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J. Aerts
Moderator of
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New approaches in rare thoracic tumors (ID 60)
- Event: ELCC 2018
- Type: Proffered Paper session
- Track:
- Presentations: 6
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Invited Discussant 112O, 213O and 214O (ID 695)
11:00 - 12:30 | Presenting Author(s): N. Girard
- Abstract
- Presentation
Abstract not provided
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Invited Discussant 135O (ID 696)
11:00 - 12:30 | Presenting Author(s): M. Perol
- Abstract
- Presentation
Abstract not provided
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112O - Primary result of an investigator-initiated phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study (NCCH1505) (ID 349)
11:00 - 12:30 | Presenting Author(s): T. Seto | Author(s): Y. Katsuya, H. Horinouchi, S. Umemura, Y. Hosomi, M. Satouchi, A. Kuchiba, Y. Ohe
- Abstract
- Presentation
Background:
Thymic carcinoma (TC) is a rare cancer with a poor prognosis. Treatment options are limited, especially after relapse. We previously reported that PD-L1 positivity was observed in 70% of TCs by immunohistochemistry suggesting anti PD-1/PD-L1 agents could be a promising treatment.
Methods:
In this open-label, two-stage, multi-center, single-arm, phase II trial, the main eligibility criteria were: unresectable or recurrent TC, an ECOG-PS of 0 or 1, the presence of measurable disease, progression after at least one previous platinum-based chemo(radio)therapy treatment, and no history of autoimmune disease. Nivolumab was administered at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the response rate (RR) as evaluated by central review using the RECIST v1.1; secondary endpoints include progression-free survival (PFS), overall survival, disease control rate, and safety. The planned sample size was 15 for the first stage and 15 for the second stage, with a threshold RR of 5%, an expected RR of 20%, one-sided alpha of 5% and power of 80%. This trial was registered with UMIN000022007.
Results:
Between July 1 and August 16, 2016, 15 patients were accrued in the first stage; at the data cutoff (August 31, 2017), all were assessable for a response. Median follow-up time was 3.8 months (range 1.4–12.0). All were Japanese, 12 were male, median age was 55 (range 34–70), 13 had squamous histology. The median number of nivolumab cycles received was 8 (range 3–29). RR by central review was 0% (no patient with complete or partial response; 95% confidence interval [CI]: 0–21.8). Eleven patients had stable disease and four had progressive disease. Median PFS was 3.8 months (95% CI: 1.9–5.6), and 12-month PFS rate was 13.3% (95% CI: 2.2–34.6). Two patients experienced a treatment-related serious adverse events (grade 3 AST increase and grade 2 adrenal insufficiency). Because the early termination criteria at the first stage (less than one responder) was fulfilled, the patient accrual was terminated.
Conclusions:
Despite of the small number of patients, our results suggested further development of nivolumab is not recommended in previously treated unresectable or recurrent TC.
Clinical trial identification:
Legal entity responsible for the study:
None
Funding:
Japan Agency for Medical Research and Development
Disclosure:
T. Seto: Consulting and advisory services, speaking or writing engagements, public presentations; AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Taiho, Takeda. Direct research support to the responsible project lead (e.g., Principal Investigator); Eisai, MSD, Nippon Boehringer Ingelheim, AstraZeneca, Astellas, Chugai, Daiichi Sankyo, Eli Lilly, Merck Serono, Novartis, Pfizer. H. Horinouchi: Research Grant; Ono pharmaceutical, BMS, MSD, Taiho, Chugai, Novartis, Astellas, Merck Serono. Honoraria; Ono pharmaceutical, BMS, Taiho, Chugai, Novartis, Lilly, AstraZeneca. S. Umemura: Corporate-sponsored research; MSD, AstraZeneca. Honoraria; AstraZeneca, Chugai pharmaceutical, Ono, Boehringer ingelheim. Y. Hosomi: Honoraria; Lilly, Ono pharmaceutical, BMS, Chugai, AstraZeneca. Corporate-sponsored research; Lilly, Ono pharmaceutical, Chugai, AstraZeneca, Taiho, MSD. M. Satouchi: Corporate-sponsored research; Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Novartis, Ono Pharmaceutical, Pfizer Japan. Lecture fees and/or honoraria; AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Merck, Novartis, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical. Y. Ohe: Corporate-sponsored research; Taiho, AstraZeneca, Chugai, Lilly, Pfizer, MSD, Novartis, Kyorin, Dainippon-Sumitomo, Ignyta. Membership on an advisory board or board of directors or other substantive relationships; Taiho, AstraZeneca, Chugai, Lilly, Pfizer, MSD, Novartis, Daiichi-Sankyo, Nipponkayaku, Boehringer Ingelheim, Bayer. All other authors have declared no conflicts of interest.
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135O - A phase 1b study of necitumumab in combination with abemaciclib in patients with stage IV non-small cell lung cancer (ID 592)
11:00 - 12:30 | Presenting Author(s): B. Besse | Author(s): F. Barlesi, I. Demedts, J. Fuentes Pradera, A. Renault, G. Robinet, B. Frimodt-Moller, M. Gil, J. Vansteenkiste
- Abstract
- Presentation
Background:
Necitumumab and abemaciclib inhibit tumor progression by different, independent mechanisms, and both have shown activity in patients with non-small cell lung cancer (NSCLC).
Methods:
This Phase 1b study was a single arm, multicenter trial to explore the safety and efficacy of necitumumab plus abemaciclib in adults with confirmed Stage IV NSCLC, who had received a maximum of 1 other prior chemotherapy for advanced and/or metastatic disease. Part A was a dose escalation study for abemaciclib in combination with necitumumab 800 mg D1D8 Q3W in up to 18 patients to determine the recommended dose for the expansion cohort (Part B, planned for 50 patients). The primary endpoint was progression-free survival (PFS) rate at 3 months compared to the historical PFS rate with single agent epidermal growth factor receptor inhibitors (50%). Secondary efficacy endpoints included PFS, overall response rate (ORR), disease control rate (DCR), and overall survival (OS).
Results:
Sixty-six patients entered the study: 71% male, 61% <65 years of age, 77% ECOG performance status 1, 41% squamous histology, and 15% never smokers. In Part A (n = 15), the maximum tolerated abemaciclib dose was determined to be 150 mg every 12 hours; overall 57 patients received this treatment. The 3-month PFS rate was 32.3% (95% CI: 20.4, 44.8); median PFS was 2.14 months (1.41, 2.76). ORR was 5.3% (1.1, 14.6), and DCR was 47.4% (34.0, 61.0). The median OS was 6.93 months (4.96, 12.85). Treatment-emergent adverse events occurring in ≥30% of all patients (n [%]) included fatigue (34 [51.5]), diarrhea (33 [50.0]), dermatitis acneiform (31 [47.0]), decreased appetite (26 [39.4]), nausea (26 [39.4]), anemia (24 [36.4]), dyspnea (22 [33.3]), hypomagnesemia (21 [31.8]), vomiting (21 [31.8]), and dry skin (20 [30.3]).
Conclusions:
In patients with Stage IV NSCLC, the combination of abemaciclib with necitumumab did not meaningfully impact the PFS rate at 3 months. The safety profile was consistent with the individual study drugs, and no new significant safety concerns emerged.
Clinical trial identification:
ClinicalTrials.gov NCT02411591
Legal entity responsible for the study:
Eli Lilly and Company
Funding:
Eli Lilly and Company
Disclosure:
B. Besse: Research support from Eli Lilly and Company. B. Frimodt-Moller, M. Gil: Employee and stockholder of Eli Lilly and Company. All other authors have declared no conflicts of interest.
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213O - Nintedanib + pemetrexed/cisplatin in malignant pleural mesothelioma (MPM): Phase II biomarker data from the LUME Meso study (ID 206)
11:00 - 12:30 | Presenting Author(s): N. Pavlakis | Author(s): F. Grosso, N. Steele, A. Nowak, S. Novello, S. Popat, L. Greillier, M. Reck, T. Kitzing, G. Scagliotti
- Abstract
- Presentation
Background:
The randomised Phase II/III LUME-Meso study is evaluating nintedanib + pemetrexed/cisplatin versus placebo + pemetrexed/cisplatin (≤6 cycles), followed by nintedanib or placebo maintenance, in chemo-naïve MPM. In the Phase II part, nintedanib treatment led to improved progression-free survival (PFS; hazard ratio [HR] = 0.54; p = 0.010) and a trend for longer overall survival (OS; HR = 0.77; p = 0.319) compared with placebo. Patients with epithelioid tumours derived greatest benefit. Plasma angiogenic factors and genomic markers were explored for potential associations with treatment outcome in the Phase II epithelioid population.
Methods:
Baseline plasma levels of 58 angiogenic factors were analysed by multiplex immunoassay (Human AngiogenesisMAP®, Myriad RBM). Genes implicated in the nintedanib mode of action and/or mesothelioma pathophysiology (VEGFR1, VEGFR3 and mesothelin) were evaluated for known single-nucleotide polymorphisms (SNPs). Biomarker associations with PFS/OS treatment effects were analysed by Cox regression and interaction tests with false-discovery rate (FDR) adjustment. Analyses were exploratory and hypothesis generating.
Results:
Angiogenic factor and genomic data were available for 71 and 67 patients, respectively, in the epithelioid population (n = 77). Of the angiogenic factors evaluated, only endoglin showed a possible trend for association with both PFS and OS improvement, with potentially greater benefit in patients with low plasma levels. Major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A) showed weak association with OS effect, while the VEGFR1 SNP rs9582036 A/A genotype was potentially correlated with PFS benefit. However, all biomarker treatment associations were limited by small subgroup size (especially for minor genotypes) and FDR-adjusted interaction tests were not significant.
Conclusions:
These first biomarker results for nintedanib-treated MPM showed potential signals for greater PFS/OS benefits in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, but no biomarkers showed clear and significant association with nintedanib efficacy.
Clinical trial identification:
NCT01907100
Legal entity responsible for the study:
Boehringer Ingelheim
Funding:
Boehringer Ingelheim
Disclosure:
N. Pavlakis: Advisory Boards: Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Bayer, Novartis, Pfizer, Roche, Ipsen Speaking Honoraria: Boehringer Ingelheim, Bayer, Novartis, Pfizer, Roche Travel Support: BMS, Astra Zeneca, Roche. N. Steele: Honoraria: Pfizer, Novartis Consulting/advisory role: MSD, Boehringer Ingelheim, BMS Research funding: Merck Serono, AstraZeneca, Boehringer Ingelheim, BMS, Novartis, Roche Travel, accommodation, expenses: Pfizer, MSD Oncology, Boehringer Ingelheim. A. Nowak: Consulting/ Advisory Role: Aduro Biotech, Morphotek, Bayer, AstraZeneca, Sellas Life Sciences, Trizell, Boehringer Ingelheim, Epizyme, Roche Research Funding: Boehringer Ingelheim, AstraZeneca Travel and expenses: Amgen, AstraZeneca, Boehringer Ingelheim. S. Novello: Speakers’ Bureau: AstraZeneca, MSD, Bristol-Myers Squibb, Roche, Pfizer, Eli Lilly. S. Popat: Honoraria: Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novartis, Roche Consulting/advisory role: Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Roche Research funding: Boehringer Ingelheim, Epizyme, BMS, Clovis Oncology, Eli Lilly, Roche. L. Greillier: Honoraria: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, AstraZeneca, Novartis Pharma, Roche Consulting/advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Roche Research funding: Roche. M. Reck: Honoraria: Boehringer Ingelheim, Proacta, BMS, MSD, Pfizer, Eli Lilly, AstraZeneca, Merck Inc., Celgene, Novartis Consulting/advisory role: Boehringer Ingelheim, Eli Lilly, BMS, MSD, Pfizer, AstraZeneca, Merck Inc., Celgene, Novartis, Roche Speaker's bureau: Roche, Eli Lilly, MSD Oncology, Merck, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Pfizer, Novartis. T. Kitzing: Employment: Boehringer Ingelheim. G. Scagliotti: Honoraria: Eli Lilly, Pfizer, MSD, AstraZeneca, Roche Consulting/Advisory role: Eli Lilly Speakers’ Bureau: Eli Lilly, MSD. All other authors have declared no conflicts of interest.
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214O - Multiplexed proteomics biomarkers for malignant pleural mesothelioma detection in blood (ID 385)
11:00 - 12:30 | Presenting Author(s): F. Cerciello | Author(s): M. Choi, S.L. Sinicropi-Yao, E. Felley-Bosco, R.A. Stahel, B. Robinson, J. Creaney, H.I. Pass, O. Vitek, D.P. Carbone
- Abstract
Background:
Blood biomarkers are not routinely applied for the diagnosis of malignant pleural mesothelioma (MPM). We investigated a multiplexed biomarkers signature composed of 6 glycopeptides for the diagnosis of MPM in blood using mass spectrometry based targeted proteomics.
Methods:
We applied the targeted proteomics technology selected reaction monitoring (SRM, also known as multiple reaction monitoring – MRM) to investigate more than 400 serum samples from early and advanced stages MPM patients and asbestos exposed donors. Samples were from biobanks in the USA, Australia and Europe. Samples were enriched for N-linked glycoproteins using hydrazide chemistry. After tryptic digestion, N-linked glycopeptides were separated by liquid chromatography before analysis on a triple quadrupole mass spectrometer (LC-MS/MS). Logistic regression was fitted on a training set of 212 samples followed by evaluation of predictive accuracy of the signature in a validation set of 193 samples.
Results:
The proteomics platform for serum processing on 96-well plates and LC-MS/MS analysis had coefficient of variation between 2.0 and 11.4% for peptide quantification over more than 700 measurements, and standard deviation of 0.42 for processing more than 400 replicates. The predictive accuracy for MPM discrimination was significantly higher using multiplexed biomarkers by mass spectrometry compared to using single biomarkers alone. The multiplexed proteomics signature separated MPM patients and asbestos exposed donors with an area under the receiver operating characteristic curve (AUC) of 0.72 in the validation set, and AUC for discriminating early stage MPM from asbestos exposed donors was 0.74. Predictive accuracy of the proteomics signature was not inferior to the currently best available MPM blood biomarker soluble-mesothelin related peptides (SMRP) measured in the samples of the validation set using an enzyme-linked immunosorbent assay (ELISA) approved by the US food and drug administration (FDA). Furthermore, signature was significantly associated with survival of MPM patients after treatment.
Conclusions:
Mass spectrometry based proteomics biomarkers have potential for MPM diagnosis in blood.
Clinical trial identification:
Legal entity responsible for the study:
The Ohio State University Medical Center
Funding:
Kathy and Jay Worly Lung Cancer Early Detection Fund Don Ward, President, Special Claims Services, Inc. at The Ohio State University Comprehensive Cancer Center (OSUCCC) The Swiss National Science Foundation (postdoc mobility fellowship)
Disclosure:
All authors have declared no conflicts of interest.
Author of
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Mesothelioma: New roads through understanding biology (ID 24)
- Event: ELCC 2018
- Type: Educational session
- Track:
- Presentations: 1
- Moderators:A. Scherpereel, R.A. Stahel
- Coordinates: 4/13/2018, 09:00 - 10:30, Room C
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Immunotherapy: The basics (ID 100)
09:00 - 10:30 | Presenting Author(s): J. Aerts
- Abstract
- Presentation
Abstract not provided
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Optimizing targeted therapy in lung cancer (ID 56)
- Event: ELCC 2018
- Type: Poster Discussion session
- Track:
- Presentations: 1
- Moderators:F. Cappuzzo, N. Peled
- Coordinates: 4/12/2018, 16:45 - 17:45, Room W
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132PD - Plasma concentrations of pemetrexed to predict clinical outcomes in patients with advanced NSCLC (ID 614)
16:45 - 17:45 | Author(s): J. Aerts
- Abstract
Background:
Currently, there are no clinically useful predictors of efficacy and toxicity to pemetrexed (PMX) in advanced non-small-cell lung cancer (NSCLC). Using population pharmacokinetic (pop-PK) modelling, we explored whether total exposure to PMX predicts for progression-free and overall survival (PFS/OS) and occurrence of (severe) chemotherapy (CTx)-related adverse events (AEs).
Methods:
In a prospective observational multi-center study, patients with stage IIIB/IV NSCLC receiving first- or second-line PMX(/platinum) were enrolled. PMX (500 mg/m[2]) was administered as a 10-min intravenous infusion every 21 days. Prior to and weekly after each PMX administration, plasma sampling was performed (cycle PK). In a subgroup, blood samples were also collected at 10, 30 minutes and 1, 2, 4, 8, 24 hours after start of PMX infusion (24h PK). With pop-PK modelling total exposure (AUC) to PMX per patient was estimated. The relation between AUC during cycle 1 (AUC~1~) and OS/PFS in treatment-naïve patients was examined using Cox regression analyses and in all patients we compared the difference in mean AUC~1~ between patients with and without grade ≥3 CTx-related AEs (CTCAE 4.03) during total treatment of 4 cycles.
Results:
For 106 of the 165 patients, concentrations of PMX were quantified (24h PK, n = 15; cycle PK, n = 106). Median estimated AUC~1~ was 201 mg·h/L (interquartile range: 179–224). In treatment-naive patients (n = 95), AUC~1~ did neither univariably predict for OS/PFS, nor multivariably when adjusted for prognostic factors sex, disease stage and WHO performance score (OS, HR = 1.05, 95%CI: 1.00–1.11; PFS, HR = 1.03, 95%CI:0.98–1.08). Compared to patients without ≥ grade 3 CTx-related AEs (n = 51), patients with ≥ grade 3 CTx-related AEs (n = 55) had significantly higher AUC~1~ values (220 vs 191, p < 0.001). When seperating ≥ grade 3 CTx-related AEs into clinical and laboratory AEs, identical results were found.
Conclusions:
Total systemic exposure to PMX does not predict for PFS/OS, but is significantly associated with more frequent occurrence of severe CTx-related AEs. Although the impact of peak concentrations on efficacy remains unclear, our findings suggest that lower dosage might prevent severe toxicity with preservation of efficacy.
Clinical trial identification:
Legal entity responsible for the study:
Erasmus MC
Funding:
ZonMw
Disclosure:
J. Aerts: Member of Scientific Committee ELCC 2018; consultant/advisory role with Eli Lilly and Company. All other authors have declared no conflicts of interest.
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Poster Display session (Friday) (ID 65)
- Event: ELCC 2018
- Type: Poster Display session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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168P - Pemetrexed dosing regimens in patients with advanced NSCLC (ID 617)
12:30 - 13:00 | Author(s): J. Aerts
- Abstract
Background:
There is a lack of rationale to use body surface area (BSA)-based dosing if BSA is not a predictor of systemic clearance and thus total systemic exposure (AUC). Using population pharmacokinetic (Pop-PK) modelling, we evaluated the influence of BSA and renal function on pemetrexed (PMX) clearance and compared different dosing strategies.
Methods:
In a prospective observational multi-center study, patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) receiving PMX(/platinum) first- or second-line were enrolled. PMX (500 mg/m[2]) was administered as a 10-min intravenous infusion every 21 days. Prior to and weekly after each PMX administration, plasma sampling was performed (cycle-PK) and glomerular filtration rate (eGFR) was estimated. In a subgroup, sampling was also performed at 10,30 minutes and 1,2,4 and 8 hours after start of PMX infusion (24h PK). With the ultimate Pop-PK model, we simulated different dosing strategies and compared differences in median AUC (interquartile range [IQR]) and interindividual variability (coefficient of variation [CV]) of AUC to standard BSA-based dosing.
Results:
For 106 of the 165 patients, concentrations of PMX were quantified (24h PK, n = 15; cycle PK, n = 106). A two-compartment model (population estimate (%standard error of the estimate) in terms of PMX clearance (CL; 4.58L/h (3.1%)), central distribution volume (V~1~; 15.9L (3.3%)), peripheral distribution volume (V~2~; 21.6L (5.0%)), intercompartimental clearance (Q; 0.05L/h (4.7%)) and between-patient variability of CL (16.7%), fitted PK data appropriately. Covariate eGFR significantly reduced between-patient variability in CL from 20.2% to 16.7% (p < 0.005), while BSA did not. Compared to BSA-based dosing (CV 22.5%, AUC 206 (IQR 178–240)), simulation of eGFR-based dosing (CV 18.5%, AUC 206 (IQR 183–232)) and fixed dose of 900 mg with 25% dose reduction if eGFR < 60 (CV 19.1%, AUC 197 (174–224)) both showed less interindividual variability of AUC.
Conclusions:
Although we currently dose PMX based on BSA, our data show better rationale for eGFR-based dosing as it offers additional control of systemic exposure to PMX, indicated by the decreased variability. Using fixed dose of 900 mg with 25% dose reduction if eGFR < 60 may be an acceptable alternative in clinical practice.
Clinical trial identification:
Legal entity responsible for the study:
Erasmus MC
Funding:
ZonMw
Disclosure:
J. Aerts: Member of scientific committee ELCC 2018 consultant/advisory role with Eli Lilly and Company All other authors have declared no conflicts of interest.
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169P - Nephrotoxicity of pemetrexed maintenance in patients with advanced NSCLC: Two cohort studies (ID 534)
12:30 - 13:00 | Author(s): J. Aerts
- Abstract
Background:
Optimal survival benefit from different lines of anticancer treatment in advanced non-small-cell lung cancer (NSCLC) requires conservation of renal function. We evaluated the development of renal impairment and its clinical significance during pemetrexed maintenance.
Methods:
In a prospective multi-center cohort study, patients with advanced (stage IIIB/IV) NSCLC treated with first-line (platinum-combined) or second-line pemetrexed were enrolled. After platinum-based induction patients were eligible for pemetrexed maintenance if no disease progression occurred. We evaluated the incidence of acute and chronic kidney disease (AKD/CKD), treatment discontinuation frequency due to renal impairment and associations of clinical variables with AKD during maintenance. Both AKD and CKD were defined in accordance with the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines. We validated findings in an independent cohort of advanced NSCLC patients treated with pemetrexed maintenance.
Results:
In total 213 patients received pemetrexed. In the primary cohort 165 patients started induction of whom 47 (28%) continued maintenance. During maintenance 16 patients (34%) developed AKD, leading to CKD in 11 (69%) and treatment discontinuation in 9 (56%) in the primary cohort. Lower eGFR (unit 5 mL/min/1.73 m[2]) before start of induction (OR 1.32, 95%CI: (1.06–1.64) and relative decline (per 10%) in eGFR during induction (OR 2.11, 95%CI: 1.22–3.65) were univariably associated with AKD during maintenance. In the independent cohort (n = 48), these similar associations could be demonstrated. In this cohort, 24 patients (50%) developed AKD, leading to CKD in 13 (54%) and treatment discontinuation in 7 (29%).
Conclusions:
Patients are at risk for renal impairment during pemetrexed maintenance, which may jeopardize further lines of anticancer treatment. Patients whose renal function is impaired before – or declines during – induction treatment are more vulnerable. Renal protective strategies for patients at increased risk might be beneficial, such as continuation of hydration during pemetrexed maintenance or dosing based on renal function.
Clinical trial identification:
Legal entity responsible for the study:
Erasmus MC
Funding:
ZonMw
Disclosure:
J. Aerts: Member of Scientific Committee ELCC; Consultant/advisory role with Eli Lilly and Company. All other authors have declared no conflicts of interest.
