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Duration of PFS in the patient subgroup with MET amplification

Representativeness of study population

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Purpose:The final analyses of the INSIGHT phase II study evaluating tepotinib (a selective MET inhibitor) plus gefitinib versus chemotherapy in patients with MET-altered EGFR-mutant NSCLC (data cut-off: September 3, 2021).Patients and Methods:Adults with advanced/metastatic EGFR-mutant NSCLC, acquired resistance to first-/second-generation EGFR inhibitors, and MET gene copy number (GCN) ≥5, MET:CEP7 ≥2, or MET IHC 2+/3+ were randomized to tepotinib 500 mg (450 mg active moiety) plus gefitinib 250 mg once daily, or chemotherapy. Primary endpoint was investigator-assessed progression-free survival (PFS). MET-amplified subgroup analysis was preplanned.Results:Overall (N = 55), median PFS was 4.9 months versus 4.4 months [stratified HR, 0.67; 90% CI, 0.35–1.28] with tepotinib plus gefitinib versus chemotherapy. In 19 patients with MET amplification (median age 60.4 years; 68.4% never-smokers; median GCN 8.8; median MET/CEP7 2.8; 89.5% with MET IHC 3+), tepotinib plus gefitinib improved PFS (HR, 0.13; 90% CI, 0.04–0.43) and overall survival (OS; HR, 0.10; 90% CI, 0.02–0.36) versus chemotherapy. Objective response rate was 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy; median duration of response was 19.9 months versus 2.8 months. Median duration of tepotinib plus gefitinib was 11.3 months (range, 1.1–56.5), with treatment >1 year in six (50.0%) and >4 years in three patients (25.0%). Seven patients (58.3%) had treatment-related grade ≥3 adverse events with tepotinib plus gefitinib and five (71.4%) had chemotherapy.Conclusions:Final analysis of INSIGHT suggests improved PFS and OS with tepotinib plus gefitinib versus chemotherapy in a subgroup of patients with MET-amplified EGFR-mutant NSCLC, after progression on EGFR inhibitors.

Purpose:Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups.Patients and Methods:This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity.Results:152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies.Conclusions:Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations.See related commentary by Rosner and Spira, p. 1055

Supplementary Data from Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

MET exon 14 ( MET ex14) skipping mutations occur in 3% to 4% of non-small cell lung cancer (NSCLC) cases. Currently, four oral MET tyrosine kinase inhibitors (TKIs) are in use for the treatment of patients with MET ex14 skipping NSCLC (tepotinib, capmatinib, savolitinib, and crizotinib). To support optimal management of MET ex14 skipping NSCLC in this typically older patient population, the safety profiles of these treatment options are reviewed here. Published safety data from prospective clinical trials with MET TKIs in patients with MET ex14 skipping NSCLC were reviewed. Treatmentrelated adverse events (TRAEs) occurring in > 10% of patients were reported where feasible. Guidance on clinical monitoring and management of key MET TKI TRAEs and dr ug-dr ug interactions is provided. Across the clinical trials, safety data for MET TKIs were reported for 442 patients with MET ex14 skipping. Peripheral edema was the most reported TRAE (50%-63% of patients; grade > 3: 1%-11%), followed by nausea (26%-46% of patients; grade > 3: 0%1%). TRAEs led to dose reductions in 33% to 38% of patients and to discontinuation in 7% to 14% of patients, across the MET TKIs. Considerations on interpreting available safety data are provided, along with insights into monitoring and managing specific MET TKI TRAEs of interest and dr ug-dr ug interactions. Overall, MET TKIs are tolerable treatment options for patients with MET ex14 skipping NSCLC, an older population for whom chemo- or immuno-therapy may not be an effective nor tolerable option. More data regarding the effectiveness of safety interventions and management strategies are needed.

Edema; Nausea; Non-small cell lung cancer Edema; Náuseas; Cáncer de pulmón de células no pequeñas Edema; Nàusees; Càncer de pulmó de cèl·lules no petites Introduction The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors. Patients and Methods Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial. Results Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks. Conclusion Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population.

Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. Methods: Adult patients with advanced solid tumours received peposertib 100–200 mg once daily or 150–400 mg twice daily (BID) in 21-day cycles. Results: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. Conclusions: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. Clinical trial registration: NCT02316197, SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose Tepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes. Methods Exposure–efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure–safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30–1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia’s method (QTcF). Results Tepotinib exhibited flat exposure–efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure–safety relationships for all endpoints within the exposure range observed with 30–1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses. Conclusions These analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations. Registration Numbers NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.

Introduction: In the primary analysis of VISION, tepotinib — a highly selective, potent MET inhibitor — demonstrated durable efficacy, and a tolerable safety profile in patients (pts) with METex14 skipping NSCLC. We report updated outcomes, with interim analyses from a confirmatory cohort. Methods: In the Phase II VISION study, pts with advanced/metastatic METex14 skipping NSCLC, identified by liquid (L+) and/or tissue (T+) biopsy, received 500 mg (450 mg active moiety) tepotinib once daily. All pts were assessed for safety; pts with ≥3 months’ follow-up were assessed for efficacy. Primary endpoint was objective response by independent review (RECIST v1.1). Secondary endpoints were disease control (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of Feb 1, 2021, 7,882 pts were pre-screened, and 275 pts were analyzed for efficacy. Patients analyzed for efficacy had a median age of 72.4 years (range, 41-94]), 50.9% were female, 46.5% had smoking history, and median tumor load [target lesions by IRC] was 57.4 mm [range, 10.2-227.8]). Tumor load in L+ pts was 68.0 mm (11.6-227.8) and 52.9 mm (10.2-227.8) in T+ pts. In treatment-naïve pts (n=137), ORR was 54.0% (95% CI: 45.3, 62.6), DCR was 74.5% (66.3, 81.5), and >90% of pts had tumor shrinkage. Median (m) DOR was 32.7 months (9.0, not estimable), mPFS was 10.4 months (8.4, 15.3), and mOS was 17.6 months (13.4, 29.7). In previously treated pts (n=138), ORR was 44.2% (35.8, 52.9), DCR was 75.4% (67.3, 82.3), and >90% of pts had tumor shrinkage. mDOR was 11.1 months (8.4, 18.5), mPFS was 11.0 months (8.2, 12.4), and mOS was 19.9 months (15.8, 22.3). Meaningful clinical activity was observed in L+ and T+ pts (Table). Overall, 14.1% of pts discontinued due to TRAEs; tepotinib was well-tolerated across treatment lines (Table). Conclusions: Tepotinib demonstrated robust and durable clinical activity across treatment lines in pts with METex14 skipping NSCLC, with particularly durable efficacy in first line. TRAEs were manageable with few discontinuations. Table 1. Tepotinib efficacy and safety in patients with METex14 skipping NSCLC (VISION) Tepotinib efficacy (pts with ≥3 months’ follow-up in Cohorts A+C) Overall Treatment-naϊve (n=137) Previously treated (n=138) Combined (N=275) Liquid biopsy* (n=81) Tissue biopsy* (n=86) Liquid biopsy* (n=78) Tissue biopsy* (n=88) Objective response rate, % (95% CI) 49.1 (43.0, 55.2) 54.3 (42.9, 65.4) 54.7 (43.5, 65.4) 43.6 (32.4, 55.3) 47.7 (37.0, 58.6) Disease control rate, % (95% CI) 74.9 (69.4, 79.9) 71.6 (60.5, 81.1) 80.2 (70.2, 88.0) 69.2 (57.8, 79.2) 79.5 (69.6, 87.4) Median duration of response, months (95% CI) 13.8 (9.9, 19.4) 13.8 (7.2, ne) 32.7 (10.8, 32.7) 11.1 (8.4, 19.4) 10.1 (8.3, 15.7) Median progression-free survival, months (95% CI) 10.8 (8.5, 12.4) 8.5 (6.9, 11.3) 15.3 (9.6, ne) 8.3 (5.7, 11.0) 11.1 (8.2, 16.8) Median overall survival, months (95% CI) 19.7 (15.6, 22.1) 15.1 (9.5, 22.1) 29.7 (15.3, ne) 19.9 (12.8, 22.3) 22.3 (17.0, 27.2) Tepotinib safety (all pts who received tepotinib in Cohorts A+C) Overall (N=291) Treatment-naϊve (n=148) Previously treated (n=143) Treatment-related AEs†, n (%) Any grade 264 (90.7) 137 (92.6) 127 (88.8) Grade ≥3 86 (29.6) 49 (33.1) 37 (25.9) Leading to death 2 (0.7) 1 (0.7) 1 (0.7) Leading to a dose reduction 90 (30.9) 51 (34.5) 39 (27.3) Leading to temporary discontinuation 114 (39.2) 63 (42.6) 51 (35.7) Leading to permanent discontinuation 41 (14.1) 24 (16.2) 17 (11.9) All-cause AEs† in ≥20% of patients, n (%) Peripheral edema 191 (65.6) 98 (66.2) 93 (65.0) Nausea 88 (30.2) 51 (34.5) 37 (25.9) Diarrhea 81 (27.8) 42 (28.4) 39 (27.3) Hypoalbuminemia 81 (27.8) 41 (27.7) 40 (28.0) Blood creatinine increase 76 (26.1) 34 (23.0) 42 (29.4) Dyspnea 60 (20.6) 40 (27.0) 20 (14.0) Data cut-off: Feb 1, 2021. *Patients with METex14 skipping detected by both liquid and tissue biopsy are included in both analysis sets (overall, n=59; treatment-naïve, n=30; previously treated, n=29); testing by both methods was not required for enrollment. †AEs were defined as events that started within the day of first dose of trial treatment until 30 days after last dose of treatment or started prior to first dose but worsened during the treatment period. AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. AE, adverse event; CI, confidence interval; MET, mesenchymal-epithelial transition factor; METex14; MET exon 14; ne, not estimable. Citation Format: Marina C. Garassino, Xiuning Le, Wade T. Iam, Enriqueta Felip, Hiroshi Sakai, Remi Veillon, Egbert F. Smit, Julien Mazieres, Jo Raskin, Alexis B. Cortot, Karin Berghoff, Rolf Bruns, Gordon Otto, Paul K. Paik. Tepotinib efficacy and safety in patients with MET exon 14 (METex14) skipping NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT536.

9120 Background: Tepotinib is a highly selective, potent MET inhibitor approved in several Asian countries for the treatment of advanced METex14 skipping NSCLC. In VISION (n=275; data cut-off: Feb 1, 2021), tepotinib had an objective response rate (ORR) of 49.1% (95% CI: 43.0, 55.2) by independent review (IRC), with a median (m) DOR of 13.8 months (9.9, 19.4) across treatment lines. Here, we report outcomes in Asian pts. Methods: Pts with advanced METex14 skipping NSCLC, detected by liquid (L+) or tissue (T+) biopsy, received tepotinib 500 mg (450 mg active moiety) QD. Primary endpoint was objective response by IRC. Efficacy was assessed in 79 Asian pts with ≥3 months’ follow-up, and safety was assessed in 88 Asian pts who received tepotinib by data cut-off (Feb 1, 2021). Only pts enrolled in Asia were assessed for HRQoL. Results: In 79 Asian pts assessed for efficacy (38% female, 42% smoking history, 34% treatment-naïve [1L] and 82% adenocarcinoma), ORR was 54.4% (42.8, 65.7), mDOR was 18.5 months (8.3, ne), mPFS was 12.1 months (6.9, ne) and mOS was 20.4 months (19.1, ne). ORR was 66.7% (46.0, 83.5) in 1L pts (n=27), and 48.1% (34.0, 62.4) in previously treated pts (n=52). Meaningful activity was observed irrespective of METex14 skipping detection method (Table). In pts analyzed for HRQoL (n=73), mean change from baseline for EORTC QLQ-C30 GHS (3.94), EQ-5D-5L VAS (0.83), and EORTC QLQ-LC13 for cough (-6.59), dyspnea (-1.26), and chest pain (-6.14) symptom scores, demonstrated stability in QoL. In 88 Asian pts analyzed for safety, the most common adverse events (AEs) were peripheral edema, increased blood creatinine, and diarrhea. 29.5% of pts had Grade ≥3 treatment-related (TR) AEs. TRAEs led to dose reductions in 29.5%, temporary interruption in 43.2%, and permanent discontinuation in 14.8% of pts. Conclusions: In VISION, tepotinib showed robust and durable clinical activity in Asian pts with METex14 skipping NSCLC. TRAEs were manageable, with few leading to treatment discontinuation. Currently, VISION has enrolled 106 Asian pts with METex14 skipping NSCLC; analysis in this population is ongoing. Clinical trial information: NCT02864992. [Table: see text]

Background Promising clinical activity has been reported in patients with MET-altered NSCLC treated with tepotinib, an oral, selective, potent MET tyrosine kinase inhibitor. To support clinical development, we aimed to further characterize the safety profile of tepotinib in patients with cancer. Methods In this analysis from 5 phase I and II studies of tepotinib administered 500 mg once daily, adverse events (AEs), graded by NCI CTCAE v4.03, were pooled and summarized for all patients and for the subgroup of Asian patients. Results As of 28 Sep 2018, 228 patients (81 [35.5%] Asian, 59 [25.9%] NSCLC, 121 [53.1%] HCC) had received tepotinib 500 mg/day for a median of 2.7 months (range 0–21.5); in the ongoing phase II VISION study (NCT02864992), median was 4.1 months. The most common treatment-related AE of any grade was peripheral edema occurring in 33.8% of patients overall and in 24.7% of Asian patients. Other common treatment-related AEs were diarrhea, fatigue, and nausea (Table). Dose reduction due to an AE regardless of causality occurred in 33 (14.5%) patients and discontinuation in 49 (21.5%) patients; peripheral edema led to a dose reduction in 12 (5.3%) patients and discontinuation in 7 (3.1%) patients. In the Asian population, 13 (16.0%) patients had a dose reduction and 13 (16.0%) patients discontinued due to an AE; peripheral edema led to a dose reduction in 4 (4.9%) Asian patients and to no discontinuations. Two AEs leading to death were considered by the investigator to be potentially treatment-related and occurred in patients with HCC (upper gastrointestinal hemorrhage [in an Asian patient] and hypoglycemic coma).Table67PTableAll patients (N = 228)Asian patients (N = 81)Any GradeGrade ≥3Any GradeGrade ≥3Treatment-related AE (≥10%), n (%)172 (75.4)52 (22.8)64 (79.0)26 (32.1)Peripheral edema77 (33.8)8 (3.5)20 (24.7)0Diarrhea45 (19.7)4 (1.8)27 (33.3)4 (4.9)Fatigue34 (14.9)3 (1.3)14 (17.3)3 (3.7)Nausea29 (12.7)09 (11.1)0Decreased appetite27 (11.8)012 (14.8)0Blood creatinine increased18 (7.9)1 (0.4)11 (13.6)0Hypoalbuminemia16 (7.0)1 (0.4)10 (12.3)0Amylase increased13 (5.7)4 (1.8)9 (11.1)2 (2.5) Conclusions Tepotinib demonstrated an acceptable safety profile in patients with advanced cancer, with a similar profile in Asian patients and in the overall population. Further characterization of the clinical relevance of peripheral edema is ongoing. Clinical trial identification NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992. Editorial acknowledgement Medical writing assistance (funded by Merck Healthcare KGaA, Darmstadt, Germany) was provided by Jen Lewis, PhD of Bioscript Science (Macclesfield, UK). Legal entity responsible for the study Merck KGaA. Funding Merck KGaA. Disclosure K. Yamazaki: Honoraria (self): Chugai; Honoraria (self): Takeda; Honoraria (self): Yakult; Honoraria (self): Daiichi‐Sankyo; Honoraria (self): Merck Serono; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Bayer; Honoraria (self): Eli Lilly; Honoraria (self): Taiho; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. P.K. Paik: Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Honoraria (self): Takeda. R. Veillon: Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Merck. T. Decaens: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Travel / Accommodation / Expenses: Gilead; Honoraria (self), Travel / Accommodation / Expenses: AbbVie; Honoraria (self): Sanofi; Advisory / Consultancy: BTG; Advisory / Consultancy: Sirtex; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Genoscience Pharma. S. Faivre: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Blueprint; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis. G.S. Falchook: Licensing / Royalties: Wolters Kluwer; Advisory / Consultancy, Travel / Accommodation / Expenses: Fujifilm; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Millennium; Speaker Bureau / Expert testimony: Total Health Conferencing; Research grant / Funding (institution): 3-V Biosciences; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): American Society of Clinical Oncology; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bioatla; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ciclomed, Curegenix, Curis, DelMar, eFFECTOR, Eli Lilly, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, No. J. Scheele: Full / Part-time employment: Merck KGaA. R. Bruns: Full / Part-time employment: Merck KGaA. K. Berghoff: Full / Part-time employment: Merck KGaA. All other authors have declared no conflicts of interest.

2518Background: DNA-dependent protein kinase (DNA-PK), regulates one of the major pathways responsible for repair of DNA double-strand breaks. The combination of RT and DNA-PK inhibition (DNA-PKi) ...

BACKGROUND: In contrast to other extracorporeal treatments no established regime exists for anticoagulation with low-molecular-weight heparin (LMWH) in plasmapheresis therapy. A study was conducted to investigate whether LMWH (dalteparin-Na) is suitable as an effective anticoagulant in plasmapheresis therapy. STUDY DESIGN AND METHODS: Eleven patients with autoimmune neurological diseases and the necessity for a plasmapheresis therapy were enrolled. A capillary membrane filter was used. A total of 2000 mL of human plasma was isovolumetrically exchanged per plasmapheresis cycle. The anticoagulation was accomplished with a single bolus of LMWH (dalteparin) of 80 to 90 IU per kg of body weight. The system was visually monitored. Anti-factor (F)Xa activity, thrombin–antithrombin III complex (TAT), and prothrombin fragment 1+2 (F 1+2) were determined at regular intervals. Samples were taken from the collected plasma pool to determine the loss of LMWH during the plasmapheresis procedure. RESULTS: All plasmapheresis cycles with LMWH were successful without complications. Approximately 40 percent of the initially administered LMWH bolus was lost by the large porous filter during the plasmapheresis. The anti-FXa values were determined to be 0.5 IU per mL during the entire plasmapheresis. TAT values were elevated (TAT median, 14.3 µg/L). F 1+2 values measured before the filter cartridge remained within the normal range for the entire plasmapheresis cycle (