RESUMO
Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.
Assuntos
Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Bevacizumab , Microbioma Gastrointestinal , Inibidores de Checkpoint Imunológico , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Bevacizumab/uso terapêutico , Bevacizumab/farmacologia , Masculino , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Pessoa de Meia-Idade , Idoso , Mesotelioma Maligno/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Mesotelioma/imunologia , Mesotelioma/tratamento farmacológico , Mesotelioma/microbiologia , Mesotelioma/patologia , Microambiente Tumoral/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/microbiologia , Resultado do TratamentoRESUMO
Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Feminino , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Reino Unido/epidemiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/mortalidade , Adulto , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with marginal zone lymphoma (MZL).
Assuntos
Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Biópsia , Linfoma de Zona Marginal Tipo Células B/classificação , Linfoma Extranodal de Células T-NKRESUMO
ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.
Assuntos
Adenina , Linfoma de Célula do Manto , Piperidinas , Adulto , Idoso , Feminino , Humanos , Masculino , Adenina/análogos & derivados , Estudos de Coortes , Inglaterra , Linfoma de Célula do Manto/tratamento farmacológico , Rituximab/uso terapêuticoRESUMO
PURPOSE: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. RESULTS: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. CONCLUSIONS: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors.
Assuntos
Neoplasias Pulmonares , Neoplasias , Carcinoma de Pequenas Células do Pulmão , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Gencitabina , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias/etiologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
INTRODUCTION: This study examined real-world data from patients who received eribulin for metastatic breast cancer (MBC) collected from 14 hospitals across the UK. METHODS: Anonymized data were collected retrospectively from patients with MBC who had received eribulin. The data included the hormone-receptor status, histological diagnosis, age, prior chemotherapy, response to eribulin, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 577 patients analyzed, the median age was 56 years, and most patients (73%) were estrogen-receptor positive. The median OS was 288 days (95% confidence interval [CI]: 261-315), and the PFS was 117 days (95% CI: 105-129). The median OS was higher among older patients (≥65 vs. <65 years: 325 days [95% CI: 264-385] vs. 285 days [95% CI: 252-317]; p = 0.028). The median OS was also higher in patients who received eribulin after fewer prior lines of chemotherapy (≤2 vs. >2 prior: 328 days [95% CI: 264-385] vs. 264 days [95% CI: 229-298]; p = 0.042). DISCUSSION/CONCLUSION: These retrospective data suggest that eribulin can be successfully used in older patients with MBC. Eribulin treatment was more effective in earlier-line settings, which, while predictable, supports consideration of eribulin as a second-line treatment option.
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Neoplasias da Mama , Humanos , Idoso , Pessoa de Meia-Idade , Feminino , Neoplasias da Mama/patologia , Estudos Retrospectivos , Furanos/uso terapêutico , Cetonas/uso terapêutico , Reino Unido , Resultado do TratamentoRESUMO
More people in the UK are living with cancer than ever before. With an increasingly ethnically diverse population, greater emphasis must be placed on understanding factors influencing cancer outcomes. This review seeks to explore UK-specific variations in engagement with cancer services in minority ethnic groups and describe successful interventions. The authors wish to highlight that, despite improvement to engagement and education strategies, inequalities still persist and work to improve cancer outcomes across our communities still needs to be prioritised. There are many reasons why cancer healthcare inequities exist for minority communities, reported on a spectrum ranging from cultural beliefs and awareness, through to racism. Strategies that successfully enhanced engagement included language support; culturally-sensitive reminders; community-based health workers and targeted outreach. Focusing on the diverse city of Leicester the authors describe how healthcare providers, researchers and community champions have worked collectively, delivering targeted community-based strategies to improve awareness and access to cancer services.
Assuntos
Grupos Minoritários , Neoplasias , Detecção Precoce de Câncer , Minorias Étnicas e Raciais , Etnicidade , Humanos , Neoplasias/diagnóstico , Reino UnidoRESUMO
BACKGROUND: To evaluate the utility of positron-emission tomography (FDG PET) in initial staging and management of head and neck cancers. METHODS: This is a retrospective study of 99 treatment naïve head and neck cancer patients treated between January 2017 and December 2020 at a tertiary teaching centre. Change in initial staging and management was noted based on PET scan compared to cross-sectional imaging (CT and MRI). RESULTS: There were 73 (73.7%) males and 26 (26.2%) females with male-to-female ratio of 2.8:1.Overall, change in management was seen in 36/99 (36.4%) patients due to PET scan. With regards to initial staging, T, N and M stage was changed in 14/99 (14.1%), 19/99 (19.1%) and 3/99 (3%) patients, respectively. These changes were significantly higher in patients with unknown primary (63.3%, p value -0.001) and N3 (41%, p -0.045) nodal disease. CONCLUSION: PET-CT plays an important role in appropriate initial staging and subsequent treatment planning of head and neck cancers. ADVANCES IN KNOWLEDGE: Initial staging PETCT changes management in 36.4% cases. Accuracy of various different imaging modalities have been compared.
Assuntos
Neoplasias de Cabeça e Pescoço , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Feminino , Fluordesoxiglucose F18 , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12-15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/uso terapêutico , COVID-19/mortalidade , Leucemia Linfocítica Crônica de Células B/mortalidade , SARS-CoV-2/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/terapia , COVID-19/virologia , Gerenciamento Clínico , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/terapia , Leucemia Linfocítica Crônica de Células B/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Taxa de Sobrevida , Estados Unidos/epidemiologiaAssuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Pirazinas/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.