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101. High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients

Author

Cantini, Luca, primary, Pecci, Federica, additional, Hurkmans, Daan P., additional, Belderbos, Robert A., additional, Lanese, Andrea, additional, Copparoni, Cecilia, additional, Aerts, Sophie, additional, Cornelissen, Robin, additional, Dumoulin, Daphne W., additional, Fiordoliva, Ilaria, additional, Rinaldi, Silvia, additional, Aerts, Joachim G.J.V., additional, and Berardi, Rossana, additional

Published
2021
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102. Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients

Author

Agema, Bram C., Koolen, Stijn L.W., de With, Mirjam, van Doorn, Nadia, Heersche, Niels, Oomen-De Hoop, Esther, Visser, Sabine, Aerts, Joachim G.J.V., Bins, Sander, van Schaik, Ron H.N., Mathijssen, Ron H.J., Agema, Bram C., Koolen, Stijn L.W., de With, Mirjam, van Doorn, Nadia, Heersche, Niels, Oomen-De Hoop, Esther, Visser, Sabine, Aerts, Joachim G.J.V., Bins, Sander, van Schaik, Ron H.N., and Mathijssen, Ron H.J.

Abstract

Cisplatin is a chemotherapeutic agent widely used for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin, dose-limiting acute kidney injury (AKI) occurs. Here, we assessed the association of 3 catechol-O-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) with increased cisplatin-induced nephrotoxicity. In total, 551 patients were genotyped for the 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316), and c.616 – 367 C>T (rs9332377) polymorphisms. Associations between these variants and AKI grade ≥3 were studied. The presence of a homozygous variant of c.616-367C>T was associated with a decreased occurrence of AKI grade 3 toxicity (p = 0.014, odds ratio (OR) 0.201, 95% confidence interval (CI) (0.047–0.861)). However, we could not exclude the role of dehydration as a potential cause of AKI in 25 of the 27 patients with AKI grade 3, which potentially affected the results substantially. As a result of the low incidence of AKI grade 3 in this dataset, the lack of patients with a COMT variant, and the high number of patients with dehydration, the association between COMT variants and AKI does not seem clinically relevant.

Published
2020

103. Plasma predictive features in treating egfr-mutated non-small cell lung cancer

Author

Steendam, Christi M.J., Marijn Veerman, G. D., Pruis, Melinda A., Atmodimedjo, Peggy, Paats, Marthe S., van der Leest, Cor, von der Thüsen, Jan H., Yick, David C.Y., Hoop, Esther Oomen De, Koolen, Stijn L.W., Dinjens, Winand N.M., van Schaik, Ron H.N., Mathijssen, Ron H.J., Aerts, Joachim G.J.V., Dubbink, Hendrikus Jan, Dingemans, Anne Marie C., Steendam, Christi M.J., Marijn Veerman, G. D., Pruis, Melinda A., Atmodimedjo, Peggy, Paats, Marthe S., van der Leest, Cor, von der Thüsen, Jan H., Yick, David C.Y., Hoop, Esther Oomen De, Koolen, Stijn L.W., Dinjens, Winand N.M., van Schaik, Ron H.N., Mathijssen, Ron H.J., Aerts, Joachim G.J.V., Dubbink, Hendrikus Jan, and Dingemans, Anne Marie C.

Abstract

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC), not all patients benefit. We therefore explored the impact of the presence of mutations found in cell-free DNA (cfDNA) and TKI plasma concentrations during treatment on progression-free survival (PFS). In the prospective START-TKI study blood samples from 41 patients with EGFR-mutated NSCLC treated with EGFR-TKIs were available. Next generation sequencing (NGS) on cfDNA was performed, and plasma TKI concentrations were measured. Patients without complete plasma conversion of EGFR mutation at week 6 had a significantly shorter PFS (5.5 vs. 17.0 months, p = 0.002) and OS (14.0 vs. 25.5 months, p = 0.003) compared to patients with plasma conversion. In thirteen (second line) osimertinib-treated patients with a (plasma or tissue) concomitant TP53 mutation at baseline, PFS was significantly shorter compared to six wild-type cases; 8.8 vs. 18.8 months, p = 0.017. Erlotinib Cmean decrease of ≥10% in the second tertile of treatment was also associated with a significantly shorter PFS; 8.9 vs. 23.6 months, p = 0.037. We obtained evidence that absence of plasma loss of the primary EGFR mutation, isolated plasma p.T790M loss after six weeks, baseline concomitant TP53 mutations, and erlotinib Cmean decrease during treatment are probably related to worse outcome.

Published
2020

104. Blood-based kinase activity profiling:A potential predictor of response to immune checkpoint inhibition in metastatic cancer

Author

Hurkmans, Daan P., Verdegaal, Els M.E., Hogan, Sabrina A., De Wijn, Rik, Hovestad, Lies, Van Den Heuvel, Dianne M.A., Ruijtenbeek, Rob, Welters, Marij J.P., Van Brakel, Mandy, Basak, Edwin A., Pinedo, Herbert M., Lamers, Cor H.J., Van De Werken, Harmen J.G., Groten, John P., Debets, Reno, Levesque, Mitchell P., Dummer, Reinhard, Kapiteijn, Ellen, Mathijssen, Ron H.J., Aerts, Joachim G.J.V., Van Der Burg, Sjoerd H., Hurkmans, Daan P., Verdegaal, Els M.E., Hogan, Sabrina A., De Wijn, Rik, Hovestad, Lies, Van Den Heuvel, Dianne M.A., Ruijtenbeek, Rob, Welters, Marij J.P., Van Brakel, Mandy, Basak, Edwin A., Pinedo, Herbert M., Lamers, Cor H.J., Van De Werken, Harmen J.G., Groten, John P., Debets, Reno, Levesque, Mitchell P., Dummer, Reinhard, Kapiteijn, Ellen, Mathijssen, Ron H.J., Aerts, Joachim G.J.V., and Van Der Burg, Sjoerd H.

Abstract

Background Many cancer patients do not obtain clinical benefit from immune checkpoint inhibition. Checkpoint blockade targets T cells, suggesting that tyrosine kinase activity profiling of baseline peripheral blood mononuclear cells may predict clinical outcome. Methods Here a total of 160 patients with advanced melanoma or non-small-cell lung cancer (NSCLC), treated with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-programmed cell death 1 (anti-PD-1), were divided into five discovery and cross-validation cohorts. The kinase activity profile was generated by analyzing phosphorylation of peripheral blood mononuclear cell lysates in a microarray comprising of 144 peptides derived from sites that are substrates for protein tyrosine kinases. Binary grouping into patients with or without clinical benefit was based on Response Evaluation Criteria in Solid Tumors V.1.1. Predictive models were trained using partial least square discriminant analysis (PLS-DA), performance of the models was evaluated by estimating the correct classification rate (CCR) using cross-validation. Results The kinase phosphorylation signatures segregated responders from non-responders by differences in canonical pathways governing T-cell migration, infiltration and co-stimulation. PLS-DA resulted in a CCR of 100% and 93% in the anti-CTLA-4 and anti-PD1 melanoma discovery cohorts, respectively. Cross-validation cohorts to estimate the accuracy of the predictive models showed CCRs of 83% for anti-CTLA-4 and 78% or 68% for anti-PD-1 in melanoma or NSCLC, respectively. Conclusion Blood-based kinase activity profiling for response prediction to immune checkpoint inhibitors in melanoma and NSCLC revealed increased kinase activity in pathways associated with T-cell function and led to a classification model with a highly accurate classification rate in cross-validation groups. The predictive value of kinase activity profiling is prospectively verified in an ongoing trial.

Published
2020

110. Prediction of Lifetime and 10-Year Risk of Cancer in Individual Patients With Established Cardiovascular Disease

Author

van ’t Klooster, Cilie C., primary, Ridker, Paul M., additional, Cook, Nancy R., additional, Aerts, Joachim G.J.V., additional, Westerink, Jan, additional, Asselbergs, Folkert W., additional, van der Graaf, Yolanda, additional, Visseren, Frank L.J., additional, Asselbergs, F.W., additional, Nathoe, H.M., additional, de Borst, G.J., additional, Bots, M.L., additional, Geerlings, M.I., additional, Emmelot, M.H., additional, de Jong, P.A., additional, Leiner, T., additional, Lely, A.T., additional, van der Kaaij, N.P., additional, Kappelle, L.J., additional, Ruigrok, Y., additional, Verhaar, M.C., additional, and Westerink, J., additional

Published
2020
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112. Molecular data show conserved DNA locations distinguishing lung cancer subtypes and regulation of immune genes

Author

Hurkmans, Daan P., primary, Tamminga, Menno, additional, van Es, Bram, additional, Peters, Tom, additional, Karman, Wouter, additional, van Wijck, Rogier T.A., additional, van der Spek, Peter J., additional, Tauber, Tjebbe, additional, Los, Maureen, additional, van Schetsen, Anouk, additional, Vu, Thu, additional, Hiltermann, T. Jeroen. N., additional, Schuuring, Ed, additional, Aerts, Joachim G.J.V., additional, Chen, Sissy, additional, and Groen, Harry J.M., additional

Published
2020
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114. Overt Thyroid Dysfunction and Anti-Thyroid Antibodies Predict Response to Anti-PD-1 Immunotherapy in Cancer Patients

Author

Basak, Edwin A., primary, van der Meer, Jan W.M., additional, Hurkmans, Daan P., additional, Schreurs, Marco W.J., additional, Oomen-de Hoop, Esther, additional, van der Veldt, Astrid A.M., additional, Bins, Sander, additional, Joosse, Arjen, additional, Koolen, Stijn L.W., additional, Debets, Reno, additional, Peeters, Robin P., additional, Aerts, Joachim G.J.V., additional, Mathijssen, Ron H.J., additional, and Medici, Marco, additional

Published
2020
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116. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial

Author

de Koning, Harry J., primary, van der Aalst, Carlijn M., additional, de Jong, Pim A., additional, Scholten, Ernst T., additional, Nackaerts, Kristiaan, additional, Heuvelmans, Marjolein A., additional, Lammers, Jan-Willem J., additional, Weenink, Carla, additional, Yousaf-Khan, Uraujh, additional, Horeweg, Nanda, additional, van ’t Westeinde, Susan, additional, Prokop, Mathias, additional, Mali, Willem P., additional, Mohamed Hoesein, Firdaus A.A., additional, van Ooijen, Peter M.A., additional, Aerts, Joachim G.J.V., additional, den Bakker, Michael A., additional, Thunnissen, Erik, additional, Verschakelen, Johny, additional, Vliegenthart, Rozemarijn, additional, Walter, Joan E., additional, ten Haaf, Kevin, additional, Groen, Harry J.M., additional, and Oudkerk, Matthijs, additional

Published
2020
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118. Tumour growth rate as a tool for response evaluation during PD-1 treatment for non-small cell lung cancer:A retrospective analysis

Author

Ten Berge, Deirdre M.H.J., Hurkmans, Daniel P., Den Besten, Ilse, Kloover, Jeroen S., Mathijssen, Ron H.J., Debets, Reno J.E.M.A., Smit, Egbert F., Aerts, Joachim G.J.V., Ten Berge, Deirdre M.H.J., Hurkmans, Daniel P., Den Besten, Ilse, Kloover, Jeroen S., Mathijssen, Ron H.J., Debets, Reno J.E.M.A., Smit, Egbert F., and Aerts, Joachim G.J.V.

Abstract

Background: Immune checkpoint inhibitors have emerged as a standard of care treatment for non-small cell lung cancer (NSCLC). To get insight into variations in tumour growth kinetics and their potential predictive values for outcome, we evaluated tumour growth rate (TGR) in patients receiving programmed cell death 1 (PD-1) checkpoint inhibitors. Patients and methods: Differences in TGR before and after the start of treatment were calculated by entering the sum of the longest diameters from computer tomography scans before and after the initiation of therapy into a formula that assumes volumetric exponential tumour growth. TGR variations, possible predictors for TGR changes and its relationship to overall survival (OS) were studied. For comparison, tumour response was assessed using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Results: Among the 58 evaluable patients, 37 patients (64%) showed deceleration of TGR and 16 patients (27%) showed an acceleration of TGR after initiation of therapy, with a significant difference in median OS of 18.0 months versus 6.0 months (hazard ratio 0.35, 95% CI 0.18–0.71) between these groups. Four patients (7%) were defined as having hyperprogressive disease. In five patients (9%), tumour growth remained stable. These TGR categories were not significantly different according to age, sex, histology, smoking or previous radiotherapy. Of the patients defined as having progressive disease by RECIST version 1.1 at first follow-up, 40% showed response to checkpoint inhibitors by a decrease in TGR. Conclusion: Tumour growth kinetics can be used as a clinically relevant predictor for OS in anti-PD-1- treated patients with NSCLC, and may provide additional information to RECIST measurements.

Published
2019

119. A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients

Author

Hurkmans, Daan P., Basak, Edwin A., Van Dijk, Tanja, Mercieca, Darlene, Schreurs, Marco W.J., Wijkhuijs, Annemarie J.M., Bins, Sander, Hoop, Esther Oomen De, Debets, Reno, Joerger, Markus, Odink, Arlette, Van Der Veldt, Astrid A.M., Van Der Leest, Cor H., Aerts, Joachim G.J.V., Mathijssen, Ron H.J., Koolen, Stijn L.W., Hurkmans, Daan P., Basak, Edwin A., Van Dijk, Tanja, Mercieca, Darlene, Schreurs, Marco W.J., Wijkhuijs, Annemarie J.M., Bins, Sander, Hoop, Esther Oomen De, Debets, Reno, Joerger, Markus, Odink, Arlette, Van Der Veldt, Astrid A.M., Van Der Leest, Cor H., Aerts, Joachim G.J.V., Mathijssen, Ron H.J., and Koolen, Stijn L.W.

Abstract

Background: Nivolumab is administered in a weight-based or fixed-flat dosing regimen. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported and may argue against the current dosing strategies. The primary objectives were to determine nivolumab pharmacokinetics (PK) and to assess the relationship between drug clearance and clinical outcome in NSCLC, melanoma, and renal cell cancer (RCC). Methods: In this prospective observational cohort study, individual estimates of nivolumab clearance and the impact of baseline covariates were determined using a population-PK model. Clearance was related to best overall response (RECISTv1.1), and stratified by tumor type. Results: Two-hundred-twenty-one patients with metastatic cancer receiving nivolumab-monotherapy were included of whom 1,715 plasma samples were analyzed. Three baseline parameters had a significant effect on drug clearance and were internally validated in the population-PK model: gender, BSA, and serum albumin. Women had 22% lower clearance compared to men, while the threshold of BSA and albumin that led to > 20% increase of clearance was > 2.2m2 and < 37.5 g/L, respectively. For NSCLC, drug clearance was 42% higher in patients with progressive disease (mean: 0.24; 95% CI: 0.22-0.27 L/day) compared to patients with partial/complete response (mean: 0.17; 95% CI: 0.15-0.19 L/day). A similar trend was observed in RCC, however, no clearance-response relationship was observed in melanoma. Conclusions: Based on the first real-world population-PK model of nivolumab, covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab clearance. A clearance-response relationship was observed in NSCLC, with a non-significant trend in RCC, but not in melanoma. Individual pharmacology of nivolumab in NSCLC appears important and should be prospectively studied.

Published
2019

120. CD45RA+CCR7- CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab

Author

Kunert, Andre, Basak, Edwin A., Hurkmans, Daan P., Balcioglu, Hayri E., Klaver, Yarne, Van Brakel, Mandy, Oostvogels, Astrid A.M., Lamers, Cor H.J., Bins, Sander, Koolen, Stijn L.W., Van Der Veldt, Astrid A.M., Sleijfer, Stefan, Mathijssen, Ron H.J., Aerts, Joachim G.J.V., Debets, Reno, Kunert, Andre, Basak, Edwin A., Hurkmans, Daan P., Balcioglu, Hayri E., Klaver, Yarne, Van Brakel, Mandy, Oostvogels, Astrid A.M., Lamers, Cor H.J., Bins, Sander, Koolen, Stijn L.W., Van Der Veldt, Astrid A.M., Sleijfer, Stefan, Mathijssen, Ron H.J., Aerts, Joachim G.J.V., and Debets, Reno

Abstract

Background: Checkpoint inhibitors have become standard care of treatment for non-small cell lung cancer (NSCLC), yet only a limited fraction of patients experiences durable clinical benefit, highlighting the need for markers to stratify patient populations. Methods: To prospectively identify patients showing response to therapy, we have stained peripheral blood samples of NSCLC patients treated with 2nd line nivolumab (n = 71), as well as healthy controls, with multiplex flow cytometry. By doing so, we enumerated 18 immune cell subsets and assessed expression for 28 T cell markers, which was followed by dimensionality reduction as well as rationale-based analyses. Results: In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells. Conclusions: This study demonstrates that high numbers of peripheral CD8 T cells expressing differentiation markers and lacking co-stimulatory receptors at baseline are associated with response to nivolumab in NSCLC patients.

Published
2019

122. Late Breaking Abstract - Effect of adjunctive tobramycin inhalation therapy in the treatment of ventilator-associated pneumonia: findings from the randomized VAPORISE trial

Author

Stokker, Jason, primary, Karami, Mina, additional, Hoek, Rogier A.S., additional, Van Duijn, Ditty, additional, Ormskerk, Patricia, additional, Muskens, Femke M., additional, Aerts, Joachim G.J.V., additional, Gommers, Diederik A.M.P.J., additional, and van der Eerden, Menno M., additional

Published
2019
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124. Reply to K. Masuda et al

Author

Fennell, Dean A., primary, Taylor, Paul, additional, Gilligan, David, additional, Nakano, Takashi, additional, Scherpereel, Arnaud, additional, Pavlakis, Nick, additional, van Meerbeeck, Jan P., additional, Aerts, Joachim G.J.V., additional, Nowak, Anna K., additional, Kindler, Hedy, additional, and Baas, Paul, additional

Published
2019
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126. Effect of targeting CD40 for DC vaccination in pancreatic adenocarcinoma.

Author

Lau, Sai Ping, primary, van Montfoort, Nadine, additional, Kinderman, Priscilla, additional, Lukkes, Melanie, additional, Dumas, Jasper, additional, van Nimwegen, Menno, additional, Mustafa, Dana, additional, Vroman, Heleen, additional, van Hall, Thorbald, additional, van der Burg, Sjoerd H., additional, Aerts, Joachim G.J.V., additional, Dammeijer, Floris, additional, and van Eijck, Casper H.J., additional

Published
2019
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127. Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND—A Double-Blind, Randomized, Phase II Study

Author

Fennell, Dean A., primary, Baas, Paul, additional, Taylor, Paul, additional, Nowak, Anna K., additional, Gilligan, David, additional, Nakano, Takashi, additional, Pachter, Jonathan A., additional, Weaver, David T., additional, Scherpereel, Arnaud, additional, Pavlakis, Nick, additional, van Meerbeeck, Jan P., additional, Cedrés, Susana, additional, Nolan, Luke, additional, Kindler, Hedy, additional, and Aerts, Joachim G.J.V., additional

Published
2019
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128. Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of Paclitaxel, Carboplatin, and Bevacizumab in Non–small Cell Lung Cancer Patients

Author

de Goeje, Pauline L., primary, Poncin, Myrthe, additional, Bezemer, Koen, additional, Kaijen-Lambers, Margaretha E.H., additional, Groen, Harry J.M., additional, Smit, Egbert F., additional, Dingemans, Anne-Marie C., additional, Kunert, André, additional, Hendriks, Rudi W., additional, and Aerts, Joachim G.J.V., additional

Published
2019
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129. Correlation between nivolumab exposure and treatment outcomes in non–small-cell lung cancer

Author

Basak, Edwin A., primary, Koolen, Stijn L.W., additional, Hurkmans, Daan P., additional, Schreurs, Marco W.J., additional, Bins, Sander, additional, Oomen – de Hoop, Esther, additional, Wijkhuijs, Annemarie J.M., additional, Besten, Ilse den, additional, Sleijfer, Stefan, additional, Debets, Reno, additional, van der Veldt, Astrid A.M., additional, Aerts, Joachim G.J.V., additional, and Mathijssen, Ron H.J., additional

Published
2019
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132. Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients

Author

Bins, Sander, Basak, Edwin A., El Bouazzaoui, Samira, Koolen, Stijn L.W., Oomen De Hoop, E., Van Der Leest, Cor H., Van Der Veldt, Astrid A.M., Sleijfer, Stefan, Debets, Reno, Van Schaik, Ron H.N., Aerts, Joachim G.J.V., Mathijssen, Ron H.J., Bins, Sander, Basak, Edwin A., El Bouazzaoui, Samira, Koolen, Stijn L.W., Oomen De Hoop, E., Van Der Leest, Cor H., Van Der Veldt, Astrid A.M., Sleijfer, Stefan, Debets, Reno, Van Schaik, Ron H.N., Aerts, Joachim G.J.V., and Mathijssen, Ron H.J.

Abstract

Background: Treatment with PD-1 inhibitors can be hampered by severe auto-immune-related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology. Methods: We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i.e., PDCD1, PTPN11, ZAP70 and IFNG. Every SNP was tested for its association with toxicity endpoints. Significant associations were tested in a validation cohort. Results: A multivariable analysis in the exploration cohort showed that homozygous variant patients for PDCD1 804C>T (rs2227981) had decreased odds for any grade treatment-related toxicities (n = 96; OR 0.4; 95% CI 0.2-1.0; p = 0.039). However, this result could not be validated (n = 85; OR 0.9; 95% CI 0.4-1.9; p = NS). Conclusions: Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments.

Published
2018

135. Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

Author

Noordam, Lisanne, primary, Kaijen, Margaretha E.H., additional, Bezemer, Koen, additional, Cornelissen, Robin, additional, Maat, Lex A.P.W.M., additional, Hoogsteden, Henk C., additional, Aerts, Joachim G.J.V., additional, Hendriks, Rudi W., additional, Hegmans, Joost P.J.J, additional, and Vroman, Heleen, additional

Published
2018
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136. Identifying t cell profiles that associate with clinical response to anti-PD-1 treatment in non-small cell lung carcinoma (NSCLC) patients.

Author

Kunert, Andre, primary, Basak, Edwin A., additional, Hurkmans, Daan, additional, Klaver, Yarne, additional, van Brakel, Mandy, additional, Oostvogels, Astrid, additional, Lamers, Cor, additional, Bins, Sander, additional, Koolen, Stijn L.W., additional, Van Der Veldt, Astrid, additional, Sleijfer, Stefan, additional, Mathijssen, Ron H.J., additional, Aerts, Joachim G.J.V., additional, and Debets, Reno, additional

Published
2018
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137. Blood-based multiplex kinase activity profiling as a predictive marker for clinical response to checkpoint blockade in advanced melanoma.

Author

Hurkmans, Daan, primary, Verdegaal, Els M.E., additional, Schindler, Sabrina A., additional, Basak, Edwin A., additional, van den Heuvel, Dianne M.A., additional, de Wijn, Rik, additional, Ruijtenbeek, Rob, additional, Groten, John P., additional, Dummer, Reinhard, additional, Koolen, Stijn L.W., additional, Welters, Marij J.P., additional, Mathijssen, Ron H.J., additional, Kapiteijn, Ellen, additional, Aerts, Joachim G.J.V., additional, Levesque, Mitchell P., additional, and van der Burg, Sjoerd H., additional

Published
2018
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138. A modular, multi-arm, multi-part, first time in patient study to evaluate the safety and tolerability of the dual MET kinase/OCT2 inhibitor, OMO-1, alone and in combination with anti-cancer treatments, in patients with locally advanced, unresectable or metastatic solid malignancies.

Author

Plummer, Elizabeth Ruth, primary, Lolkema, Martijn P., additional, Aerts, Joachim G.J.V., additional, De Vos, Filip Yves Francine Leon, additional, Forster, Martin, additional, ANGEVIN, ERIC, additional, Kristeleit, Rebecca Sophie, additional, Perera, Tim, additional, Clack, Glen, additional, Meulemans, Ann, additional, Libouban, Marion, additional, Hari Dass, Prashanth, additional, Drew, Yvette, additional, Tinsley, Nadina, additional, Balaratnam, Shankar, additional, Blagden, Sarah Patricia, additional, and Krebs, Matthew, additional

Published
2018
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140. Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human

Author

Aerts, Joachim G.J.V., primary, de Goeje, Pauline L., additional, Cornelissen, Robin, additional, Kaijen-Lambers, Margaretha E.H., additional, Bezemer, Koen, additional, van der Leest, Cor H., additional, Mahaweni, Niken M., additional, Kunert, André, additional, Eskens, Ferry A.L.M., additional, Waasdorp, Cynthia, additional, Braakman, Eric, additional, van der Holt, Bronno, additional, Vulto, Arnold G., additional, Hendriks, Rudi W., additional, Hegmans, Joost P.J.J., additional, and Hoogsteden, Henk C., additional

Published
2018
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141. Immunotherapy: a new standard of care in thoracic malignancies?

Author

Costantini, Adrien, primary, Grynovska, Marta, additional, Lucibello, Francesca, additional, Moisés, Jorge, additional, Pagès, Franck, additional, Tsao, Ming S., additional, Shepherd, Frances A., additional, Bouchaab, Hasna, additional, Garassino, Marina, additional, Aerts, Joachim G.J.V., additional, Mazières, Julien, additional, Mondini, Michele, additional, Berghmans, Thierry, additional, Meert, Anne-Pascale, additional, and Cadranel, Jacques, additional

Published
2018
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146. Renal Toxicity From Pemetrexed and Pembrolizumab in the Era of Combination Therapy in Patients With Metastatic Nonsquamous Cell NSCLC

Author

Dumoulin, Daphne W., Visser, Sabine, Cornelissen, Robin, van Gelder, Teun, Vansteenkiste, Johan, von der Thusen, Jan, and Aerts, Joachim G.J.V.

Abstract

The combination of chemotherapy and immune checkpoint inhibition (ICI) therapy is the current standard of care for most patients who are fit to undergo treatment for metastatic NSCLC. With this combination, renal toxicity was slightly higher than with chemotherapy alone in initial clinical trials. However, in recent real-world data, loss of kidney function is reported to be more frequent. Both chemotherapy and ICI therapy can induce renal impairment, although the mechanism of renal damage is different. Renal injury from chemotherapy is often ascribed to acute tubular injury and necrosis, whereas the main mechanism of injury caused by ICI therapy is acute tubulointerstitial nephritis. In cases of concomitant use of chemotherapy and ICI therapy, distinguishing the cause of renal failure is a challenge. Discriminating between these two causes is of utmost importance, as it would help assess which drug can be safely continued and which drug must be halted. This review aims to describe the underlying mechanisms of the renal adverse effects caused by chemotherapy and ICI therapy, leading to a suggested diagnostic and treatment algorithm on the basis of clinical, laboratory, radiographic, and pathologic parameters. This algorithm could serve as a supportive tool for clinicians to diagnose the underlying cause of acute kidney injury in patients treated with the combination of chemotherapy and immunotherapy.

Published
2020
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147. Plasma Cell-Free DNA Testing of Patients With EGFR Mutant Non–Small-Cell Lung Cancer: Droplet Digital PCR Versus Next-Generation Sequencing Compared With Tissue-Based Results.

Author

Steendam, Christi M.J., Atmodimedjo, Peggy, de Jonge, Evert, Paats, Marthe S., van der Leest, Cor, Oomen-de Hoop, Esther, von der Thüsen, Jan H., Dinjens, Winand N.M., van Schaik, Ron H.N., Aerts, Joachim G.J.V., and Dubbink, Hendrikus Jan

Subjects
CELL-free DNA, NON-small-cell lung carcinoma, EPIDERMAL growth factor receptors, INTRACLASS correlation
Abstract

PURPOSE: To compare the results of plasma cell-free DNA (cfDNA) droplet digital PCR (ddPCR) and next-generation sequencing (NGS) on detection of epidermal growth factor receptor (EGFR) primary activating mutations and p.T790M with results of tissue analysis in patients with EGFR mutated non–small-cell lung cancer. METHODS: All patients with EGFR mutated non–small cell lung cancer for which a pathology and a plasma specimen were available upon progression between November 2016 and July 2018 were selected. Concordance, Cohen's κ, and intraclass correlation coefficients were calculated. RESULTS: Plasma cfDNA and pathology specimens of 36 patients were analyzed. Agreement between ddPCR and NGS was 86% (κ = 0.63) for the primary activating mutation and 94% (κ = 0.89) for the p.T790M detection. Allele ratios were comparable, with an intraclass correlation coefficient of 0.992 and 0.997, respectively. Discrepancies of some degree were found in 15 patients (41.7%). In six patients (16.7%), no mutations were detected in cfDNA. In three patients (8.3%), p.T790M was detected in plasma but not in the pathology specimen, whereas in three other patients (8.3%), p.T790M was demonstrated in the pathology specimen but not in plasma. Concordance of cfDNA and pathology for the primary activating mutation was 69% for ddPCR and 83% for NGS. For the detection of p.T790M, this was 75% (κ = 0.49) for ddPCR as well as for NGS. CONCLUSION: Mutual agreement is high between NGS and ddPCR in cfDNA on the level of a specific mutation, with comparable ratio results. Plasma testing of EGFR primary activating mutations and p.T790M shows high concordance with pathology results, for NGS as well as for ddPCR, depending on the extent of the panel used. In NGS, more genetic aberrations can be investigated at once. [ABSTRACT FROM AUTHOR]

Published
2019
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