Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886 Hydrogen Sulfate) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN).

Abstract

3612 Background: NF1-related PN are locally invasive tumors characterized by increased activation of the RAS pathway causing significant morbidity including disfigurement, pain and functional limitations. Selumetinib has received breakthrough designation for NF1 PN based on phase I / II trials in children. We present results for the ongoing phase II study of selumetinib in adults with NF1 PN, which includes pharmacodynamic (PD) evaluation of serial tumor biopsies as well as functional/patient-reported outcomes (PROs). Methods: Open-label Simon 2-stage design. Eligibility: NF1 patients (pts) ≥18 years old with inoperable/symptomatic/progressive PN. First 2 pts received selumetinib 75 mg BID; subsequent pts received selumetinib 50 mg BID. Primary objective: response rate by volumetric MRI analysis (partial response [PR]; ≥20% volume decrease). Secondary objectives: PD studies on pre/on-treatment biopsies of PN and cutaneous neurofibromas, assessment of clinical benefit using PROs (Numeric Rating Scale-11, Pain Interference Index), and PN-specific functional assessments. Validated, fit-for-purpose, isozyme-specific measurements of pERK/ERK/pMEK/MEK performed using SOPs designed for labile phosphoproteins (PMID 27001313). Results: As of February 2020, 27 pts have enrolled. Outcomes are reported for 23 pts (74% male; median age 33 years, range 18-60). Most common PN-related morbidity: pain (19 pts). Sixteen pts achieved PR (69%), with 13/16 confirmed; no disease progression. Time to response: 11 months (range 5-25); median change in PN volume at best response: -22% (range -41% to +5.5%); median duration of treatment: 28 months (range 2-50). Selumetinib suppressed tumor pERK1,2/ERK1,2 but not pMEK1,2/MEK1,2 ratios from 1-10 hours following oral dosing (one t½). Pt-reported target tumor pain intensity and pain interference scores significantly improved (both p < 0.03). Pts 1 and 2 were dose-reduced due to grade 3 intolerable rash (n = 2) and pain (n = 1). Grade ≥3 drug-related toxicities on 50 mg (21 pts) include transaminitis (5 pts), rash (1 pt) and pancreatic enzyme elevation (1 pt). Two pts were dose reduced (rash = 1 pt, transaminitis = 1 pt). Two pts discontinued by choice, 2 pts withdrawn by PI (best interest of patient), and 1 pt each removed for transaminitis, surgical resection, serious concurrent medical illness, and non-compliance. Conclusions: Selumetinib shrinks the majority of adult PN and results in molecular target suppression and clinical benefit. Clinical trial information: NCT02407405 .

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review

“…Searches were updated on 28 February 2021. undergoing screening (Figure 2). Nine reports from eight clinical trials have communicated results on the efficacy of novel targeted therapies in patients with NF1 and PNs (Table 1), [17][18][19][20][21][22][23][24][25] and eight of them have reported positive results. Nine trials are ongoing (Table 2).…”

“…[26][27][28][29][30][31][32][33][34] Out of the eight reports with positive results [17][18][19][20][21][22][23][24] (seven trials, one of them 18 with two strata reported separately 18,19 ), four have been published in peer-reviewed scientific journals 17,18,21,22 and the other four have been communicated as abstracts in international congresses. 19,20,23,24 All the studies included in the final analysis are single-arm phase I/II trials and included between 19 and 50 patients. Four of the trials with positive results were focused on children and adolescents [17][18][19]23,25 and three on adults with progressive/symptomatic inoperable PNs.…”

“…Four of the trials with positive results were focused on children and adolescents [17][18][19]23,25 and three on adults with progressive/symptomatic inoperable PNs. [20][21][22] Two trials also included patients with inoperable PNs that did not necessarily cause symptoms. 17,19 Selumetinib [17][18][19][20] 23 and binimetinib (n ¼ 1) 24 were the MEK inhibitors used in the trials.…”

“…[20][21][22] Two trials also included patients with inoperable PNs that did not necessarily cause symptoms. 17,19 Selumetinib [17][18][19][20] 23 and binimetinib (n ¼ 1) 24 were the MEK inhibitors used in the trials. Other targeted therapies include cabozantinib (n ¼ 1).…”

“…Mirdametinib (PD-0325901) is an oral, non-ATPcompetitive, highly selective, and potent small-molecule Selumetinib [18] Selumetinib [19] Trametinib [23] Binimetinib [24] Selumetinib [20] Cabozantinib [21] Mirdametinib [22] Children Adults Overall response rate (%)…”