Merck Healthcare KGaA Research Articles

Bioequivalence of Related GelShieldⓇ Sustained-release Formulations of Metformin: A Pooled Pharmacokinetic Analysis

PurposeGlucophageⓇ (Merck Healthcare KGaA, Darmstadt, Germany) is the originator brand of metformin hydrochloride, an oral antidiabetic drug. Metformin is recommended in guidelines as first-line treatment of type 2 diabetes mellitus and increasingly in related insulin-resistant conditions, such as prediabetes and polycystic ovary syndrome. The GelShieldⓇ sustained-release formulation tablet of GlucophageⓇ has been improved from the historic version marketed in 2000. Bioequivalence has been demonstrated stepwise along this evolution; however, a head-to-head evaluation between the initial and the current version is missing. This analysis aims to close this gap and to determine bioequivalence between related originator GelShieldⓇ sustained-release formulations of metformin, GlucophageⓇ (GXR 500 mg), from Europe and the United States. MethodsData from seven randomized crossover bioequivalence studies in 361 healthy participants of Asian and non-Asian ethnicity from Europe, the United States, and Asia were considered. All evaluated a single oral dose of 500 mg of the test and reference formulation in healthy male and female participants in fed and fasted state. Bioequivalence was evaluated by means of a combined bridging analysis of available data on the current round tablet from Europe (rGXR EU) and the historic oblong tablet from the United States (oGXR US) in healthy Asian and non-Asian participants under fed and fasting conditions. Bioequivalence between the two formulations was assessed statistically with a mixed effects model for AUC0-t, Cmax, and AUC0-inf. FindingsIn all studies, bioequivalence between the respective test and reference formulations of GXR was shown. Statistical analysis of pooled pharmacokinetic data of 2 (primary pooling set) or 3 studies (secondary pooling set) demonstrated bioequivalence between rGXR EU and oGXR US via bridging with oGXR EU. The 90% CI for the geometric mean ratio of all pharmacokinetic parameters was within the bioequivalence range of 0.80 to 1.25. In the primary pooling set, geometric least squares mean ratios in the fed group ranged from 0.9931 (90% CI, 0.9151–1.0778) for AUC0-inf to 1.1344 (90% CI, 1.0711–1.2014) for Cmax; results in the fasted group were similar. The secondary pooling set, which added a study in Asians, confirmed these findings. ImplicationsBioequivalence was determined between sustained-release formulations of GlucophageⓇ from Europe and the United States under fasted and fed conditions in healthy men and women, including different ethnicities. The efficacy and safety of GlucophageⓇ XR can be claimed along the evolution from oGXR US, via oGXR EU to rGXR EU, and in several ethnicities and production sites.

Improving Data Collection in Pregnancy Safety Studies: Towards Standardisation of Data Elements in Pregnancy Reports from Public and Private Partners, A Contribution from the ConcePTION Project.

The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.

415-P: Reduction in the Risk of Peripheral Neuropathy and Preservation of Kidney Function with Metformin, Linagliptin, or Their Fixed-Dose Combination, Compared with Placebo in Prediabetes—A Randomized Controlled Trial

Objective: To compare the effect of glucose-lowering drugs plus lifestyle modification with lifestyle alone on peripheral nerve and kidney function in people with prediabetes. Methods: Multicenter, randomized, placebo-controlled trial in 658 individuals aged 45-74 years with prediabetes (IFG or IGT), were randomized to either metformin monotherapy, linagliptin monotherapy, fixed-dose combination of linagliptin/metformin or masked placebo. Main outcomes: 1-year reduction in the risk of small fiber peripheral neuropathy (SFPN) estimated by foot electrochemical skin conductance <70 µSiemens, measured with the SUDOSCAN® and estimated glomerular filtration rate (eGFR). Results: The percentage of people at high-risk of SFPN increased by 29.6% in the placebo group, while the increase was significantly lower in the three active-drug groups:1.8% in the metformin group, 4.3% in the linagliptin group, and 3.9% in the combination linagliptin/metformin group (p<0.001 for all three comparisons). eGFR remained significantly higher with the fixed-dose combination linagliptin/metformin (3.3 mL/min; 95% CI: 0.38; 6.22, p = 0.03) than with placebo. FPG was significantly lower with metformin monotherapy (-0.3 mmol/L: 95%CI: -0.48; 0.12, p=0.0009), and with the fixed-dose combination metformin/linagliptin (-0,2 mmol/L; 95% CI: -0.37; -0.03, p = 0.0219) than with placebo. Reduction in body weight was significantly greater (-2.0 kg/year, 95% CI:-5.65; -1.65, p=0.0006) with metformin monotherapy, and with the combination metformin/linagliptin (-1.9 kg/year; 95% CI: -3.02; -0.97, p=0.0002) than with placebo. Conclusion: In people with prediabetes, 1-year treatment with metformin and linagliptin, combined or in monotherapy, was associated with a lower risk of SFPN, and with a better preservation of kidney function than with placebo. Disclosure R.Gabriel: None. J.Tuomilehto: Stock/Shareholder; Orion pharma. Funding European Commission (FP7EC-GA 279074); Boehringer Ingelheim Germany (1218.166); Merck Healthcare KGaA (EMR200084_621); Instituto de Salud Carlos III (PI11/01653)

Quantification of Thalamic Volume in Multiple Sclerosis: From the Multicenter INNI Dataset Towards the Clinical Application (P10-3.002)

Quantification of Thalamic Volume in Multiple Sclerosis: From the Multicenter INNI Dataset Towards the Clinical Application (P10-3.002)

Updated Post-Approval Safety of Cladribine Tablets in the Treatment of Multiple Sclerosis, With Particular Reference to Liver Safety (P7-3.010)

Updated Post-Approval Safety of Cladribine Tablets in the Treatment of Multiple Sclerosis, With Particular Reference to Liver Safety (P7-3.010)

Evobrutinib therapeutic response is associated with an increase in the number and maturation of peripheral and central classical dendritic cells (P7-3.005)

<h3>Objective:</h3> To assess the impact of evobrutinib on classical dendritic cells (cDCs) in the MOG_35–55-induced chronic-progressive experimental autoimmune encephalomyelitis (EAE) Multiple sclerosis (MS) model (with limited B cell contribution). <h3>Background:</h3> Evobrutinib is an oral, highly selective covalent Bruton’s tyrosine kinase (BTK) inhibitor with promising results in a Phase II trial for relapsing MS. Lately, the role of BTK in myeloid cell activity, including cDCs, has been gaining importance in MS pathogenesis. <h3>Design/Methods:</h3> Female EAE mice received individualized daily oral treatment of vehicle (EAE-Veh) or evobrutinib (EAE-Evo) for 4 days from the day of disease onset. EAE was scored clinically each day and flow cytometry analyses of spleens and spinal cords were performed. EAE-Evo mice with a clinical course indistinguishable from that of EAE-Veh were classified as non-responders (Evo-NR), whereas those with less severe disease were considered responders (Evo-R). <h3>Results:</h3> The therapeutic response in Evo-R was associated with an increase in MHC-II⁺ cDC (mature cDCs) in the spleen. Evobrutinib shifted the correlation between CD69⁺ T cells/cDCs from positive to inverse. However, Evo-NR mice showed myeloid content similar to EAE-Veh mice and Evo-R mice exhibited a lower myeloid cell infiltrate in the spinal cord, albeit enriched in mature cDCs. Evobrutinib induced specific modifications in the immunological synapse components in cDCs. Whereas both Evo-R and Evo-NR showed a decrease in MHC-II in splenic cDCs, only Evo-R exhibited a decrease in CD80. In contrast, spinal cord cDCs showed decreased CD80 with no modification of MHC-II brightness. <h3>Conclusions:</h3> In the EAE model, evobrutinib therapeutic response shows a clear relationship with the enrichment of mature cDCs at both the peripheral and central levels, with a decrease in activated T cell presence. The interpretation of the immunological alteration of cDCs by evobrutinib will be further investigated using functional <i>ex vivo</i> assays. <b>Disclosure:</b> The institution of Dr. Clemente has received research support from EMD Serono Research &amp; Development Institute, Inc.. The institution of Dr. Clemente has received research support from Bristol Myers Squibb. The institution of Dr. Clemente has received research support from Instituto de Salud Carlos III. Dr. Clemente has received personal compensation in the range of $500-$4,999 for serving as a Reviewer of Grants with Spanish National Investigation Agency. Dr. Serrano Regal has nothing to disclose. Dr. Calahorra has nothing to disclose. Miss Alonso García has nothing to disclose. Ursula Boschert has nothing to disclose. Philipp Haselmayer has received personal compensation for serving as an employee of Merck Healthcare KGaA. Dr. Ortega has nothing to disclose. Miss Díaz has nothing to disclose. Mrs. Camacho Toledano has nothing to disclose. Mrs. Arocha has nothing to disclose.

Immune Response Following COVID-19 Vaccination (mRNA or Non-mRNA) in Patients with Relapsing Multiple Sclerosis Treated with the Bruton’s Tyrosine Kinase Inhibitor Evobrutinib: An Update (P2-3.017)

Immune Response Following COVID-19 Vaccination (mRNA or Non-mRNA) in Patients with Relapsing Multiple Sclerosis Treated with the Bruton’s Tyrosine Kinase Inhibitor Evobrutinib: An Update (P2-3.017)

Adherence to r-hGH Therapy in Pediatric Growth Hormone Deficiency: Current Perspectives on How Patient-Generated Data Will Transform r-hGH Treatment Towards Integrated Care.

Pediatric growth hormone (GH) deficiency is a licensed indication for replacement therapy with recombinant human growth hormone (r-hGH). Treatment, consisting of daily subcutaneous injections, extends from the time of diagnosis until cessation of linear growth at completion of puberty. Suboptimal adherence to r-hGH therapy is common and has been well documented to substantially impair the growth response and achievement of the optimal goal which is attainment of adult height within the genetic target range. The causes of poor adherence are complex and include disease-, patient-, doctor-, and treatment-related factors. Interventions for suboptimal adherence are important for a long-term successful outcome and can include both face-to-face and digital strategies. Face-to-face interventions include behavioral change approaches such as motivational interviewing and non-judgmental assessment. Medical and nursing staff require training in these techniques. Digital solutions are rapidly advancing as evidenced by the electronic digital auto-injector device, easypod® (Merck Healthcare KGaA, Darmstadt, Germany), which uses the web-based easypod® connect platform allowing adherence data to be transmitted electronically to healthcare professionals (HCPs), who can then access GH treatment history, enhancing clinical decisions. Over the past 10 years, the multi-national Easypod® Connect Observational Study has reported high levels of adherence (>85%) from up to 40 countries. The easypod® connect system can be supported by a smartphone app, growlink™, which facilitates the interactions between the patients, their care team, and patient support services. HCPs are empowered by new digital techniques, however, the human–digital partnership remains essential for optimal growth management. The pediatric patient on r-hGH therapy will benefit from these innovations to enhance adherence and optimize long-term response.

A comparative, observational study evaluating dosing characteristics and ovarian response using the recombinant human follicle-stimulating hormone pen injector with small-dose dial in assisted reproductive technologies treatment in Asia: IMPROVE study

BackgroundOvarian stimulation during medically assisted reproduction treatment should be individualized to optimize outcomes and reduce complications. This study assessed whether use of the recombinant human follicle-stimulating hormone (r-hFSH) pen injector allowing small 12.5 IU dose increments resulted in lower r-hFSH dose per oocyte retrieved in a subgroup of patients at risk of OHSS, compared with r-hFSH injection devices allowing only 37.5 IU increments.MethodsThis multicenter, comparative, observational study evaluated patients from a prospective (study group) and historical (control group) cohort. The study group enrolled 1783 patients using the redesigned r-hFSH pen injector (GONAL-f®, Merck Healthcare KGaA, Darmstadt, Germany) from a prospective phase IV, non-interventional, open-label study, conducted in Korea, Vietnam, Indonesia, and China. The control group consisted of 1419 patients from a historical study using r-hFSH devices allowing 37.5 IU increments. In the study group, 397 patients were considered at risk of OHSS; this information was unavailable for the control group, so biomarkers and patient characteristics were used to match 123 patients from the study group and control group. Each center adhered to standard practice; starting dose and intra-cycle dose adjustments were allowed at any point. The primary endpoint, amount of r-hFSH (IU) administered per oocyte retrieved, was assessed in matched patients only. Additional outcomes and safety were assessed in the overall populations.ResultsBaseline characteristics were comparable between groups. Mean (SD) total dose of r-hFSH administered per oocyte retrieved in patients at risk of OHSS, was significantly lower in the study group compared with the control group (132.5 [85.2] vs. 332.7 [371.6] IU, P < 0.0001, n = 123). Implantation rate, clinical pregnancy rate, and live birth rates in the overall study and control groups were 30.0 vs. 20.6%, 50.3 vs. 40.7%, and 43.8 vs. 34.0%, respectively. OHSS incidence was significantly lower in the study group compared with the control group (27/1783 [1.5%] vs. 57/1419 [4.0%] patients, P < 0.0001). AEs were reported by 5.0% of patients in the study group.ConclusionsA significantly lower r-hFSH dose per oocyte retrieved and lower OHSS incidence were observed in patients using the redesigned injector compared with patients using other injection devices.

Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in &gt;3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following &gt; 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

Pharmacological Perturbation of the Immunoproteasome in Hematologic Neoplasias: Therapeutic Implications

Pharmacological inhibition of the canonical proteasome by inhibitors targeting its beta5 (PSMB5) subunit represent a cornerstone of the therapeutic management of plasma cell neoplasias. However, proteasome inhibitors have limited clinical applications in other hematologic malignancies. Notably, a broad spectrum of cell lines and patient-derived samples from lymphoma, leukemia and myeloma tend to express high levels of transcripts for and exhibit substantial activity of the immunoproteasome, an alternative proteasome particle which is enriched in hematopoietic/immune tissues. Established proteasome inhibitors used in clinical practice (e.g. bortezomib, carfilzomib, ixazomib) target both the canonical 20S proteasome and the immunoproteasome. We reasoned though that targeting of the immunoproteasome with more selective small molecule inhibitors that largely spare the canonical proteasome may provide insights into the specific functional role of the immunoproteasome in hematologic neoplasias, and importantly may also uncover underappreciated therapeutic opportunities related to targeting of hematologic neoplasias beyond myeloma, that might be more dependent on the immunoproteasome vs. the canonical proteasome; as well as potential benefits related to the therapeutic index of these agents. To address these questions, we characterized the activity of the previously disclosed selective immunoproteasome inhibitor M3258, which targets the LMP7 (beta5i subunit). The bortezomib-resistant cell line MM1VDR, which has a "gatekeeper" PSMB5 mutation preventing bortezomib binding to the canonical proteasome, remained sensitive to in vitro treatment with M3258, in further support of the functional specificity of this inhibitor. To obtain a comprehensive assessment of the activity of M3258 across hematologic malignancies, we studied a pool of 74 "DNA-barcoded" cell lines (PRISM system) from hematologic malignancies, including multiple myeloma (MM), leukemias and lymphomas, which were treated for 48hr with M3258. MM cell lines (9/16) were strongly represented among the sensitive lines which displayed &lt;50% relative cell viability (compared to DMSO control) after M3258 treatment. Notably, 15 of 58 non-MM lines also exhibited &gt;50% reduction in their cell viability in this analysis; and their responsiveness did not differ significantly from the M3258-responsive MM lines. Importantly, we observed no correlation between the responses of leukemia, lymphoma or MM lines to in vitro treatment with M3258 vs. clinically-relevant pulse of bortezomib. Furthermore, 7 of the 15 lymphoma/leukemia lines that were M3258-responsive had limited, if any, response to a clinically-relevant pulse of bortezomib. Taken together, these observations suggest that immunoproteasome inhibition with M3258 can be active against subsets of hematologic neoplasias with resistance/limited responsiveness to canonical proteasome inhibitors. To further examine the in vivo relevance of these observations, we studied the in vivo activity of M3258 against the MM.1S myeloma cell line, which has only moderate in vitro response to M3258 compared to other blood cancer cell lines tested in our "DNA-barcoded" pooled analysis. M3258 significantly increased the overall survival of mice with diffuse MM-bone lesions established after tail vein injection of MM.1S cells; and of mice harboring MM.1S lesions within a subcutaneously implanted ceramic scaffold-based system engineered to establish a bone marrow-like histological and functional unit with a "humanized" stromal compartment. The anti-tumor activity of M3258 in this scaffold model exhibited a trend for increased efficacy compared to twice weekly subcutaneous treatments with bortezomib. These results highlight that in vivo administration of M3258 exhibits anti-tumor activity against clinically-relevant models of MM lesions, even from cell lines that have modest in vitro responsiveness to this immunoproteasome inhibitor. Furthermore, our studies with a large panel of "DNA-barcoded" cell lines indicates that the anti-tumor effects of M3258 may extend beyond MM and into other classes of hematologic malignancies, including subsets of leukemias and lymphomas, identifying previously underappreciated therapeutic implications for the class of selective immunoproteasome inhibitors. Disclosures Walter: Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Sanderson:Merck Healthcare KGaA: Employment. Mitsiades:Takeda: Other: employment of a relative ; Ionis Pharmaceuticals: Honoraria; Fate Therapeutics: Honoraria; Arch Oncology: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Abbvie: Research Funding; TEVA: Research Funding; EMD Serono: Research Funding; Janssen/Johnson &amp; Johnson: Research Funding.

536TiP - INSIGHT 2: Tepotinib plus osimertinib in patients with EGFR-mutant NSCLC having acquired resistance to EGFR TKIs due to MET-amplification: A phase II trial in progress study

BackgroundMET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) occurring via over activation of downstream signaling pathways such as PI3K and MAPK. METamp occurs in ≈10% of patients receiving erlotinib, gefitinib, afatinib, or icotinib, and is the most common resistance mechanism to osimertinib in phase III trials, occurring in ≈19% of patients. Tepotinib, an oral once daily potent and selective MET inhibitor, is associated with improved survival in combination with gefitinib in patients with EGFR-mutant MET-amplified NSCLC with EGFR TKI resistance compared with standard chemotherapy in the INSIGHT study (NCT01982955): investigator-reported progression free survival (PFS) was 21.2 vs 4.2 months (HR 0.13; 90% CI 0.04, 0.43) and overall survival, (OS) was 37.3 vs. 13.1 months (HR 0.08; 90% CI 0.01, 0.51). Trial designINSIGHT 2 (NCT03940703) is a global single-arm, open-label, phase II trial of tepotinib in patients with advanced (stage IIIB/IV) NSCLC with resistance to 1st–3rd generation EGFR TKIs driven by METamp. Eligibility criteria include patients aged ≥18 years with advanced EGFR-mutant NSCLC and known T790M status, having acquired resistance to EGFR TKIs, and are METamp positive by plasma ‘liquid’ biopsy, with an ECOG PS of 0 or 1 and normal organ function. Prior immunotherapy is permitted but prior MET pathway-targeted therapy is not. Tepotinib (500 mg orally once daily) in combination with osimertinib (80 mg once daily) will be administered until disease progression, unacceptable toxicity, or withdrawal of consent. An initial safety run-in will comprise 6 patients (endpoint; dose-limiting toxicities); anticipated full enrollment is 90 patients. The primary endpoint is objective response rate (ORR) by independent review committee (RECIST v1.1). Secondary objectives include investigator-assessed ORR, duration of response, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety (NCI-CTCAE v5.0). Recruitment is ongoing and approximately 80 study sites in 17 countries in Europe, Asia, and North America are expected to participate in this study. Clinical trial identificationNCT03940703. Legal entity responsible for the studyMerck Healthcare KGaA. FundingMerck Healthcare KGaA. DisclosureJ.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche/Genentech/Chugai; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo ; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda Oncology; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (self), Advisory / Consultancy: Hansoh Pharmaceuticals. B. Ellers-Lenz: Full / Part-time employment: Merck Healthcare KGaA. J. Straub: Full / Part-time employment: Merck Healthcare KGaA. A. Johne: Full / Part-time employment: Merck Healthcare KGaA. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Sanofi.

67P - Pooled safety analysis of tepotinib in Asian patients with advanced solid tumours

67P - Pooled safety analysis of tepotinib in Asian patients with advanced solid tumours

584P - Noninferiority on overall survival of every-2-weeks vs weekly schedule of cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer

584P - Noninferiority on overall survival of every-2-weeks vs weekly schedule of cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer

481P - Bioavailability of tepotinib: Impact of omeprazole and food

BackgroundAcid-inhibitory drugs (e.g. proton pump inhibitors - PPIs) increase intragastric pH, which may decrease solubility, bioavailability, and efficacy of oral cancer drugs. Furthermore, polypharmacy in cancer patients is common and different requirements for treatment with or without food can impact compliance. Tepotinib is an oral, highly selective MET inhibitor being investigated in patients with solid tumors with MET dysregulation (METex14 mutations or MET amplification). In the pivotal clinical trial, tepotinib has been administered with breakfast; this represents the intended posology. Tepotinib has pH-dependent low solubility, suggesting that food intake and/or co-administration with a PPI may impact bioavailability. We investigated the effects of the PPI omeprazole and food on tepotinib. MethodsIn a 3-period, cross-over study, healthy volunteers (n=12) received 500mg/day tepotinib as a single dose 30 mins after a continental breakfast (treatment A) and co-administered on Day 5 after receiving omeprazole (40mg QD for 5 days) under fasted conditions (treatment B) and after a continental breakfast (treatment C). The impact of omeprazole on the AUC0-t, AUC0-∞, and Cmax of tepotinib under fed conditions was evaluated comparing treatments A and C; corresponding ratios of the geometric least-squares means (GLSM) (90% CI) were reported. In a separate study, food effect was investigated in healthy volunteers (n=12) by administering single doses of 500mg tepotinib under fasted state and after a high-fat, high-calorie breakfast. ResultsIn the first study, there was a negligible effect of omeprazole co-administration on the bioavailability of tepotinib under fed conditions. The GLSM ratios (90% CI) for treatment C/A were 1.09 (1.01, 1.17) for AUC0-t; 1.10 (1.02, 1.19) for AUC0-∞; and 1.04 (0.93, 1.17) for Cmax. In the second study, the ratio (90% CI) of “high-fat” /”fasted” for tepotinib AUC0-∞ was 1.87 (1.64, 2.13) and for Cmax was 2.37 (2.16, 2.59). ConclusionsThe intended posology of tepotinib, i.e. with food, is in agreement with the moderate food effect (approximately 2-fold increase in exposure of tepotinib). When tepotinib is administered at 500mg/day together with food, co-administration of PPI is not expected to have clinically relevant drug interactions. Clinical trial identificationNCT03531762 and NCT03629223. Editorial acknowledgementMedical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Sandra Cuscó, PhD of Bioscript Group (Macclesfield, UK). Legal entity responsible for the studyMerck Healthcare KGaA. FundingMerck Healthcare KGaA. DisclosureR. Strotmann: Full / Part-time employment: Merck Healthcare KGaA. A. Becker: Full / Part-time employment: Merck Healthcare KGaA. A. Krebs-Brown: Full / Part-time employment: Merck Healthcare KGaA. N. Mammasse: Full / Part-time employment: Merck Healthcare KGaA. Ö. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.

1975P - The tumor static exposure (TSE) concept & utility: Application to combination treatment of radiation and radiosensitizing agent in tumor xenograft experiments

BackgroundWe present a pharmacodynamic model that describes the tumor volume evolution during and after treatment with radiation and in combination with a radiosensitizing agent. A key contribution is the inclusion of a long-term radiation effect, which allows the model to describe distinct tumor behaviors including tumor eradication and tumor regrowth with different growth rates. Additionally, we introduce the concept of TSE (Tumor Static Exposure), the exposures of one or multiple compounds that result in tumor stasis and provide an example of its utility for optimizing drug combinations in oncology. MethodsThe model was challenged with data from four treatment groups (Vehicle, radiation, radiation + radiosensitizer 25 or 100mg/kg) in xenograft study using a clinically-relevant administration schedule (6 weeks treatment, 5 days on/2 days off) and a mixed-effects approach was used for model-fitting. The model incorporated a permanent inhibition of the natural growth rate. This step was required to capture the complete tumor eradication and the observed tumor regrowth with different rates with animals having slower regrowth compared to control animals. The presence of a radiosensitizer will lead to the same tumor evolution as if a higher dose of radiation had been administered. The model was applied to predict exposure combinations that result in tumor eradication using the TSE. ResultsThe developed model captured experimental data from all treatment groups adequately, with the parameter estimates taking biologically reasonable values. Model simulation showed that tumor eradication is observed at total radiation dose of 110Gy, which is reduced to 80 or 30Gy with co-administration of 25 or 100mg/kg of a radiosensitizer. ConclusionsThe new model can describe different tumor dynamics including tumor eradication and tumor regrowth with different rates. The proposed model can be expanded for radiation in combination with chemical interventions or immunotherapy. The model and TSE can be applied to generate treatment predictions for different dosing schedules or determining drug synergies. The translational utility of the TSE concept is currently under investigation. Legal entity responsible for the studyMerck Healthcare KGaA. FundingTim Cardilin was supported by an education Grant from Merck Healthcare KGaA, Darmstadt, Germany. This work was also partially funded by the Swedish Foundation for Strategic Research (Grant no. AM13-0046). DisclosureS. El Bawab: Full / Part-time employment: Merck Healthcare KGaA. A. Zimmermann: Full / Part-time employment: Merck Healthcare KGaA. F. Lignet: Full / Part-time employment: Merck Healthcare KGaA. All authors have declared no conflicts of interest.

1320P - Health-related quality of life in patients with metastatic Merkel cell carcinoma receiving second-line or later avelumab treatment: 36-month follow-up data

BackgroundIn the single-arm, open-label, multicentre, international phase II trial (NCT02155647 Part A), metastatic Merkel cell carcinoma (mMCC) patients received second-line or later avelumab 10mg/kg every two weeks. Health-related quality of life (HRQoL) was assessed using the skin cancer-specific FACT-M and the generic EQ-5D. We report HRQoL results 36 months after enrolment of the last patient with focus on HRQoL deterioration-free survival (QFS) rates. MethodsHRQoL data were obtained at baseline, week 7, and every 6 weeks until disease progression and/or treatment discontinuation. QFS was defined as the time interval between first dose and HRQoL deterioration event i.e. when a HRQoL domain score (FACT-M/EQ VAS) decreased from baseline equivalent to the minimal important difference (MID) threshold, with no further improvement thereafter. For sensitivity analyses, two thresholds are applied termed as minimum and maximum MID. QFS rates were derived from Kaplan-Meier curves and could be interpreted as the likelihood of a patient to endure a time period without relevant HRQoL deterioration until a certain time point. ResultsBased on the intention-to-treat population (n=88), QFS rates ranged from 40.6% (FACT-M functional well-being, FWB) to 56.3% (EQ VAS) at 12 months when applying minimum MIDs (Table). At 36 months, rates ranged from 20.7% (FWB) to 37.7% (FACT-M social well-being). When applying the maximum MID, QFS rates ranged from 48.6% to 64.9% at 12 months, and 25.3% to 42.7% at 36 months. ConclusionsAs expected, QFS rates decreased over time; however, in the context of an aggressive cancer such as mMCC, various HRQoL domains show promising QFS rates suggesting a substantial proportion of patients reported stable or improved HRQoL on treatment with avelumab across time points, aligned with the clinical efficacy results throughout the long study follow-up of over 36 months.Table1320P HRQoL deterioration-free survival rates (QFS) by time interval (12, 24, 36 months) based on EQ VAS and FACT-M scores applying (negative) minimum/maximum Minimal Important Difference (MID) thresholds, ITT population (N=88)TableMID thresholds1 (min./max.)HRQoL deterioration-free survival rates (%)Minimum MIDMaximum MIDMonth 12Month 24Month 36Month 12Month 24Month 36EQ-5DEQ VAS-7 / -1056.347.434.859.045.538.5FACT-MPhysical well-being (PWB)-1 / -346.743.036.452.646.135.8Social/Family well-being (SWB)-1/ -344.037.737.749.549.540.5Emotional well-being (EWB)-1 / -349.241.032.855.951.242.7Functional well-being (FWB)-2 / -440.632.620.752.848.533.6Melanoma subscale (MS)-2 / -549.745.737.464.949.138.2Melanoma surgery scale (MSS)-2 / -351.451.436.748.648.634.7Trial Outcome Index (TOI)-4 / -950.438.231.261.242.132.7FACT-G Total Score-4 / -846.837.724.051.743.427.6FACT-M Total Score-5 / -1246.637.623.956.939.725.31Published in Bharmal, et al. (2017). "Psychometric properties of the FACT-M questionnaire in patients with Merkel cell carcinoma." Health Qual Life Outcomes 15(1): 247. Legend: HRQoL=Health-Related Quality of Life; QFS=HRQoL deterioration-free survival rate; MID=Minimal Important Difference; ITT=Intention-to-treat population; VAS=visual analogue scale; EQ VAS=VAS of the EQ-5D questionnaire Clinical trial identificationNCT02155647. Legal entity responsible for the studyMerck Healthcare KGaA. FundingThis study was sponsored by Merck Healthcare KGaA, Darmstadt, Germany, and is part of an alliance between Merck Healthcare KGaA, Darmstadt, Germany and Pfizer Inc., New York, NY, USA. DisclosureS.P. D’Angelo: Advisory / Consultancy: Incyte; Advisory / Consultancy: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar; Advisory / Consultancy: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: EMD Serono; Advisory / Consultancy: GSK; Advisory / Consultancy: ImmuneDesign; Travel / Accommodation / Expenses: Adaptimmune. S. Nolte: Full / Part-time employment, Employee of ICON plc, which is a paid consultant to the study sponsor: ICON plc. M. Schlichting: Full / Part-time employment: Merck Healthcare KGaA. M. Henry-Szatkowski: Full / Part-time employment, Employee of ICON plc, which is a paid consultant to the study sponsor: ICON plc. M. Hennessy: Full / Part-time employment: EMD Serono, Inc. M. Bharmal: Full / Part-time employment: Merck Healthcare KGaA.

480P - Drug-drug interaction profile of tepotinib with CYP3A and P-gp substrates

BackgroundTepotinib is an oral, highly selective MET inhibitor being investigated in MET-driven solid tumors. Cancer patients often receive co-medications, many of which are subject to cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp)-dependent pharmacokinetics.The potential of tepotinib to alter the exposure to such drugs was investigated in two clinical drug-drug interaction (DDI) trials. MethodsThe effect of multiple doses of the RP2D of tepotinib (500mg QD) on the exposure of single doses of the sensitive CYP3A4 substrate midazolam and the sensitive P-gp substrate dabigatran etexilate were tested in healthy subjects, using randomized single-sequence two-period cross-over designs. The primary endpoints were Cmax and AUC for the respective probe drugs; their corresponding ratios of the geometric least-squares means (GLSM) (90% CI) in the presence/absence of tepotinib were reported. Additional PK measures, safety and tolerability were also evaluated. ResultsMost participants were male (12/12 midazolam; 19/20 dabigatran etexilate); mean age 34 years (range 19–44). There was no increase in midazolam exposure with co-administration of tepotinib (Table), suggesting that no effect on the metabolism of CYP3A is to be expected. Co-administration of tepotinib led to a 39–45% increase in dabigatran etexilate exposure. No clinically relevant effects on laboratory values, vital signs or ECG parameters were observed or reported as an AE.Table480PTableCYP3A substrate (Midazolam) Ratio of GLSM% (90% CI)P-gp substrate (Dabigratan) Ratio of GLSM% (90% CI)Tepotinib + Midazolam / MidazolamTepotinib + Dabigatran etexilate / Dabigatran etexilateAUC0-t1.01 (0.89; 1.15)1.51 (1.27; 1.80)AUC0-∞1.01 (0.89; 1.15)1.45 (1.23; 1.70)Cmax1.04 (0.87;1.24)1.38 (1.22; 1.58)AUC0-t, area under the plasma concentration-time curve from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification;AUC0-∞, area under the plasma concentration-time curve from time zero (= dosing time) extrapolated to infinity; Cmax, maximum plasma concentration observed; GLSM, geometric least-squares mean. ConclusionsAfter multiple doses of tepotinib at the RP2D (500mg QD), there was no relevant exposure increase of the sensitive CYP3A substrate midazolam, and a<2-fold mean exposure increase of the sensitive P-gp substrate dabigatran etexilate, indicating that tepotinib is a weak P-gp inhibitor. Tepotinib was considered safe and well tolerated in these studies of healthy volunteers. In summary, the potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the intended posology is considered low. Clinical trial identificationNCT03492437 and NCT03628339. Editorial acknowledgementMedical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Sandra Cuscó, PhD of Bioscript Group (Macclesfield, UK). Legal entity responsible for the studyMerck Healthcare KGaA. FundingMerck Healthcare KGaA. DisclosureÖ. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. A. Becker: Full / Part-time employment: Merck Healthcare KGaA. A. Krebs-Brown: Full / Part-time employment: Merck Healthcare KGaA. R. Strotmann: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.

596P - The cost of adverse event management in patients with RAS wild-type metastatic colorectal cancer treated with first-line cetuximab and panitumumab: An Italian healthcare payer perspective

BackgroundIn Italy, previously untreated patients with RAS wild-type metastatic colorectal cancer (mCRC) may receive an epidermal growth factor receptor (EGFR) inhibitor with a chemotherapy regimen (CT). The choice of anti-EGFR, either cetuximab (cet+CT) or panitumumab (pan+CT), depends on various factors, including adverse event (AE) profiles. Although AE profiles will evolve with increasing use and familiarity, the differences in AE profiles can be explored using literature and safety data from the summary of product characteristics (SmPC). The financial impact of these differences on the Italian National Health Service has yet to be estimated. MethodsWe developed a model to estimate costs of AE management. Frequencies of common and very common AEs associated with cet+CT or pan+CT were sourced from the respective SmPC.1,2 Applicable resource use costs were obtained from hospital services price lists from the Ministry of Health using the DRG outpatient tariff.3 The national-level financial impact was calculated from the number of cet+CT–eligible patients with mCRC treated in the first line based on published literature, national guidelines, and pan+CT market share. Inputs were validated by practicing Italian oncologists. ResultsAll-grade AEs were estimated to be 58.1% lower and grade 3/4 AEs were estimated to be 70.2% lower in patients receiving cet+CT than in those receiving pan+CT. Mean costs of AE management per patient treated with cet+CT and pan+CT were estimated at €1,194 and €2,951, respectively, resulting in average savings of €1,758 (59.6%) per patient. Differences are mainly driven by a lower frequency of AEs that are costly to manage, such as GI disorders. Annual savings could reach €2,191,839 for a population of 1,247 cet+CT–eligible patients with mCRC. ConclusionsFewer AEs for cet+CT may result in markedly lower AE management costs vs pan+CT. Although results should be considered together with overall costs and clinical outcomes, cet+CT could decrease cost burden on the Italian National Health Service and AE burden for patients with mCRC. Editorial acknowledgementClinicalThinking, Inc, Hamilton, NJ, USA (funded by Merck Healthcare KGaA, Darmstadt, Germany). Legal entity responsible for the studyMerck Healthcare KGaA. FundingMerck Healthcare KGaA. DisclosureN. Personeni: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono. V. Gebbia: Honoraria (self): Merck; Honoraria (self): Amgen; Honoraria (self): Roche. P. Novelli: Full / Part-time employment: Merck Serono S.p.A. S. Di Matteo: Research grant / Funding (institution): Merck. G. Colombo: Research grant / Funding (institution): Merck. C. Pescott: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.

908PD - Primary renal tumour shrinkage in patients (pts) who did not undergo upfront cytoreductive nephrectomy (uCN): Subgroup analysis from the phase III JAVELIN Renal 101 trial of first-line avelumab + axitinib (A + Ax) vs sunitinib (S) for advanced renal cell carcinoma (aRCC)

908PD - Primary renal tumour shrinkage in patients (pts) who did not undergo upfront cytoreductive nephrectomy (uCN): Subgroup analysis from the phase III JAVELIN Renal 101 trial of first-line avelumab + axitinib (A + Ax) vs sunitinib (S) for advanced renal cell carcinoma (aRCC)