Safety, pharmacokinetics and efficacy of selumetinib in Chinese adult and paediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas: The primary analysis of a phase 1 open‐label study

Abstract

We present data from a phase 1 study (NCT04590235; D1346C00011; CTR20200357) investigating the safety and pharmacokinetics (PK) of selumetinib for the first time in Chinese paediatric and adult patients with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN). In NF1, neurofibromin is dysfunctional, causing constitutive activation of the rat sarcoma (RAS)–rapidly accelerated fibrosarcoma (RAF)–mitogen-activated protein kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) pathway.1 Patients with NF1 can develop PN that can cause pain, disfigurement, functional limitations, neurologic deficits and internal organ compression.2 Although surgery is a treatment option for PN, the risks often outweigh the benefits.2 Selumetinib (ARRY-142886, AZD6244), an oral MEK1/2 inhibitor, stops NF1–PN growth by blocking RAS signalling.3, 4 Based on results of the pivotal SPRINT trial,4 selumetinib was approved in the USA (aged ≥2 years), European Union (aged ≥3 years) and China (aged ≥3 years) for paediatric patients with NF1 and symptomatic, inoperable PN.5-7 In SPRINT, patients receiving selumetinib reported improvements in quality of life during treatment and durable PN shrinkage.4 However, there was an unmet need for clinical trials designed to evaluate the safety, PK and efficacy of selumetinib in Chinese patients with NF1–PN. This phase 1, single-arm study, conducted at two centres in China, evaluated selumetinib capsules at a dosage of 25 mg/m2 twice daily in two independent cohorts (adult and paediatric; Figure 1). We present data from the primary analysis, which was required for selumetinib registration in China, and was performed after the last dosed patient had completed their cycle 10 visit (data cut-off [DCO] 16 August 2022). At primary DCO, patients were expected to have completed two post-baseline response assessments (at cycles 4 and 8). Overall, 16 adult and 16 paediatric patients received selumetinib (Table 1). One adult discontinued treatment due to the patient's decision but remained on the study; all paediatric patients continued to receive treatment at primary DCO. The reported safety profile was consistent with the known safety profile of selumetinib.5, 6 All patients in the study experienced adverse events (AEs); most experienced treatment-related AEs (Table 2). The most common AEs in the adult and paediatric cohorts were dermatitis acneiform (n = 13; 81%) and pyrexia (n = 6; 38%), respectively; all were grade 1/2 events and were reported in SPRINT.4, 5 The most common treatment-related AEs were dermatitis acneiform (n = 13; 81%) in adult patients, and decreased blood albumin and paronychia in paediatric patients (both, n = 4; 25%). One (6%) adult patient reported a serious adverse event (SAE; grade 3 pulmonary tuberculosis, not treatment related) leading to dose interruption. One (6%) adult patient experienced an AE leading to dose reduction and two (13%) experienced AEs leading to dose interruption (Table 2). One (6%) paediatric patient reported SAEs (two grade 3 sepsis and one grade 3 urinary tract infection, neither were treatment related). Three (19%) paediatric patients experienced AEs leading to dose interruption; none experienced AEs leading to dose reduction (Table 2). Two (13%) adult patients and one (6%) paediatric patient reported grade ≥3 AEs; similar to SPRINT phase 2 Stratum 1, most AEs, such as increased blood creatine phosphokinase and paronychia, were grade 1/2.4 No grade 4 AEs were reported at primary DCO; no AEs led to death or selumetinib discontinuation. No unexpected clinically significant trends of change were observed for laboratory assessments, vital signs or electrocardiogram/echocardiogram in either cohort. No abnormal reports of bone growth or Tanner stages were reported in the paediatric cohort. Selumetinib was rapidly absorbed in both cohorts; median (range) time to reach maximum plasma concentration (Tmax) at steady state was 1.5 h (.5–1.6 h) and 1.5 h (.5–3.0 h) in the adult and paediatric cohorts, respectively (Table 3). In adults, the median (range) Tmax for a single dose (1.0 h [.5–1.5 h]) and at steady state (1.5 h [.5−1.6 h]; Table 3) observed in this study showed similarity with those published for White (1.0 h [1.0−4.0 h]) and Asian (1.0 h [1.0−4.0 h]) patients in a pooled analysis of healthy subjects.8 In adult and paediatric cohorts, the metabolite-to-parent ratios of area under the concentration–time curve (AUC) from time 0−12 h at steady state (AUC0−12 h,ss) and maximum plasma concentration (Cmax) at steady state (Cmax,ss) were ≤.074 and ≤.085, respectively, indicating a higher exposure to selumetinib than its active metabolite, N-desmethyl selumetinib. The single-dose Cmax reported in the paediatric and adult cohorts were 871 and 1285 ng/mL, respectively (Table 3). A rapid elimination profile was observed in both cohorts; selumetinib had a mean half-life of 7.49 and 7.20 h in adult and paediatric patients, respectively. There was no obvious accumulation after multiple dosing. In the adult cohort, AUC0−12 h,ss and Cmax,ss accumulation ratios were 1.34 and .96, respectively. In the paediatric cohort, AUC0−12 h,ss and Cmax,ss accumulation ratios were 1.51 and 1.29, respectively. Selumetinib had a systemic exposure temporal change parameter of AUC ≤1.13 and ≤1.26 in the adult and paediatric cohorts, respectively (Table 3). Low-to-moderate variability of PK exposure was observed in adult patients at steady state with a geometric coefficient of variation (gCV) of 20%−32% for AUC0−12,ss and Cmax,ss for selumetinib and its metabolite. In paediatric patients, moderate variability of PK exposure was observed at steady state with a gCV ranging from 32% to 44% for AUC0−12 h,ss and Cmax,ss for selumetinib and its metabolite (Tables 3 and S1). The observed selumetinib PK profile was similar to that seen in SPRINT9 and in a phase 1 Japanese trial.10 PK parameters of N-desmethyl selumetinib are in Table S1. The geometric mean plasma concentration–time profiles are shown in Figure S1. Selumetinib showed promising efficacy and improvements from baseline in health-related quality of life in both cohorts (Supporting Information). Efficacy was a secondary endpoint. Therefore, these first published adult efficacy data should be interpreted with caution and considered preliminary. Efficacy and safety of selumetinib in adults with NF1–PN are being assessed in an ongoing randomised, double-blind, placebo-controlled, two-arm, global phase III study (KOMET; NCT04924608; 146 participants). Overall, within context of limitations (single-arm trial, small sample size), this study demonstrated that selumetinib has an acceptable benefit–risk profile. Therefore, selumetinib may address the unmet medical need for patients with NF1–PN in China. Conceptualisation: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Yangbo Liu, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Resources: Zhichao Wang, Xin Zhang, Qingfeng Li, Xiaoyun Ge and Xiaojun Yuan. Data curation: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Software: Zhichao Wang, Xin Zhang, Qingfeng Li and Xiaojun Yuan. Formal analysis: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Yangbo Liu, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Supervision: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Yangbo Liu, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Funding acquisition: Zhichao Wang and Qingfeng Li. Validation: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Yangbo Liu, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Investigation: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Visualisation: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Methodology: Zhichao Wang, Xin Zhang, Qingfeng Li, Yangbo Liu, Jiajia Zhao and Xiaojun Yuan. Writing—original draft: Zhichao Wang, Xin Zhang, Qingfeng Li and Xiaojun Yuan. Project administration: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Writing—review and editing: Zhichao Wang, Xin Zhang, Qingfeng Li, Chunyan Li, Xiaoyun Ge, Jiajia Zhao and Xiaojun Yuan. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Connie Feyerherm, MSci, and Emily Clark, PhD, of OPEN Health Communications (London, UK) and funded by Alexion, AstraZeneca Rare Disease and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in accordance with Good Publications Practice 2022 guidelines. We would like to acknowledge the SPRINT study team for providing data from their clinical trial used in this manuscript. The SPRINT study (NCT01362803) led by Drs. Brigitte Widemann and Andrea Gross was sponsored by the NCI Cancer Therapy Evaluation Program, and conducted under a Cooperative Research Development Agreement between NCI and AstraZeneca with additional support from the Neurofibromatosis Therapeutic Acceleration Program and the Children's Tumor Foundation. This study was funded by AstraZeneca as part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Z.W. and Q.L. received research grants from the National Natural Science Foundation of China and the Science and Technology Commission of Shanghai Municipality. Z.W., X.Z., C.L., X.G., Y.L., J.Z., X.Y. and Q.L. received support for the clinical study from AstraZeneca as part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, editorial/medical writing assistance from Connie Feyerherm and Emily Clark of OPEN Health Communications (London, UK), and financial support from Alexion, AstraZeneca Rare Disease. J.Z., Y.L., X.G. and C.L. report employment at AstraZeneca. The clinical study protocol and participant informed consent documents were submitted to the Ethics Committee for review and were approved before the initiation of the study (paediatric, XHEC-A-2020-019-1; adult, SH9H-2020-C9-3). All the participants provided written informed consent. All authors declare that they agree to publish this present manuscript with no conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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