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Runhui Wu,1 Jing Sun,2 Weiqun Xu,3 Qun Hu,4 Wenqian Li,5 Jianwen Xiao,6 Feng’e Yang,7 Xiaojing Zeng,8 Yun Zeng,9 Jianfeng Zhou,4 Irina Matytsina,10 Sali Zhang,11 Michael Pluta,12 Renchi Yang13 1Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, National Children’s Health Center, Beijing, People’s Republic of China; 2Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Hematology and Oncology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 4Department of Pediatric Hematology, Tongji Hospital, Tongji Medical College of HUST, Wuhan, People’s Republic of China; 5Department of Hematology and Rheumatology, Qinghai Provincial People’s Hospital, Xining, People’s Republic of China; 6Department of Hematology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 7Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 8Department of Blood Transfusion, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 9Department of Hematology, First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 10Biopharm Medical & Science, Novo Nordisk A/S, Søborg, Denmark; 11Biopharm Clinical, Medical and Regulatory Affairs, Novo Nordisk (China) Pharmaceuticals Co., Ltd, Beijing, People’s Republic of China; 12Statistical Consultancy, Quanticate Ltd, Hitchin, UK; 13Thrombosis and Haemostasis Centre, State Key Laboratory of Experimental Hematology, Tianjin Laboratory of Blood Disease Gene Therapy, CAMS Key Laboratory of Gene Therapy for Blood Diseases, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Renchi YangThrombosis and Haemostasis Centre, State Key Laboratory of Experimental Hematology, Tianjin Laboratory of Blood Disease Gene Therapy, CAMS Key Laboratory of Gene Therapy for Blood Diseases, National Clinical Research Center for Hematological Disorders Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaTel +86 13512078851Email rcyang65@163.comPurpose: Hemophilia care in China is characterized by widespread use of on-demand regimens and low-dose prophylaxis. With a limited number of approved recombinant factor VIII (FVIII) products, the incidence of arthropathy and disability in hemophilia patients remains high in China. The purpose of this trial was to evaluate the safety and efficacy of turoctocog alfa for prophylaxis and treatment of bleeding episodes in patients from China with severe hemophilia A across all age groups.Patients and Methods: In this Phase 3, open-label trial, previously treated males of all ages with severe hemophilia A from China received turoctocog alfa for prophylaxis or on-demand treatment of bleeds. The primary endpoint was hemostatic effect for the treatment of bleeds during the main phase of the trial. Secondary endpoints included annualized bleeding rate during prophylaxis and the frequency of FVIII inhibitor development.Results: Overall, 42 pediatric patients (age < 12 years) and 26 adolescent/adult patients (≥ 12 years) were dosed with turoctocog alfa; 51 patients initiated treatment with prophylaxis, while 17 patients initiated on-demand treatment. During the main phase of the trial (6 months), hemostatic success was 95.1%. During the full trial (up to 24 months), hemostatic success was 95.4%; the overall median ABR was 1.18 bleeds/patient/year for prophylaxis patients; and 25 (51.0%) of 49 patients with target joints at baseline had all target joints resolved. No FVIII inhibitors (≥ 0.6 BU) were reported.Conclusion: Turoctocog alfa was safe and effective for prophylaxis and treatment of bleeding episodes and for surgery in patients from China with severe hemophilia A across all ages.Keywords: hemophilia A, prophylaxis, recombinant factor VIII, turoctocog alfa, China

Background: Patients (pts) with EGFRm T790M-negative NSCLC with progressive disease (PD) on an EGFR TKI have limited therapy options. CD73 may promote immune evasion and is overexpressed in EGFRm NSCLC, suggesting the potential for combining CD73 blockers with EGFR TKIs. Oleclumab (MEDI9447) disrupts immune evasion by binding to CD73. This phase 1b/2, multicenter, dose escalation/expansion study (NCT03381274) evaluates the safety and efficacy of oleclumab plus osimertinib (osi) in locally advanced/metastatic EGFRm NSCLC. Methods: Pts had histologically or cytologically confirmed T790M-negative EGFRm NSCLC by local testing, a TKI-sensitive EGFR mutation (exon 19 del, L858R), ECOG PS 0-1, PD on a 1st or 2nd generation TKI, and no prior osi. Oleclumab 1500 mg (DL1) or 3000 mg (recommended Phase 2 dose, RP2D) IV Q2W + osi 80 mg PO QD were given until PD or intolerable AEs. Primary endpoints included AEs, SAEs and ORR by RECIST v1.1. DLTs were predefined and reviewed by a dose-escalation committee. Secondary endpoints included duration of response, disease control rate, PFS and OS. Results: As of November 9, 2020, 5 pts received DL1 and 21 pts received RP2D. Minimum follow-up was 44 wks. For the 5 pts receiving DL1, safety profile and response rate were generally similar to RP2D and no DLTs occurred. All of the 21 pts receiving RP2D had ≥1 treatment-emergent AE (TEAE), 38.1% had Grade 3/4 TEAEs and 23.8% had SAEs. Treatment-related AEs (TRAEs) occurred in 81.0% (19.0% Grade 3/4); none were SAEs or deaths. The most common TRAEs were rash (33.3%), stomatitis (28.6%), diarrhea (23.8%) and paronychia (23.8%). At data cutoff, 38.1% remained on treatment; 47.6% discontinued due to PD, with death, pt decision and AE (pneumonitis) as other causes. Response and survival for pts receiving RP2D are shown in Table 1. Conclusions: Oleclumab + osi was well tolerated at RP2D. Compared to T790M-negative EGFRm NSCLC pts in a prior study of osi monotherapy, ORR was similar (21% vs 19%) but mPFS was longer (2.8 vs 11.0 mos). Table 1.Disease response and survivalOutcomeN=21Best overall response, n (%)CR0PR4 (19.0)SD13 (61.9)PD3 (14.3)Not evaluable1 (4.8)ORR, n (%)4 (19)Median duration of response, months (range)Not assessable (9.2-11.1)Disease control rate, n (%)17 (81.0)Median PFS (95% CI), months11 (3.7-not evaluable)6-month PFS rate (95% CI), %63.5 (38.3, 80.7)9-month PFS rate (95% CI), %52.9 (29.0, 72.1)Median OS (95% CI), monthsNot reached (11.7-not evaluable)6-month OS rate (95% CI), %100 (100, 100)9-month OS rate (95%CI), %90.0 (65.6, 97.4) Citation Format: Dong-Wan Kim, Sang-We Kim, D. Ross Camidge, Naiyer A. Rizvi, Kristen A. Marrone, Xiuning Le, Collin Blakely, Keunchil Park, Gee-Chen Chang, Sandip Pravin Patel, Zachary A. Cooper, Rakesh Kumar, Ramin Samadani, Rebecca McCombs, Michael Pluta, Kevin Yufeng Wu, Suresh Ramalingam. CD73 inhibitor oleclumab plus osimertinib for advanced EGFRm NSCLC: First report of a Phase 1b/2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT163.

Background Factor VIII (FVIII) products are usually dosed according to body weight (BW). This may lead to under- or over-dosing in underweight or obese patients, respectively. Objective This article evaluates the pharmacokinetics (PK) of recombinant FVIII concentrate, particularly recovery, in relation to body mass index (BMI) and other body composition descriptors. Materials and Methods Thirty-five previously treated adults with severe haemophilia A from five BMI categories (underweight, normal, overweight, obese class I and II/III) were included. PK was evaluated after 50 IU per kilogram of BW single-dose recombinant FVIII (turoctocog alfa). The body composition variable was based on measurements of weight, height, bioimpedance analysis, and dual-energy X-ray absorptiometry. A dosing model was derived to achieve similar peak FVIII activity levels across BMI categories. Results A statistically significant positive association between BMI and C30min, IR30min, and AUC0–inf was observed; CL and Vss showed a significant negative association with BMI; t½ was independent of BMI and other parameters. The dosing model introduced a correction factor ‘M’ for each BMI category, based on linear regression analysis of C30min against BMI, which ranged from 0.55 for underweight to 0.39 for obese class II/III. This model achieved similar peak FVIII activity levels across BMI categories, estimating an average dose adjustment of þ243.3 IU (underweight) to –1,489.6 IU (obese class II/III) to achieve similar C30min. Conclusion BMI appears to be the best predictor of recombinant FVIII recovery; however, PK endpoints were also dependent on other body composition variables. The model demonstrated that dosing can be adjusted for individual BMI to achieve better FVIII predictability across BMI categories, This work was funded by Novo Nordisk A/S (Bagsværd, Denmark).