BackgroundAlmost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a... Show moreBackgroundAlmost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy.MethodsWe did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847.FindingsBetween March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6-8·7]) than in the supportive care group (3·2 months [2·8-4·1]; hazard ratio [HR] 0·48 [95% CI 0·33-0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33-0·72]; p=0·0002). Grade 3-4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection.InterpretationSwitch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma.FundingDutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies. Show less
Blomberg, O.S.; Spagnuolo, L.; Garner, H.; Voorwerk, L.; Isaeva, O.I.; Dyk, E. van; ... ; Kok, M. 2023
Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune... Show moreImmune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. Here, we combine unbiased analysis of blood and tumors from metastatic breast cancer patients treated with ICB with mechanistic studies in mouse models of breast cancer. We observe an increase in systemic and intratumoral eosinophils in patients and mice responding to ICB treatment. Mechanistically, ICB increased IL-5 production by CD4(+) T cells, stimulating elevated eosinophil production from the bone marrow, leading to systemic eosinophil expansion. Additional induction of IL-33 by ICB-cisplatin combination or recombinant IL-33 promotes intratumoral eosinophil infiltration and eosinophil-dependent CD8(+) T cell activation to enhance ICB response. This work demonstrates the critical role of eosinophils in ICB response and provides proof-of-principle for eosinophil engagement to enhance ICB efficacy. Show less
Disselhorst, M.J.; Lubeck, Y.; Noort, V. van der; Quispel-Janssen, J.; Seignette, I.M.; Sanders, J.; ... ; Baas, P. 2022
Introduction: Malignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better... Show moreIntroduction: Malignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better understanding of the tumor micro environment is needed. We investigated subgroups of immune cells in subsequent tumor biopsies of patients treated with ICI. Methods: Biopsies from MPM patients included in two clinical ICI trials (nivolumab alone and an ipilimumab/nivolumab combination) were examined. At baseline and after 6 weeks of treatment, pleural biopsies were taken to examine the tumor microenvironment (CD20+, CD4+, CD8+, FoxP3+ and PD-1+ ). Cell density was defined as the number of marker positive cells per mm(2). Radiological responses were evaluated as partial response, stable disease or progressive disease according to modified RECIST criteria. Results: Thirty-four and 36 patients were included in the nivolumab and ipiliumumab/nivolumab trial respectively. In the nivolumab trial, no significant differences in cell densities were seen in baseline biopsies of patients with partial response versus progressive disease. In contrast, in the ipilimumab/nivolumab trial, a higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells at baseline was significantly correlated with partial responses. On-treatment biopsies of both trials did not show significant changes when compared to baseline biopsies. Conclusion: Biopsies from patients responding to nivolumab plus ipilimumab treatment show a significant higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells, without a change after 6 weeks of treatment. This observation is a first step in exploring the tumor microenvironment as predictor of response in ICI treatment in MPM. Show less
Ruschoff, J.H.; Haberecker, M.; Tsourti, Z.; Nackaerts, K.; Perrot, M. de; Brcic, L.; ... ; Consortium, E.M. 2022
Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The... Show morePleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naive and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies. Show less
Societal Impact Statement Combining natural and social science approaches to conduct archeological research on wooden cultural relics is important for exploring major aspects of ancient... Show moreSocietal Impact Statement Combining natural and social science approaches to conduct archeological research on wooden cultural relics is important for exploring major aspects of ancient civilizations. The Forbidden City in Beijing, China, is the largest existing wooden palace complex in the world. We examined ancient DNA of imperial wood "Nanmu" specimens taken from representative structural components of the Forbidden City, in order to provide a new perspective on the long-standing dispute about its species. This allowed us to accurately identify and properly restore these wooden artifacts and improved our understanding of the past interactions between plant distribution, forest resources, and human activities. Exploring the life styles and production methods of past generations using plant resources can help us to improve our understanding of human civilization. Nanmu, known for its high wood quality, was exclusively used for imperial palace construction in the 15th-19th centuries in China, yet its species has been a subject of long-standing debate. Here, we revisit this unresolved problem, using morphology and ancient DNA (aDNA) to analyze 21 centuries-old Nanmu specimens sampled from representative palaces of the Forbidden City. Cytochemical staining demonstrated that endogenous aDNA sporadically occurs in the wood ray parenchyma cells of Nanmu specimens. High-quality plastid genomes were retrieved from archeological woods for the first time via an aDNA capture method, with 90%-100% coverage (137,663-152,805 bp) and sequence depths of 27.05- to 1409.94-fold. Utilizing these ancient genomes, our results demonstrate that Phoebe zhennan and Phoebe hui are most likely the main species of Nanmu in the Forbidden City. This finding diverges from the prevailing view that Nanmu encompasses woods from the whole genus Phoebe and even its close relative Machilus. It also shows that stringent criteria were used when selecting construction materials for the Forbidden City. By combining morphological traits with aDNA analyses, we provide a new solution for identifying the species of timber used for ancient architecture, and we increase our understanding of the way in which forest resources were recognized and utilized by our ancestors despite the lack of a plant taxonomic framework in ancient times. Show less
Carbone, M.; Pass, H.I.; Ak, G.; Alexander, H.R.; Baas, P.; Baumann, F.; ... ; Hassan, R. 2022
The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently,... Show moreThe most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact. (C) 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. Show less
Objectives: Immune checkpoint inhibitors (ICIs) improved outcomes in non-small cell lung cancer (NSCLC) patients. We report the predictive utility of human leukocyte antigen class I (HLA-I)... Show moreObjectives: Immune checkpoint inhibitors (ICIs) improved outcomes in non-small cell lung cancer (NSCLC) patients. We report the predictive utility of human leukocyte antigen class I (HLA-I) diversity and tumor mutational burden (TMB) by comprehensive next-generation sequencing. Methods: 126 patients were included. TMB high was defined as >= 10 nonsynonymous mutations/Mb. Patients exhibit high HLA-I diversity if at least one locus was in the upper 15th percentile for DNA alignment scores. Results: No difference in response rate (RR; 44.4% versus 30.9%; p = 0.1741) or 6-month survival rate (SR; 75.6% versus 77.8%; p = 0.7765) was noted between HLA-I high diversity and low diversity patients. HLA-I high diversity patients did significantly more often exhibit durable clinical benefit (DCB), defined as response or stable disease lasting minimally 6 months (64.4% [29/45] versus 43.2% [35/81]; p = 0.0223).TMB high patients exhibited higher RR (49.1% versus 25.4%; p = 0.0084) and SR 6 months after start ICI (85.5% versus 70.4%; p = 0.0468) than TMB low patients. The proportion of patients with DCB, did not differ significantly between TMB high and low subgroups (60.0% [33/55] versus 42.3% [30/71]; p = 0.0755).Patients with combined dual high TMB and HLA-I diversity had higher RR (63.2% versus 22.2%; p = 0.0033), but SR at 6 months did not differ significantly (84.2% versus 64,4%; p = 0.1536). A significantly higher rate of patients experienced DCB in dual high compared to the dual low group (73.7% [14/19] versus 35.6% [16/45]; p = 0.0052). Triple positive patients (high TMB and HLA-I diversity and PD-L1 positive) had higher RR (63.6% versus 0.0%; p = 0.0047) and SR at 6 months (100% versus 66.7%; p = 0.0378) compared to triple-negative patients. Conclusion: HLA-I diversity was able to predict durable clinical benefit in ICI treated NSCLC patients, but failed to confirm as a predictor of response or survival. TMB confirmed as a predictive biomarker. Show less
Background: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable... Show moreBackground: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. Patients and methods: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of <= 1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). Results: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61e0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for >= 3 years after discontinuation. Conclusions: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology. Show less
Objective: In CheckMate 743 (NCT02899299), nivolumab + ipilimumab significantly prolonged overall survival in patients with unresectable malignant pleural mesothelioma (MPM). We present patient... Show moreObjective: In CheckMate 743 (NCT02899299), nivolumab + ipilimumab significantly prolonged overall survival in patients with unresectable malignant pleural mesothelioma (MPM). We present patient-reported outcomes (PROs). Materials and Methods: Patients (N = 605) were randomized to nivolumab + ipilimumab or chemotherapy. Changes in disease-related symptom burden and health-related quality of life (HRQoL) were evaluated descriptively using the Lung Cancer Symptom Scale (LCSS)-Mesothelioma (Meso) average symptom burden index (ASBI), LCSS-Meso 3-item global index (3-IGI), 3-level EuroQol 5-dimensional (EQ-5D-3L) visual analog score (VAS), and EQ-5D-3L utility index. PROs were assessed at baseline and every 2 (nivolumab + ipilimumab) or 3 weeks (chemotherapy) through 12 weeks, every 6 weeks through 12 months, every 12 weeks thereafter, and at specified follow-ups. Mixed-effect model repeated measures (MMRM) and time to deterioration analyses were conducted. Results: Completion rates were generally > 80%. LCSS-Meso ASBI mean changes from baseline trended to improve over time with nivolumab + ipilimumab and deteriorate with chemotherapy, but did not meet clinically important difference thresholds [& PLUSMN;10 score change]. EQ-5D-3L VAS mean scores improved over time with nivolumab + ipilimumab; by week 60, patients had scores consistent with United Kingdom normal population values. MMRM analyses favored nivolumab + ipilimumab for all individual symptoms except cough. Nivolumab + ipilimumab delayed time to definitive deterioration in HRQoL (hazard ratio 0.52 [95% confidence interval 0.36-0.74]) and showed a trend in symptom delay versus chemotherapy. Conclusions: Nivolumab + ipilimumab decreased the risk of deterioration in disease-related symptoms and HRQoL versus chemotherapy and maintained QoL in patients with unresectable MPM. Show less
Boosman, R.J.; Gooijer, C.J. de; Groenland, S.L.; Burgers, J.A.; Baas, P.; Noort, V. van der; ... ; Steeghs, N. 2022
Background Although kinase inhibitors (KIs) are generally effective, their use has a large impact on the current health care budget. Dosing strategies to reduce treatment costs are warranted.... Show moreBackground Although kinase inhibitors (KIs) are generally effective, their use has a large impact on the current health care budget. Dosing strategies to reduce treatment costs are warranted. Boosting pharmacokinetic exposure of KIs metabolized by cytochrome P450 (CYP)3A4 with ritonavir might result in lower doses needed and subsequently reduces treatment costs. This study is a proof-of-concept study to evaluate if the dose of erlotinib can be reduced by co-administration with ritonavir. Methods In this open-label, cross-over study, we compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (QD) (control arm) with erlotinib 75 mg QD plus ritonavir 200 mg QD (intervention arm). Complete pharmacokinetic profiles at steady-state were taken up to 24 h after erlotinib intake for both dosing strategies. Results Nine patients were evaluable in this study. For the control arm, the systemic exposure over 24 h, maximum plasma concentration and minimal plasma concentration of erlotinib were 29.3 mu g*h/mL (coefficient of variation (CV):58%), 1.84 mu g/mL (CV:60%) and 1.00 mu g/mL (CV:62%), respectively, compared with 28.9 mu g*h/mL (CV:116%, p = 0.545), 1.68 mu g/mL (CV:68%, p = 0.500) and 1.06 mu g/mL (CV:165%, p = 0.150) for the intervention arm. Exposure to the metabolites of erlotinib (OSI-413 and OSI-420) was statistically significant lower following erlotinib plus ritonavir dosing. Similar results regarding safety in both dosing strategies were observed, no grade 3 or higher adverse event was reported. Conclusions Pharmacokinetic exposure at a dose of 75 mg erlotinib when combined with the strong CYP3A4 inhibitor ritonavir is similar to 150 mg erlotinib. Ritonavir-boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP3A4. Show less
Introduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other... Show moreIntroduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy.Methods: Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves.Results: Although tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The "regulation of antigen processing and presentation of peptide antigen" gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors.Conclusions: Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. Show less
Introduction: Malignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure. This study reviewed the Dutch... Show moreIntroduction: Malignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure. This study reviewed the Dutch population-based incidence, treatment and survival since the national ban on asbestos in 1993. Materials and methods: Patients with MPM or MPeM diagnosed from 1993 to 2018 were selected from the Dutch cancer registry. Annual percentage change (APC) was calculated for (age-specific and sex-specific) revised European standardised incidence rates (RESR). Treatment pattern and Kaplan-Meier overall survival analyses were performed. Results: In total, 12 168 patients were included in the study. For male patients younger than 80 years, the MM incidence significantly decreased in the last decade (APC ranging between -9.4% and -1.8%, p<0.01). Among both male and female patients aged over 80 years, the incidence significantly increased during the entire study period (APC 3.3% and 4.6%, respectively, p<0.01). From 2003 onwards, the use of systemic chemotherapy increased especially for MPM (from 9.3% to 39.4%). Overall, 62.2% of patients received no antitumour treatment. The most common reasons for not undergoing antitumour treatment were patient preference (42%) and performance status (25.6%). The median overall survival improved from 7.3 (1993-2003) to 8.9 (2004-2011) and 9.3 months from 2012 to 2018 (p<0.001). Conclusion: The peak of MM incidence was reached around 2010 in the Netherlands, and currently the incidence is declining in most age groups. The use of systemic chemotherapy increased from 2003, which likely resulted in improved overall survival over time. The majority of patients do not receive treatment though and prognosis is still poor. Show less
Objectives: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer with a poor prognosis and limited treatment options. This study assessed the characteristics, treatment patterns,... Show moreObjectives: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer with a poor prognosis and limited treatment options. This study assessed the characteristics, treatment patterns, and outcomes for patients diagnosed with MPM in England. Materials and methods: As part of I-O Optimise, this retrospective cohort study analyzed data recorded in the Cancer Analysis System in England for all adult patients newly diagnosed with MPM between 2013 and 2017, with follow-up to March 2018 or death, whichever occurred first. Overall survival (OS) was estimated using Kaplan-Meier methods. A Cox regression model was used to describe the impact of sociodemographic and clinical characteristics at diagnosis on OS. Results: 9458 patients diagnosed with MPM were analyzed. Median age at diagnosis was 75 years; 83.4% were male. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 44.5%; 2 for 11.5%; 2 for 9.1%; and missing for 34.9% of patients. TNM stage was missing for 60.4%. A majority of patients had epithelioid histology (36.4%) or not otherwise specified (NOS) MPM (43.3%). After diagnosis, 48.7% of all patients received best supportive care (BSC; no surgery, radiotherapy, SACT); 11.4% received palliative radiotherapy alone; 6.5% underwent surgery; 33.4% received systemic anticancer therapy (SACT) as initial treatment. Platinum plus pemetrexed was the main SACT regimen used in both first and second line. Median OS (8.3 months) varied by histopathology and ranged from 4.3 to 13.3 months for sarcomatoid and epithelioid MPM, respectively. After adjusting for age, sex, and ECOG PS, sarcomatoid, biphasic, and NOS MPM remained significantly associated with worse OS than epithelioid MPM (all p < 0.001). Median OS varied from 4.6 to 17.0 months for patients receiving BSC/palliative radiotherapy, and patients receiving surgery, respectively. Conclusion: Outcomes for patients with MPM in England remain poor. Future studies will investigate the impact of newer therapies on the treatment patterns and survival of MPM patients. Show less
Buma, A.I.G.; Muller, M.; Vries, R. de; Sterk, P.J.; Noort, V. van der; Wolf-Lansdorf, M.; ... ; Heuvel, M.M. van den 2021
Introduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1)... Show moreIntroduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) >= 50% and >= 1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study.Methods: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m(2) once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis.Results: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0-77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44. 0.69) for patients with PD-L1 TPS >= 50% and 0.70 (0.61. 0.80) with PD-L1 TPS >= 1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS >= 50% and 15.6% versus 6.5% with PD-L1 TPS >= 1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (similar to 5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (>= 175 mutations per exome) was associated with improved outcomes with pembrolizumab.Conclusions: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS >= 50% and >= 1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting. (C) 2021 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. Show less
