treatment sequencing strategies in lung cancer.@*METHODS@#A comprehensive search of related articles was performed focused on phases II and III clinical trials studies.@*RESULTS@#The lung cancer management should take into consideration the tumor characteristics, histology, molecular pathology and be discussed in a multidisciplinary team. Lung cancer treatment options comprises surgery whenever possible, radiotherapy associate with/or chemotherapy and immunotherapy as monotherapy, or combined with chemotherapy and best palliative care.@*CONCLUSIONS@#The screening predictability in more patients, smoking reduction, early diagnosis, better disease understanding and individualized, more effective and tolerable therapeutics are related to an increasing in overall survival and quality of life. In the near future improvement of personalized therapy in precision medicine is expected, enhancing new predictive biomarkers, optimal doses and optimal treatment sequencing as well as anti-cancer vaccines development.
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Humains , Carcinome pulmonaire non à petites cellules/thérapie , Dépistage précoce du cancer , Immunothérapie/méthodes , Tumeurs du poumon/thérapie , Qualité de vieRÉSUMÉ
Objective:To investigate the relationship between CD8 +FoxP3 +CD25 + T cell subsets and the therapeutic effect of programmed death receptor 1 (PD-1) inhibitor pembrolizumab in treatment of uterine cervical cancer. Methods:The data of 105 patients with uterine cervical cancer who received pemblizumab therapy based on chemotherapy in the First Hospital of Qinhuangdao from January 2018 to January 2020 were retrospectively analyzed. Flow cytometry was used to detect the ratio of CD8 +FoxP3 +CD25 + T cell in peripheral blood of patients. The efficacy and safety were analyzed. According to the efficacy, all patients were divided into remission group (complete remission + partial remission) and non-remission group (stable disease + progressive disease). The clinical characteristics and CD8 +FoxP3 +CD25 + T cell ratio of the two groups were compared. Multivariate logistic regression model was used to analyze the influencing factors for the efficacy. The efficacy of CD8 +FoxP3 +CD25 + T cell ratio predicting the therapeutic effect of patients was analyzed by using receiver operating characteristic (ROC) curve. Results:The objective remission rate of all patients was 17.14% (18/105), and the incidence of adverse reaction was 39.05% (41/105). The proportion of patients with a family history of cervical cancer in the remission group was lower than that than in the non-remission group [5.56% (1/18) vs. 34.48% (30/87)], and the difference was statistically significant ( χ2=6.00, P=0.014). The proportion of CD8 +FoxP3 +CD25 + T cell of 105 patients before and after treatment was (0.83±0.21)% and (0.77±0.10)%, respectively; the proportion of CD8 +FoxP3 +CD25 + T cell before and after treatment in the remission group was (0.55±0.26)%, (0.31±0.12)%, respectively; the proportion of CD8 +FoxP3 +CD25 + T cell before and after treatment in the non-remission group was (0.89±0.30)%, (0.87±0.28)%, respectively. The proportion of CD8 +FoxP3 +CD25 + T cell after treatment in the remission group was lower than that before treatment ( P < 0.05); there was no statistically significant difference in the proportion of CD8 +FoxP3 +CD25 + T cell before and after treatment in the non-remission group ( P>0.05). The proportion of CD8 +FoxP3 +CD25 + T cell before and after treatment in the non-remission group was higher than that in the remission group (all P<0.001). The proportion of CD8 +FoxP3 +CD25 + T cell higher than the mean value of both groups before treatment and the proportion of CD8 +FoxP3 +CD25 + T cell higher than the mean value of both groups after treatment were independent risk factor of disease remission ( OR=2.542, 95% CI 1.649-3.918, P<0.001; OR=2.936, 95% CI 2.154-4.002, P<0.001). ROC curve analysis showed that the area under the curve of CD8 +FoxP3 +CD25 + T cell ratio predicting the disease remission before treatment was 0.720, and its best cut-off value was 0.77%, the senfitivity was 77.78%, the specificity was 70.11%. Conclusions:Early detection of CD8 +FoxP3 +CD25 + T cell ratio helps to predict the effect of PD-1 inhibitor pembrolizumab therapy for uterine cervical cancer.
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Introduction@#Lung cancer is the leading malignancy metastatic to the central nervous system with approximately 20% to 44% of all cases developing brain metastasis. Immunotherapy using pembrolizumab, an anti-PD1monoclonal antibody, is a novel method in lung cancer treatment and has shown favorable results in patients with metastatic brain lesions from non-small cell lung carcinoma (NSCLC). However, the cost of the recommended treatment dose limits its use especially in developing countries like the Philippines. @*Case Presentation@#The authors report two patients with lung cancer with brain metastasis upon diagnosis. The first patient is a 65-year-old male, non-smoker with PD-L1 expression of 60%. He was started on pembrolizumab 100 mg IV every three (3) weeks and a repeat CT scan after 11 cycles revealed a reduction of the two brain metastatic lesions and no fluoro-D-glucose (FDG) uptake on positron emission tomography (PET) scan even after one year into treatment. The second patient is a 67-year-old female, a previous smoker with PD-L1 expression of 50% with a metastatic solitary solid nodule in the cortex of the right cerebellum. After five cycles of pembrolizumab 100 mg IV every three weeks, there was noted complete resolution of brain metastasis on PET scan even after one year of treatment. @*Conclusion@#A lower dose of pembrolizumab (100 mg given every 3 weeks) was found to be effective in the management of advanced NSCLC with brain metastasis in the two patients. Further studies are recommended to investigate lower dose pembrolizumab as monotherapy without radiation therapy or surgery in patients with NSCLC with brain metastasis especially in the setting of a resource-limited country like the Philippines.
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Immunothérapie , Tumeurs du poumon , Pays en voie de développementRÉSUMÉ
OBJECTIVE To evaluate the cost-utility of pembrolizumab combined with chemotherapy versus chemotherapy alone in the first-line treatment of advanced or metastatic esophageal carcinoma. METHODS Cost-utility analysis of pembrolizumab combined with chemotherapy versus chemotherapy alone for advanced or metastatic esophageal carcinoma was conducted by using a three-state partitioned survival model from the perspective of health system in China. The model use d a lifetime simulation time frame with 3 weeks as a cycle. The survival data were extrapolated using KEYNOTE- 590 data；cost data were obtained from the median of 2022 public winning bid on Yaozhi network ，among which the price of pembrolizumab was obtained after discounting by a patient assistance program ；utility data were obtained from the literatures ，and a 5％ discount rate was used for both cost and utility. One-way sensitivity analysis and probabilistic sensitivity analysis were also conducted to examine model robustness. RESULTS Analysis of the base case results showed that compared to chemotherapy alone ，the incremental cost-effectiveness ratio （ICER）of pembrolizumab combined with chemotherapy regimens were 950 528.42 yuan/QALY，107 845.39 yuan/QALY and 315 754.56 yuan/QALY for esophageal squamous cell carcinoma （ESCC），programmed deathligand- 1 combined positive score （PD-L1 CPS）≥10 and intention-to-treat population （ITT），respectively. The results of sensitivity analysis verified the robustness of the basic analysis results. CONCLUSIONS Under our healthcare system ，using a threshold of willingness-to-pay of 1-3 times our GDP per capita in 2021，pembrolizumab combined with chemotherapy regimen isn ’t cost-utility compared with chemotherapy alone in the ESCC and ITT subgroups of patients ，while it is cost-utility in the PD-L 1 CPS≥10 subgroup of patients.
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The antitumor drug has become one of the focused areas in new drug research and development. Their clinical research generally consumes a long period of time, with high cost and high risk. Model-informed drug development (MIDD) integrates and quantitatively analyzes physiological, pharmacological, and disease progression information through modeling and simulation, which can reduce the cost of drug development and improve the efficiency of clinical research. In this essay, Osimertinib and Pembrolizumab are given as examples to illustrate the specific application of MIDD in different phases of clinical research, aiming to provide references for the application of MIDD to guide the clinical research of antitumor drugs. .
Sujet(s)
Humains , Antinéoplasiques/usage thérapeutique , Développement de médicament , Tumeurs du poumonRÉSUMÉ
OBJECTIVE：To evaluate the econo mics of pembrolizumab in the second-line treatment of advanced hepatocellular carcinoma in China. METHODS ：From the perspective of Chinese healthcare system ，a three-state PartSA model and Markov model were established ；the cost and utility for the second-line treatment of advanced hepatocellular carcinoma in China were compared between pembrolizumab and placebo. The circulation cycle of the model was 3 weeks and the study time limit was lifetime；one-way sensitivity analysis ，probability sensitivity analysis and scenario analysis were used to verify the robustness of the base-case analysis results. RESULTS ：PartSA results showed that the ICER for the second-line treatment of advanced hepato- cellular carcinoma with pembrolizumab was 1 266 846.18 yuan/QALY，which is far more than 1-3 times of China ’s per capita GDP in 2020. The results of one-way sensitivity analysis showed that the three parameters that had the greatest impact on ICER were the PFS status utility of the placebo group ，the PFS status utility of the pembrolizumab group ，and the cost of pembrolizumab. The results of probability sensitivity analysis verified the robustness of the base-case analysis. The scenario analysis showed that the treatment cost of pembrolizumab had dropped significantly when the charity donation of pembrolizumab was considered. Although it was still not economical ，ICER was close to 3 times of per capita GDP of China in 2020. When WTP threshold was 1 and 3 times of China ’s per capita GDP ，the economic prices of pabolizumab （100 mg）were 4 157.67 and 5 829.24 yuan，respectively. The results of Markov model were similar to those of PartSA model. CONCLUSIONS ：Under the WTP threshold of 1-3 times China ’s per capita GDP in 2020，pembrolizumab is not economical for second-line treatment of advanced hepatocellular carcinoma.
RÉSUMÉ
OBJECTIVE：To explore the role of clinical pharmacists in the diagnosis and tre atment of immune checkpoint inhibitor related adrenocortical insufficiency ，so as to provide reference for the diagnosis and treatment of similar cases. METHODS：A lung squamous carcinoma patient with tumor immunotherapy ，who received long-term intravenous infusion of Pembrolizumab injection ，was hospitalized for more than 10 days due to fatigue and poor appetite. The clinical pharmacists consulted the literature and evaluated the correlation of ADR on the basis of patient ’s physical examination results （plasma cortisol 16.41 nmol/L at 8：00 in the morning on the second day of admission ，adrenocorticotropic hormone 8.39 pg/mL，serum electrolyte sodium 126.00 mmol/L，chlorine 88.00 mmol/L，etc.）and medication history （receiving the treatment with immune checkpoint inhibitors）. The clinical pharmacists assisted the doctor to confirm that the patient was adrenocortical insufficiency ，and the correlation with pembrolizumab was “very likely ”. On the basis of discontinuation of pembrolizumab ，it was recommended to take Hydrocortisone tablets orally （20 mg at 8：00 in the morning and 10 mg at 4：00 in the afternoon ）for glucocorticoid physiological dose substitution therapy. Before treatment ，the patient and his families should be educated on the use of drugs ，pharmaceutical care should be implemented to evaluate the glucocorticoid doseand efficacy during treatment ，and medication education was carried out at discharge. RESULTS ：The doctor adopted theli_xyan suggestions of the clinical pharmacist. On the 5th day after @126.com administration，the symptoms of adrenocortical insufficiency were significantly impro ved，and the patient was discharged with medicine. CONCLUSIONS ：During the treatment of the patient ， the clinical pharmacist gave full play to his pharmaceutical expertise ，assisted the doctor to formulate an appropriate medication plan，and carried out medication education for the patient and his family members ，so as to ensure the effectiveness and safety of the patient ’s medication. It is suggested that the baseline examination of patients should be improved before immune checkpoint inhibitor treatment ，including physical examination and plasma cortisol level at 8：00 in the morning ；the frequency of monitoring plasma cortisol level and serum electrolyte level at 8：00 in the morning. should be increased during medication ；the patients should be followed up for at least 1 year after withdrawal ，so as to early detect and treat immune checkpoint inhibitor related adrenocortical dysfunction.
RÉSUMÉ
@#Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumor that seriously threatens human health and life. With increasing studies on the mechanism of tumor immune escape, programmed death receptor 1 (PD-1) and programmed death ligand receptor 1 (PD-L1) have been proven to be involved in tumor immune escape. The primary mechanism is that PD-1 recruits protein tyrosine phosphatase (SHP-2) to dephosphorylate downstream tyrosine kinase (SyK) and phosphatidylinositol 3-kinase (PI3K), thereby inhibiting downstream protein kinase B (AKT), extracellular regulated protein kinases (ERK) and other important signaling pathways, ultimately inhibiting T cell activation. In recent years, PD-1/PD-L1 inhibitors have become popular immunotherapies. Pembrolizumab and nivolumab have been approved for HNSCC patients by the U.S. Food and Drug Administration. Both durvalumab and atezolizumab are still in clinical trials, and published data show that both have certain safety and efficacy but still need much clinical data to support them. Meanwhile, the combination of PD-1/PD-L1 inhibitors with radiotherapy, chemotherapy and immunotherapy is still controversial in terms of clinical efficacy and adverse events, and further research is needed. However, serious immune-related adverse reactions limit the clinical application of PD-1/PD-L1 inhibitors, despite promising curative effects. Therefore, developing novel inhibitors and investigating stable and effective biomarkers and upstream and downstream signaling mechanisms are urgent issues.