Search

Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8(+) and CD4(+) T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.

Objectives To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). Methods In two 52-week phase 1 b trials, s.c.-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight ≥30 kg or Results Study participants were 51 sJIA patients and 52 pJIA patients aged 1–17 years who received s.c.-TCZ. Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with i.v.-TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were similar between body weight groups. Improvements in Juvenile Arthritis DAS-71 were comparable between s.c.-TCZ and i.v.-TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of i.v.-TCZ except for injection site reactions, reported by 41.2% and 28.8% of sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered to be related to TCZ. Conclusion s.c.-TCZ provides exposure and risk/benefit profiles similar to those of i.v.-TCZ. S.c. administration provides an alternative administration route that is more convenient for patients and caregivers and that has potential for in-home use. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279

This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens. Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens. The dose-escalation study investigated lumretuzumab doses up to 2000 mg q2w and a maximum tolerated dose was not reached. However, the model described in this report predicted linear lumretuzumab pharmacokinetics and >95% target saturation at doses ≥400 mg q2w. These data, along with safety data, contributed to the decision to begin dose-escalation studies in combination with cetuximab and erlotinib using a starting dose of 400 mg lumretuzumab. Pharmacokinetic data from patients treated with lumretuzumab 400–2000 mg q2w in combination regimens were consistent with the model predictions. PK/PD modelling of emerging clinical data might accelerate development programs by enabling additional parts of a trial to commence before completion of the monotherapy part. The dose and schedule of lumretuzumab were optimised for concomitant therapy at doses substantially below the highest dose investigated.

Background The anti–interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years. Methods Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2–17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing

Crovalimab (RO7112689) is a novel anti-human C5 antibody engineered with Sequential Monoclonal Antibody Recycling Technology (SMART Ig)(Fukuzawa et al., Sci Rep. (2017) 7(1):1080), resulting in significant half-life extension and enabling infrequent SC dosing using small volumes (1mL - 4mL) in C5 mediated diseases. We aimed at characterizing the exposure-response relationship of crovalimab used to define the minimum concentration of crovalimab achieving complete terminal inhibition. To establish pharmacokinetics (PK), pharmacodynamics (PD), safety, efficacy, and optimal dose of crovalimab, we conducted a four-part adaptive clinical trial (Figure 1): Part 1: 15 healthy subjects were enrolled. 3 received 75 mg RO7112689 IV, 3 received 125 mg RO7112689 IV, 3 received 100 mg RO7112689 SC, and 6 received placeboPart 2: 10 treatment-naïve PNH patients were enrolled in Part 2 to receive increasing IV doses of 375mg, 500mg, and 1000mg on days 1, 8 and 22, respectively, followed by weekly doses of 170mg SC starting on day 36Part 3: 19 eculizumab pre-treated PNH patients were enrolled in Part 3 to receive 1000mg IV before randomization into 3 different arms: Arm A: 680mg SC Q4W (N=7)Arm B: 340mg SC Q2W (N=6)Arm C: 170mg SC QW (N=6) SC dosing was initiated on day 8 after the IV dose in all the dosing groups. Part 4: 5 eculizumab pre-treated PNH patients and 5 treatment-naïve PNH patients are planned to be enrolled to receive IV dose of 1000mg on Day 1 followed by SC dose of 340mg on Day 2, Day 8, Day 15, Day 22 followed by SC dose of 680mg given Q4W from Day 29 Crovalimab concentrations and free C5 were measured using a validated ELISA. A population PK model was developed using all the available data to describe the crovalimab concentration-time profiles. Crovalimab PD was assessed by evaluating the extent and duration of terminal complement inhibition, quantified using a validated, functional ex vivo liposome immunoassay (LIA) (http://www.wakodiagnostics.com/r_ch50.html). Relationships between crovalimab PK and PD were analyzed using graphical analysis. The PK was best described by a two-compartment open model with first-order elimination and absorption. To describe the PK in eculizumab pre-treated patients, elimination of crovalimab was modeled as a combination of the first-order elimination used for naïve patients and a faster clearance which decreases exponentially over time. Body weight was introduced using allometry on the clearance and volume of the distribution. After SC administration, bioavailability is estimated at 100% and terminal half-life around 30 days. In all PNH patients, complete complement inhibition (defined as LIA By pooling all the PK and PD data from the 3 parts of the COMPOSER study, crovalimab was shown to induce a concentration-dependent inhibition of serum hemolytic activity and of free C5 which closely correlates with terminal complement inhibition. Collectively, these data indicate that approximately 100μg/mL of crovalimab are required to achieve complement inhibition (Figure 3). At the target concentration of crovalimab between 80-100ug/mL, patients achieve complete terminal complement inhibition. Data collected in the ongoing Part 4 of COMPOSER will be used to confirm the target concentration of crovalimab. Exposure-response characterization demonstrated the potential of crovalimab as an infrequent, subcutaneous therapy for PNH. Disclosures Sostelly: F. Hoffmann-La Roche: Employment. Buatois:F. Hoffmann-La Roche: Employment. Soubret:F. Hoffmann-La Roche: Employment, Equity Ownership. Klughammer:F. Hoffmann-La Roche Ag: Employment, Equity Ownership. Hsu:Roche/Genentech: Employment, Equity Ownership. Jordan:Roche Diagnostics GmbH: Employment; F. Hoffmann-La Roche: Equity Ownership. Bucher:F. Hoffmann-La Roche: Employment. Charoin:F. Hoffmann-La Roche: Employment. Gotanda:Chugai Pharmaceutical Co., Ltd.: Employment. Shinomiya:Chugai Pharmaceutical Co., Ltd.: Employment, Patents & Royalties: (WO2018143266) A PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OR PREVENTION OF A C5-RELATED DISEASE AND A METHOD FOR TREATING OR PREVENTING A C5-RELATED DISEASE. Nagy:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Panse:Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Yoon:Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Yuhan Pharma: Research Funding; Janssen: Consultancy. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Consultancy, Membership on an entity's Board of Directors or advisory committees. Röth:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Consultancy, Honoraria.

Tocilizumab is a humanized anti-interleukin-6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24-week double-blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2-compartment population pharmacokinetic model, with first-order absorption (for subcutaneous) and linear and Michaelis-Menten elimination was used. Mean observed steady-state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every-week and every-2-week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population-predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every-2-week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every-2-week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every-week subcutaneous and every-4-week intravenous regimens and less pronounced with the every-2-week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every-week subcutaneous regimen to the every-4-week intravenous regimen and the superiority of the every-2-week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.

Background Efficacy and safety of intravenous (IV) tocilizumab (TCZ) were demonstrated in patients (pts) with systemic juvenile idiopathic arthritis (sJIA) in the phase 3 TENDER study1 (WA18221). Study WA28118 (ClinicalTrials.gov, NCT01904292) investigated dosing regimens of subcutaneous (SC) TCZ in pts with sJIA by bridging to IV TCZ data to identify the optimal SC regimen. Objectives To characterise the pharmacokinetics (PK), pharmacodynamics (PD), and safety of TCZ SC in pts with sJIA; efficacy was an exploratory objective. Methods This phase 1b multicenter, open-label study evaluated PK, PD, and safety of TCZ SC in pts aged 1–17 years with sJIA and inadequate response to glucocorticoids and nonsteroidal anti-inflammatory drugs. Interim analysis (IA) was conducted after 24 pts had received TCZ SC for 14 weeks. Pts could be either TCZ-naive or switch from TCZ IV to SC at baseline. TCZ SC was administered for 52 weeks according to body weight: Results Among enrolled pts (n=51), 25 weighed Conclusions A PK-based strategy successfully bridged TCZ SC to TCZ IV in pts with sJIA. Dosing regimens of 162 mg Q2W in pts Reference [1] De Benedetti F, et al. N Engl J Med2012;367:2385–2395. Disclosure of Interest H. Brunner: None declared, N. Ruperto Consultant for: AbbVie, Amgen, Biogenidec, Alter, AstraZeneca, Baxalta Biosimilars, Biogenidec, Boehringer, BMS, Celgene, CrescendoBio, EMD, Speakers bureau: AbbVie, Amgen, Biogenidec, Alter, AstraZeneca, Baxalta Biosimilars, Biogenidec, Boehringer, BMS, Celgene, CrescendoBio, EMD, D. Lovell Grant/research support from: National Institutes of Health, NIAMS, Consultant for: Astra-Zeneca, Bristol Meyers Squibb, AbbVie, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson and Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Janssen, Speakers bureau: Genentech, I. Calvo-Penedes: None declared, G. Horneff: None declared, M. L. Gamir Gamir: None declared, M. Hufnagel: None declared, J. Hsu Employee of: Roche, M. Bao Employee of: Roche, W. Douglass Employee of: Roche, N. L. Mallalieu Employee of: Roche, C. Wells Shareholder of: Roche, Employee of: Roche, C. M. Mela Employee of: Roche, F. De Benedetti Grant/research support from: Novartis, Roche, Pfizer, SOBI, AbbVie, Novimmune, BMS, Sanofi

Purpose Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess alectinib dose selection. Methods A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3). Results Overall, 92% of patients (n = 207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs. Conclusion Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC. Electronic supplementary material The online version of this article (10.1007/s00280-018-3597-5) contains supplementary material, which is available to authorized users.

Introduction: SKY59 is an anti-C5 antibody applying SMART* [Fukuzawa et al., SciRep 2017] to allow for infrequent SC dosing. A three-part adaptive clinical trial was conducted in healthy volunteers (part1 -previously reported, Röth et al., Blood 2017 130:4750) and PNH patients who are treatment naive (part 2) or previously treated with eculizumab (ecu) (part 3) to establish dose, safety and efficacy of SKY59. Methods: Part 2 was an intra-patient dose escalation study. Patients received IV doses of 375mg, 500mg, and 1000mg of SKY59 on days 1, 8 and 22, respectively, followed by weekly doses of SKY59 of 170mg SC starting on day 36. In part 3 PNH patients who had been on ecu for at least 3 months received an IV loading dose of 1000mg SKY59 on day 1, 2 weeks after their last ecu dose, and were randomized to receive 170mg SC QW, 340mg SC Q2W or 680mg SC Q4W of SKY59 starting on day 8. After 5 months all patients entered an open-label extension remaining on their previous dose regimen with SKY59. Terminal complement activity was quantified using an ex vivo liposome immunoassay (LIA). The study was approved by Ethics Committees and Health Authorities and conducted according to the principles of the declaration of Helsinki. Results: 17 PNH patients were included (Table 1), 10 in part 2 and 7 in part 3 at the time of writing this abstract. PK: After SC administration, bioavailability is estimated at 100%. For a patient of 75 kg, the terminal half-life was estimated around 25 days. PD: Following IV dosing, complete complement inhibition (defined as LIA values < 10 U/mL, the LLOQ of the assay), was achieved at end of infusion in all patients and maintained for all SC dose regimens. Median baseline (BL) total C5 concentration was 107 μg/mL (range: 66.9 - 130 μg/mL) in part 1, 140 μg/mL (73.6 - 184 μg/mL) in part 2, 295 μg/mL (205 - 354 μg/mL) in part 3. Following treatment with SKY59, patients in Part 2 showed a slight increase in total C5 at week 6 to 215 μg/mL (109 - 331 μg/mL). Patients in part 3 had a significant decrease in total C5 at week 6 to 228 μg/mL (184 - 305 μg/mL), likely reflecting the antigen disposing activity of SKY59. Treatment-naive patients (including one Arg885His C5 SNP patient [Nishimura et al.; N Engl J Med. 2014]) with PNH had a rapid median reduction in LDH (-79% from BL; median 1.20 x ULN, range 0.8 to 1.7 x ULN) at 6 weeks. LDH of Patients in part 3 did not show a significant change at 6 weeks or later compared to BL except for one C5 SNP patient who normalized LDH. 6/6 of naive (non-transfusion dependent) and 1/5 switch (non-transfusion dependent) patients had an increase in hemoglobin of at least 10g/L from BL to week 20, one patient in Part 2 and one patient in Part 3 normalized their hemoglobin. Overall transfusion requirements were not changed. QoL: From BL to week 10 treatment naive patients experienced a median change of +11 points (range -1 to 28) in the FACIT fatigue score. Switch patients showed no significant short-term change from BL to week 12 on the same questionnaire. Safety: Treatment with SKY59 was well tolerated, particularly, no injection site AEs and a low incidence of headache was observed. There were 2 SAEs (break-through hemolysis due to infection and atrial fibrillation) not related to study drug. No AEs resulted in withdrawal from the study or death. In 2/7 switch patients mild-moderate non-serious, likely drug-target-drug complex (DTDC) mediated reactions with clinical manifestations similar to serum sickness were observed in the initial post-switch period (day 9 and 10 respectively). These manifestations were treated with topical steroids and resolved by day 21 with no interruption in study treatment. In patients switching from ecu to SKY59, the formation of DTDC composed of SKY59, C5, and ecu are expected due to the different binding epitopes of the two antibodies. Conclusion: SKY59 administered SC in a low volume is very well tolerated, has a good benefit/risk ratio and is efficacious in treatment naive and ecu-treated patients with PNH. Transient induction of DTDC was not associated with undue toxicity. Furthermore, SKY59 has the potential to provide treatment for patients unresponsive to ecu due to SNP and significantly reduces the treatment burden associated with chronic IV administration. Updated data will be presented at the meeting. * Sequential Monoclonal Antibody Recycling Technology Disclosures Röth: Bioverativ: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Usuki:Takeda Pharmaceutical: Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Novartis: Speakers Bureau; Pfizer Japan: Research Funding, Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Shire Japan: Research Funding; SymBio Pharmaceuticals Limited.: Research Funding; GlaxoSmithKline K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical: Speakers Bureau; Celgene Corporation: Research Funding, Speakers Bureau; Sanofi K.K.: Research Funding; Janssen Pharmaceutical K.K: Research Funding; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Winter:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Hsu:Roche: Employment. Dieckmann:Roche: Employment. Anzures-Cabrera:Roche: Employment. Jordan:Roche: Employment. Shinomiya:Chugai: Employment. Klughammer:F. Hoffmann-La Roche Ag: Employment. Bucher:Roche: Employment. Jahreis:Genentech: Employment, Equity Ownership. Nishimura:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Chugai Pharmaceuticals: Consultancy, Research Funding.

Background Tocilizumab (TCZ) is approved for the treatment of systemic juvenile idiopathic arthritis (sJIA) based on clinical trials in patients (pts) ≥2 years of age. This study (NP25737) is the first for a biologic in sJIA pts Objectives To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of TCZ in sJIA pts Methods Pts with uncontrolled sJIA and symptoms for ≥1 month prescreening who failed treatment with corticosteroids and NSAIDs and had no history of allergy to TCZ or other biologics received open-label TCZ 12 mg/kg intravenously (IV) every 2 weeks (dose calculated at each visit based on body weight). Pts were treated up to week 12 and could continue until the age of 2 years or were treated for 1 year from baseline. End points included PK (primary) at week 12, PD and efficacy (exploratory), and safety. Comparison was made to exposures from a previous trial in sJIA pts ≥2 years of age (WA18221) that was the basis for approval of TCZ in sJIA. Results Eleven pts were enrolled; median (range) age was 16 (10–22) months and weight was 10.40 (6.8–11.5) kg. Serum TCZ concentrations, estimated using population PK analysis, peaked immediately after infusion; median (range) maximum concentration was 282 (195–347) μg/mL (steady state reached by week 12), and median (range) trough concentration was 34.3 (19.2–59.7) μg/mL. Peak and trough exposures were within the exposure range in older children (244 [109–382] to 54.3 [10.9–117] μg/mL; Figure). Observed mean±SD soluble IL-6 receptor levels were 47.65±16.40 ng/mL at baseline and 927.83±148.07 ng/mL at day 71. CRP levels were 250.81±425.11 mg/L and 2.80±3.56 mg/L, respectively. ESR levels were 59.40±27.47 mm/h and 2.00±1.00 mm/h, respectively. Mean±SD Juvenile Arthritis Disease Activity Score-71 improved from 22.27±10.09 at baseline to 3.66±4.66 at day 71. By week 12, 10 pts had 32 adverse events (AEs) and 4 withdrew due to AEs. Infections or infestations were the most frequently reported AEs (10 events, 9 pts). Five serious AEs (SAEs) occurred; 3 pts had SAEs of hypersensitivity that led to withdrawal; 1 of these pts then experienced SAEs of foot and mouth disease and sJIA flare after study withdrawal. No actual cases of MAS were reported, but 2 pts had laboratory abnormalities indicative of MAS according to 2016 criteria.1 No deaths occurred during the study. Conclusions TCZ exposures achieved in this study fell within the range of the previous trial in sJIA pts ≥2 years of age. This study provides evidence that TCZ is effective in sJIA pts References Ravelli A et al. Ann Rheum Dis. 2016;75:481–9. Disclosure of Interest N. Mallalieu Shareholder of: Roche, Employee of: Roche, J. Hsu Employee of: Roche, K. Wang Employee of: Roche, S. Wimalasundera Employee of: Roche Products Ltd., C. Wells Employee of: Roche Products Ltd., I. Calvo Penades: None declared, R. Cuttica Consultant for: Roche, Novartis, Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Janssen, Speakers bureau: Roche, Novartis, Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Janssen, H. Huppertz: None declared, R. Joos: None declared, Y. Kimura Consultant for: Novartis, SOBI, D. Milojevic: None declared, M. Rosenkranz: None declared, K. Schikler: None declared, T. Constantin: None declared, C. Wouters: None declared

e20575 Background: Alectinib superiority to crizotinib has been demonstrated in ALK-inhibitor naïve ALK-positive NSCLC patients (pts) in Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132316) pts receiving alectinib 300 mg BID and global (ALEX; NCT02075840) and Asian (ALESIA; NCT02838420) pts receiving alectinib 600mg BID. ER analyses are undertaken to confirm the appropriate alectinib dosing regimen for the global population. Methods: A previous population PK analysis (Hsu et al, ASCO 2016) assessed PK of alectinib and major metabolite, M4, to identify factors influencing PK variability. ER analyses across the 3 Phase III studies investigated the relationship between alectinib and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis. PK simulations for alectinib 300 mg and 600 mg BID doses were conducted to determine the proportion of pts falling above and below an identified optimal PK threshold for PFS. ER for key safety events were investigated for alectinib 600 mg BID using logistic regression. Results: Alectinib PK is influenced only by body weight and not by race/ethnicity. CPH analysis demonstrated a statistically significant relationship between alectinib exposure and PFS across the 3 Phase III studies, with an improved PFS above an identified optimal PK threshold (Table). PK simulations indicate 49% and 7% of global alectinib treated patients would fall below the optimal PK threshold for 300 and 600mg BID, respectively. Alectinib 600mg BID ensures a distribution of exposures that maximize the PFS benefit while lower alectinib doses/exposures could result in reduced efficacy. Baseline tumor size (BSIZ) was shown to negatively impact PFS with larger BSIZ seen in global pts. No significant exposure-safety relationships were identified for alectinib 600mg BID. Conclusions: Alectinib 600mg BID is the most appropriate dose in the global ALK-inhibitor naïve population. Clinical trial information: NCT02075840; JapicCTI-132316; NCT02838420. [Table: see text]

e21137Background: A pooled overall survival (OS) analysis of two single-arm, open-label phase II studies (NP28673, global [NCT01801111] and NP28761, North American [NCT01871805]) with 53.3% of deat...

e21133Background: Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132316) and global (ALEX; NCT02075840) patients with treatment-naive ALK+ NSCLC demonstrated superiority of ALC 300 and 6...

e20616 Background: J-ALEX showed superiority of ALC 300mg BID vs crizotinib (CRIZ) in Japanese ALK inhibitor naïve ALK-positive NSCLC patients (pts). PopPK and ER analyses were used to bridge J-ALEX data to the global population to confirm the appropriateness of ALC 600mg BID dose, used in global trials. Methods: The previous popPK analysis (Hsu et al, ASCO 2016) was updated to include PK data from J-ALEX and the ongoing global ALEX study to confirm any significant covariates influencing PK of ALC and major metabolite, M4, using Bayesian feedback analysis. ER analyses from J-ALEX (n=96) investigated the relationship between ALC and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis and key safety events using logistic regression. Results: The popPK models previously developed for pts who have progressed on, or are intolerant to CRIZ were able to adequately predict ALC and M4 PK in J-ALEX and ALEX. Body weight remained the only significant covariate influencing ALC and M4 PK. Administration of ALC 600mg BID in the global population ensures that ALC and M4 exposures across the body weight range are not inferior to those seen in Japanese pts receiving ALC 300mg BID, while lower doses would result in lower exposures. CPH analysis demonstrated a statistically significant relationship between ALC exposure and PFS in J-ALEX such that one third of pts in J-ALEX may benefit from a higher exposure of ALC (Table). ALC 600mg BID ensures the distribution of achieved exposures maximize the expected PFS benefit while lower ALC exposures could result in reduced efficacy. No significant exposure-safety relationships were identified in J-ALEX consistent with previous analyses conducted following ALC 600mg BID. Conclusions: ALC 600mg BID is the appropriate dose in the global ALK inhibitor naïve population. Clinical trial information: JapicCTI-132316. [Table: see text]

e20598Background: Alectinib, a potent and selective CNS-active ALK inhibitor, which has received FDA accelerated approval for treatment of patients with ALK+ NSCLC who have progressed on, or are in...

TCZ, an IL-6R inhibitor, is effective in systemic and polyarticular juvenile idiopathic arthritis (sjia, pjia). BW-adjusted, intravenous dosing regimens (TCZ8 mg/kg Q2W for sjia and Q4W for pjia) were assessed in Japanese phase 3 trials. As shown in Results, BW adjustment led to lower TCZ exposure with lower BW; thus, higher doses were proposed for patients (pts) with BW