BackgroundMany studies have compared real-world clinical outcomes of immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC) with reported outcomes data from pivotal trials.... Show moreBackgroundMany studies have compared real-world clinical outcomes of immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC) with reported outcomes data from pivotal trials. However, any differences observed could be only limitedly explored further for causation because of the unavailability of individual patient data (IPD) from trial participants. The present study aims to explore the additional benefit of comparison with IPD.MethodsThis study compares progression free survival (PFS) and overall survival (OS) of metastatic NSCLC patients treated with second line nivolumab in real-world clinical practice (n = 141) with IPD from participants in the Checkmate-057 clinical trial (n = 292). Univariate and multivariate Cox proportional hazards models were used to construct HRs for real-world practice versus clinical trial.ResultsReal-world patients were older (64 vs. 61 years), had more often ECOG PS ≥ 2 (5 vs. 0%) and were less often treated with subsequent anti-cancer treatment (28.4 vs. 42.5%) compared to trial patients. The median PFS in real-world patients was longer (3.84 (95%CI: 3.19-5.49) vs 2.30 (2.20-3.50) months) and the OS shorter than in trial participants (8.25 (6.93-13.2) vs. 12.2 (9.90-15.1) months). Adjustment with available patient characteristics, led to a shift in the hazard ratio (HR) for OS, but not for PFS (HRs from 1.13 (0.88-1.44) to 1.07 (0.83-1.38), and from 0.82 (0.66-1.03) to 0.79 (0.63-1.00), respectively).ConclusionsThis study is an example how IPD from both real-world and trial patients can be applied to search for factors that could explain an efficacy-effectiveness gap. Making IPD from clinical trials available to the international research community allows this. Show less
Ismail, R.K.; Suijkerbuijk, K.P.M.; Boer, A. de; Dartel, M. van; Hilarius, D.L.; Pasmooij, A.M.G.; ... ; Wouters, M.W.J.M. 2022
Recent results of patients with advanced melanoma treated with first-line BRAF-MEK inhibitors in clinical trials showed 5-year survival in one-third of patients with a median overall survival (OS)... Show moreRecent results of patients with advanced melanoma treated with first-line BRAF-MEK inhibitors in clinical trials showed 5-year survival in one-third of patients with a median overall survival (OS) of more than 2 years. This study aimed to investigate these patients' real-world survival and identify the characteristics of long-term survivors. The study population consisted of patients with advanced cutaneous melanoma with a BRAF-V600 mutated tumor who were treated with first-line BRAF-MEK inhibitors between 2013 and 2017. Long-term survival was defined as a minimum OS of 2 years from start therapy. The median progression-free survival (mPFS) and median OS (mOS) of real-world patients (n = 435) were respectively 8.0 (95% CI, 6.8-9.4) and 11.7 (95% CI, 10.3-13.5) months. Two-year survival was reached by 28% of the patients, 22% reached 3-year survival and 19% reached 4-year survival. Real-world patients often had brain metastases (41%), stage IV M1c disease (87%), ECOG PS >= 2 (21%), >= 3 organ sites (62%) and elevated LDH of >= 250 U/I (49%). Trial-eligible real-world patients had an mOS of 17.9 months. Patients surviving more than 2 years (n = 116) more often had an ECOG PS <= 1 (83%), normal LDH (60%), no brain metastases (60%), no liver metastases (63%) and <3 organ sites (60%). Long-term survival of real-world patients treated with first-line BRAF-MEK inhibitors is significantly lower than that of trial patients, which is probably explained by poorer baseline characteristics of patients treated in daily practice. Long-term survivors generally had more favorable characteristics with regard to age, LDH level and metastatic sites, compared to patients not reaching long-term survival. Show less
Ismaila, R.K.; Breeschoten, J. van; Wouters, M.W.J.M.; Dartel, M. van; Flier, S. van der; Reyners, A.K.L.; ... ; Hilarius, D.L. 2022
Background: Little is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR,... Show moreBackground: Little is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR, a population-based registry to monitor the quality and safety of melanoma care in the Netherlands. This study aims to describe treatment patterns, relapse, and toxicity rates of adjuvant-treated melanoma patients beyond the clinical trial setting.Methods: Analyses were performed on adjuvant-treated melanoma patients included in the DMTR. Descriptive statistics were used to analyse patient-, and treatment characteristics. A baseline registration completeness analysis was performed, and an analysis on trial eligibility in clinical practice patients. Recurrence-free survival (RFS) at 12-months was estimated with the Kaplan-Meier method.Results: A total of 641 patients were treated with adjuvant anti-PD-1 therapy. RFS at 12-months was 70.6% (95% CI, 66.9-74.6) with a median follow-up of 12.8 months. Sex, stage of disease and Breslow thickness were associated with a higher hazard for RFS. Eighteen per cent of the anti-PD-1-treated patients developed grade >= 3 toxicity. Sixty-one per cent of patients prematurely discontinued anti-PD-1 therapy.Conclusion: Adjuvant anti-PD-1 treatment of resected stage III/IV melanoma in daily practice showed slightly higher toxicity rates and more frequent premature discontinuation but similar RFS rates compared to trials. (C) 2021 The Authors. Published by Elsevier Ltd. Show less
Ismail, R.K.; Sikkes, N.O.; Wouters, M.W.J.M.; Hilarius, D.L.; Pasmooij, A.M.G.; Eertwegh, A.J.M. van den; ... ; Boer, A. de 2021
Postapproval trials and patient registries have their pros and cons in the generation of postapproval data. No direct comparison between clinical outcomes of these data sources currently exists for... Show morePostapproval trials and patient registries have their pros and cons in the generation of postapproval data. No direct comparison between clinical outcomes of these data sources currently exists for advanced melanoma patients. We aimed to investigate whether a patient registry can complement or even replace postapproval trials. Postapproval single-arm clinical trial data from the Medicines Evaluation Board and real-world data from the Dutch Melanoma Treatment Registry were used. The study population consisted of advanced melanoma patients with brain metastases treated with targeted therapies (BRAF- or BRAF-MEK inhibitors) in the first line. A Cox hazard regression model and a propensity score matching (PSM) model were used to compare the two patient populations. Compared to patients treated in postapproval trials (n = 467), real-world patients (n = 602) had significantly higher age, higher ECOG performance status, more often >= 3 organ involvement and more symptomatic brain metastases. Lactate dehydrogenase levels were similar between both groups. The unadjusted median overall survival (mOS) in postapproval clinical trial patients was 8.7 (95% CI, 8.1-10.4) months compared to 7.2 (95% CI, 6.5-7.7) months (P < 0.01) in real-world patients. With the Cox hazard regression model, survival was adjusted for prognostic factors, which led to a statistically insignificant difference in mOS for trial and real-world patients of 8.7 (95% CI, 7.9-10.4) months compared to 7.3 (95% CI, 6.3-7.9) months, respectively. The PSM model resulted in 310 matched patients with similar survival (P = 0.9). Clinical outcomes of both data sources were similar. Registries could be a complementary data source to postapproval clinical trials to establish information on clinical outcomes in specific subpopulations. Copyright (c) 2020 The Author(s). Published by Wolters Kluwer Health, Inc. Show less
Ismail, R.K.; Schramel, F.M.N.H.; Dartel, M. van; Hilarius, D.L.; Boer, A. de; Wouters, M.W.J.M.; ... ; Dutch Lung Canc Audit Sci Comm 2020
Objectives: This study describes the initiation of the Dutch Lung Cancer Audit for Lung Oncology (DLCA-L) and reports the first results of three years of clinical auditing.Methods: The initiation,... Show moreObjectives: This study describes the initiation of the Dutch Lung Cancer Audit for Lung Oncology (DLCA-L) and reports the first results of three years of clinical auditing.Methods: The initiation, dataset, and data quality of the DLCA-L are described. For the analyses, all patients registered from 2017 to 2019 were included. Descriptive statistics were used to assess the first outcomes of the DLCA-L, including results from quality indicators, patient- and tumor characteristics, and the real-world use of immunotherapy.Results: The DLCA-L was initiated after the surgery and radiotherapy audit for lung cancer. In total, 33.788 NSCLC patients and 4.293 SCLC patients were registered in the DLCA-L from 2017 to 2019. Seventy-three (97 %) Dutch hospitals participated in the DLCA-L in 2019. The registry became nation-wide in 2020. The data quality improved over the years, with complete cases in 90 % of the NSCLC patients. In total, 15 quality indicators were established based on DLCA-L data to improve processes and clinical outcomes. An example of these quality indicators was brain imaging at diagnosis of stage III NSCLC patients, which increased from 80 % in 2017 to 90 % in 2019 and hospital variation was reduced. The DLCA-L provided data on immunotherapy use in stage IV NSCLC (n = 4.415) patients. These patients had a median age of 67 years and 11 % of the patients had an ECOG PS >= 2. The number of patients treated with immunotherapy in different hospitals varied between 2 patients to 163 patients per hospital.Conclusion: The DLCA-L has become a valuable and complete data source with national coverage in 2020. A high number of registered patients and limited missing data resulted in better insights into hospital processes and outcomes of lung cancer care. Quality indicators were, with success, used to establish improvements and minimize hospital variation. The DLCA-L also provides hospitals real-world information on the use of (systemic) therapies. Show less
Zeijl, M.C.T. van; Ismail, R.K.; Wreede, L.C. de; Eertwegh, A.J.M. van den; Boer, A. de; Dartel, M. van; ... ; Wouters, M.W.J.M. 2020
The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced... Show moreThe aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune- or targeted therapy, who met >= 1 trial exclusion criteria. These criteria were derived from the KEYNOTE-006 and CHECKMATE-067/-066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan-Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population-based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) >= 2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of >= 2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long-term survival is possible. The prognosis of ineligible patients with advanced melanoma in real-world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM. Show less
