Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas

Abstract

Background: Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies.

Methods: This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index).

Results: For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment.

Conclusions: With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.

Keywords: MEK Inhibitors; Neurofibromatosis type 1; Plexiform Neurofibromas.

Figure 1.

Waterfall plots for phase 1 and phase 2, stratum 1 with data cutoff (DCO) of February 27, 2021. Includes each participant’s best tumor volumetric response (gray bar) and most recent response prior to DCO (black bar). Partial response (PR) was defined as >20% tumor shrinkage from baseline (dashed line) and progressive disease (PD) was defined as >20% increase from baseline OR from best response if there was a prior PR (marked by asterisks). (A) phase 1, (B) phase 2, Stratum 1.

Figure 2.

Swimmers plots of treatment course for phase 1 (A) and phase 2, stratum 1 (B) through data cutoff (DCO). Each participant’s duration of treatment is illustrated by the bars above. The cycle at which the participant began a confirmed partial response (cPR) (blue dot) or had progressive disease (PD) (red dot) are marked as applicable. The dark gray bars indicate those who had a durable tumor response response (≥ 12 cycles). Participants with progressive tumors at study entry (≥20% increase in plexiform neurofibromas volume within 15 months before enrollment) are marked with purple triangles at the beginning of each bar. The participant’s tumor and treatment status as of the last restaging evaluation prior to DCO is indicated at the end of each bar, including: off treatment (black line), on treatment with stable disease (white triangle), or on treatment with continued partial response (blue triangle). Dose reductions are marked with yellow squares (first dose reduction) and diamonds (second dose reduction). Data included through first-time participants were taken off treatment. (A) phase 1 (n = 24), (B) phase 2, stratum 1 (n = 50).

Figure 3.

Progression-free survival (PFS) on selumetinib: Individual phase 1 and phase 2 (stratum 1) PFS curves (3A) and combined curve (3B). Median PFS for phase 2, stratum 1 not reached. Median PFS for phase 1 was approximately 4 years (52 cycles of treatment). Median PFS for the combined phase 1 and 2 cohort was approximately 6.7 years (88 cycles of treatment), significantly longer than the previously published age-matched natural history cohort with median PFS of 1.3 years.

Figure 4.

Target plexiform neurofibroma percent volume change for participants who achieved a partial response but then had disease progression (≥ 20% volume increase from best response) and remained on treatment (n = 12).

Figure 5.

Patient-and observer-reported outcome measures of pain through 48 cycles of treatment on selumetinib show continued improvement in tumor-related pain intensity and pain interference for those who remained on treatment. (A) Self-reported numeric rating score-11 (NRS-11) Scores, (B) Self-reported pain interference index (PII) Scores, (C) Parent-reported PII Scores.