Artificial Intelligence-based Quantification of Pleural Plaque Volume and Association With Lung Function in Asbestos-exposed Patients.

PURPOSE: Pleural plaques (PPs) are morphologic manifestations of long-term asbestos exposure. The relationship between PP and lung function is not well understood, whereas the time-consuming nature of PP delineation to obtain volume impedes research. To automate the laborious task of delineation, we aimed to develop automatic artificial intelligence (AI)-driven segmentation of PP. Moreover, we aimed to explore the relationship between pleural plaque volume (PPV) and pulmonary function tests. MATERIALS AND METHODS: Radiologists manually delineated PPs retrospectively in computed tomography (CT) images of patients with occupational exposure to asbestos (May 2014 to November 2019). We trained an AI model with a no-new-UNet architecture. The Dice Similarity Coefficient quantified the overlap between AI and radiologists. The Spearman correlation coefficient ( r ) was used for the correlation between PPV and pulmonary function test metrics. When recorded, these were vital capacity (VC), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO). RESULTS: We trained the AI system on 422 CT scans in 5 folds, each time with a different fold (n = 84 to 85) as a test set. On these independent test sets combined, the correlation between the predicted volumes and the ground truth was r = 0.90, and the median overlap was 0.71 Dice Similarity Coefficient. We found weak to moderate correlations with PPV for VC (n = 80, r = -0.40) and FVC (n = 82, r = -0.38), but no correlation for DLCO (n = 84, r = -0.09). When the cohort was split on the median PPV, we observed statistically significantly lower VC ( P = 0.001) and FVC ( P = 0.04) values for the higher PPV patients, but not for DLCO ( P = 0.19). CONCLUSION: We successfully developed an AI algorithm to automatically segment PP in CT images to enable fast volume extraction. Moreover, we have observed that PPV is associated with loss in VC and FVC.

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study.

BACKGROUND: The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy. METHODS: In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort. FINDINGS: Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8-19·4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required. INTERPRETATION: Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma. FUNDING: Merck Sharp & Dohme.

Impact of centralization of care for malignant peritoneal mesothelioma: A historical cohort study from the Dutch mesothelioma expert centers.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive cancer that has a poor prognosis. An earlier population-based study found that the majority of Dutch patients do not receive anti-cancer treatment. In 2015, Dutch Malignant Mesothelioma care was centralized in two expert centers. We reviewed treatment patterns at these centers, to assess the impact of centralization of MPM care in the Netherlands. METHODS: Data from all patients referred to the Dutch MPM expert centers from 2014 to 2020, were retrospectively collected. Descriptive statistics regarding referrals, patient and tumor characteristics, and treatment patterns were provided. Population-based incidence rates were provided by the Netherlands Cancer Registry. RESULTS: From 2014 to 2020, 78 patients were referred to the Dutch Mesothelioma expert centers, of whom 32 were female (41%). From 2014 to 2017, 27 patients were referred, whereas 51 patients were referred from 2018 to 2020. This represents about 24% and 61% of the estimated population incidence, respectively. Treatment patterns were comparable between both periods. Between 2014 and 2018, 33% of patients underwent surgery, 44% systemic therapy, and 22% received best supportive care (BSC), while this was 29%, 37%, and 33% respectively from 2018 to 2020. CONCLUSION: Centralization of care for patients with MPM resulted in an increase of annual referrals to the Dutch mesothelioma expert centers. While population-based incidence did not change during the study period, the absolute number of patients receiving treatment at our centers did increase. This might be considered a first important step towards better treatment for patients with this fatal disease.

Artificial intelligence-based diagnosis of asbestosis: analysis of a database with applicants for asbestosis state aid.

OBJECTIVES: In many countries, workers who developed asbestosis due to their occupation are eligible for government support. Based on the results of clinical examination, a team of pulmonologists determine the eligibility of patients to these programs. In this Dutch cohort study, we aim to demonstrate the potential role of an artificial intelligence (AI)-based system for automated, standardized, and cost-effective evaluation of applications for asbestosis patients. METHODS: A dataset of n = 523 suspected asbestosis cases/applications from across the Netherlands was retrospectively collected. Each case/application was reviewed, and based on the criteria, a panel of three pulmonologists would determine eligibility for government support. An AI system is proposed, which uses thoracic CT images as input, and predicts the assessment of the clinical panel. Alongside imaging, we evaluated the added value of lung function parameters. RESULTS: The proposed AI algorithm reached an AUC of 0.87 (p < 0.001) in the prediction of accepted versus rejected applications. Diffusion capacity (DLCO) also showed comparable predictive value (AUC = 0.85, p < 0.001), with little correlation between the two parameters (r-squared = 0.22, p < 0.001). The combination of the imaging AI score and DLCO achieved superior performance (AUC = 0.95, p < 0.001). Interobserver variability between pulmonologists on the panel was estimated at alpha = 0.65 (Krippendorff's alpha). CONCLUSION: We developed an AI system to support the clinical decision-making process for the application to the government support for asbestosis. A multicenter prospective validation study is currently ongoing to examine the added value and reliability of this system alongside the clinic panel. KEY POINTS: • Artificial intelligence can detect imaging patterns of asbestosis in CT scans in a cohort of patients applying for state aid. • Combining the AI prediction with the diffusing lung function parameter reaches the highest diagnostic performance. • Specific cases with fibrosis but no asbestosis were correctly classified, suggesting robustness of the AI system, which is currently under prospective validation.

Ritonavir-Boosted Exposure of Kinase Inhibitors: an Open Label, Cross-over Pharmacokinetic Proof-of-Concept Trial with Erlotinib.

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. 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 µg*h/mL (coefficient of variation (CV):58%), 1.84 µg/mL (CV:60%) and 1.00 µg/mL (CV:62%), respectively, compared with 28.9 µg*h/mL (CV:116%, p = 0.545), 1.68 µg/mL (CV:68%, p = 0.500) and 1.06 µg/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.

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial.

BACKGROUND: Almost 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. METHODS: We 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. FINDINGS: Between 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. INTERPRETATION: Switch-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. FUNDING: Dutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.

Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response.

BACKGROUND: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. METHODS: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. FINDINGS: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. INTERPRETATION: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.

Nivolumab in pre-treated advanced non-small cell lung cancer: long term follow up data from the Dutch expanded access program and routine clinical care.

BACKGROUND: For advanced non-small cell lung cancer anti-PD-1 treatment has become standard care in first and second line treatment in recent years. Because many of the clinical trials with anti-PD-1 drugs have only recently been completed, long term follow up data of patients treated with these agents is scarce, even more so of patients treated in real life clinical care. We present long term follow up of patients treated with nivolumab. METHODS: Two hundred forty-eight patients with pre-treated, advanced NSCLC who received nivolumab between August 2015 and December 2018 were included in this retrospective cohort study. Overall survival and progression free survival rates were calculated for the total cohort and for subgroups defined by clinical characteristics, responses to treatment, and other parameters. Data on further lines of treatment and characteristics of long term survivors were also collected. RESULTS: Median overall survival in the total cohort was 8.1 months, median progression free survival was 2.8 months. Overall survival after two and three years was 23.8% and 17.1%, respectively. Good ECOG performance scores, absence of liver metastases, experiencing treatment-related toxicity, and response to nivolumab were significantly associated with longer overall survival and progression free survival. Three-year survival rate among patients with an objective response was 55.3%. Survival for more than two years without subsequent therapy after nivolumab was observed in 13.3% of patients. CONCLUSIONS: The results from our study confirm that long term survival rates of patients treated with nivolumab for advanced NSCLC in a real world clinical setting are comparable to survival rates shown in clinical trials.

Immunotherapy in Malignant Pleural Mesothelioma.

The only registered systemic treatment for malignant pleural mesothelioma (MPM) is platinum based chemotherapy combined with pemetrexed, with or without bevacizumab. Immunotherapy did seem active in small phase II trials. In this review, we will highlight the most important immunotherapy-based research performed and put a focus on the future of MPM. PD-(L)1 inhibitors show response rates between 10 and 29% in phase II trials, with a wide range in progression free (PFS) and overall survival (OS). However, single agent pembrolizumab was not superior to chemotherapy (gemcitabine or vinorelbine) in the recent published PROMISE-Meso trial in pre-treated patients. In small studies with CTLA-4 inhibitors there is evidence for response in some patients, but it fails to show a better PFS and OS compared to best supportive care in a randomized study. A combination of PD-(L)1 inhibitor with CTLA-4 inhibitor seem to have a similar response as PD-(L)1 monotherapy. The first results of combining durvalumab (PD-L1 blocking) with cisplatin-pemetrexed in the first line are promising. Another immune treatment is Dendritic Cell (DC) immunotherapy, which is recently tested in mesothelioma, shows remarkable anti-tumor activity in three clinical studies. The value of single agent checkpoint inhibitors is limited in MPM. There is an urgent need for biomarkers to select the optimal candidates for immunotherapy among MPM patients in terms of efficacy and tolerance. Results of combination checkpoint inhibitors with chemotherapy are awaiting.

Pembrolizumab for the treatment of non-small cell lung cancer.

INTRODUCTION: In the last years, a spectacular development of immunotherapeutic agents aimed at the PD-1/PD-L1 axis has taken place. This development of these checkpoint inhibitors has greatly influenced our approach to the treatment of lung cancer in first and second line. The limited toxicity profile and the ability to treat for prolonged periods, even in smokers, is a welcome expansion of the therapeutic arsenal of the oncologist. Areas covered: This review highlights the results of recent clinical trials on pembrolizumab for the treatment of non-small cell lung cancer. The authors discuss both first and second line treatment with pembrolizumab as monotherapy and in combination therapies. Additionally, implications of the PD-L1 immunohistochemistry assay with the 22C3 antibody and its use in clinical practice and trials is discussed. Expert commentary: A higher overall response, overall survival and a moderate toxicity profile is observed with the use of pembrolizumab, compared to chemotherapy, in both first and second line. These promising results have already translated into the registration of pembrolizumab in first and second line in patients with a high expression of PD-L1. However, as PD-L1 staining does not sufficiently discriminate responders from non-responders for all checkpoint inhibitors, there still is a need for a better predictive biomarker.

T3-T4 laryngeal cancer in The Netherlands Cancer Institute; 10-year results of the consistent application of an organ-preserving/-sacrificing protocol.

BACKGROUND: Both organ-preserving concurrent (chemo)radiotherapy ((C)RT) and organ-sacrificing surgery (total laryngectomy) are used for treatment of advanced laryngeal cancer. The purpose of this study was to present the assessment of our treatment protocol for T3 (C)RT and T4 disease (total laryngectomy + postoperative RT). METHODS: We conducted a retrospective cohort study in 182 consecutive patients (1999-2008). The primary outcome was overall survival (OS) in relation to stage and treatment. RESULTS: One hundred two patients received RT (82.4% T3), 20 patients CRT (60.0% T3), and 60 patients total laryngectomy + RT (91.7% T4). Five-year OS: T3 52%, T4 48%, for RT 50%, for CRT 43%, and for total laryngectomy + RT 52%. Five-year laryngectomy-free interval was 72% after RT, and 83% after CRT. CONCLUSION: There were no differences in survival according to T classification or treatment modality. Because the majority of T3 laryngeal cancers were treated with (C)RT and the majority of T4 with total laryngectomy + RT, this gives food for thought on whether the present protocol for T3 laryngeal cancer is optimal.