Moertel, Christopher L.

Background Neurofibromatosis type 1 (NF1) is a genetic disorder in which plexiform neurofibromas (PNs) develop in approximately 30% to 50% of affected individuals, often causing substantial morbidity. Treatment of NF1-associated PNs is challenging due to disease variability and tumor complexity. Observations In the Phase 2b ReNeu trial (NCT03962543), mirdametinib, a mitogen-activated protein kinase kinase 1/2 (MEK) inhibitor, demonstrated efficacy and a manageable safety profile in children and adults with symptomatic PNs, achieving confirmed objective responses in 52% of children and 41% of adults, with substantial reductions in target tumor PN volume and improvements in patient- and parent proxy-reported outcomes. However, dermatologic adverse events (AEs) are common with MEK inhibitors, including mirdametinib, and can impact adherence and quality of life. While the ReNeu protocol included supportive care considerations for skin reactions associated with mirdametinib, some investigators recognized a need for more detailed guidance. The ReNeu Scientific Steering Committee, in collaboration with oncology and oncodermatology experts, developed expert-driven recommendations for the proactive management of mirdametinib-related skin AEs. Conclusions These strategies emphasize early recognition, individualized care, and timely intervention to help reduce the severity of mirdametinib-related skin AEs, minimize dose modifications, and support treatment continuity and long-term treatment goals. Although these recommendations were specifically developed for mirdametinib based on ReNeu trial experience, they may also provide practical guidance for managing skin AEs associated with other MEK inhibitors in clinical practice.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children ≥2 years with NF1 who have symptomatic PN not amenable to complete resection. We report results from the phase 2b ReNeu trial (NCT03962543), including the LTFU. METHODS In ReNeu, mirdametinib was administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle treatment phase, patients could continue mirdametinib in an optional LTFU. We report results through June 12, 2024, approximately 9 months from the previous data cutoff. RESULTS Fifty-eight adults and 56 children received mirdametinib. Median (range) duration of treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered LTFU. Confirmed objective response rate (ORR, treatment+LTFU phases) was 47% (27/58; 95%CI, 33%, 60%) in adults and 55% (31/56; 95%CI, 42%, 69%) in children. Among confirmed responders, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of >50%). Median (range) best percentage change from baseline in target PN volume was –41% (–90%, 13%) in adults and –43% (–98%, 48%) in children. Median duration of response (DoR) was not reached for either age cohort. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhea, nausea, and vomiting in adults; and diarrhea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and 14%, 14%, and 9%, respectively, of children. CONCLUSIONS Improved confirmed ORR was observed with longer duration of mirdametinib, with additional deep responses achieved in both adults and children. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals in the LTFU.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2y) with symptomatic NF1-PN. In ReNeu, symptomatic improvement and PN volume reductions were observed at the earliest assessments (~91 and ~152 days, respectively) and were sustained. This analysis evaluated time to first onset and resolution of commonly reported TRAEs in the ReNeu trial. METHODS Data cutoff (DCO) was September 20, 2023. Median time to first onset and resolution (days) for common TRAEs (≥15%) were evaluated for prepubescents (≥2 to <12y, n=32), postpubescents (≥12 to <18y, n=24), younger adults (≥18 to ≤50y, n=48), and older adults (>50y, n=10). RESULTS Common TRAEs were mostly grades 1 to 2 (83%). In prepubescents, median day (range) of onset was 32 (14, 263) for vomiting, 71 (19, 386) for dermatitis acneiform, 123 (1, 663) for diarrhea, 124 (52, 775) for paronychia, and 127 (2, 663) for nausea. For postpubescents, median day (range) of onset was 8 (1, 438) for diarrhea, 8 (2, 574) for nausea, 12 (1, 252) for dermatitis acneiform, 28 (2, 354) for vomiting, and 110 (43, 245) for paronychia. In younger adults, median day (range) of onset was 5 (1, 352) for nausea, 8 (2, 15) for dermatitis acneiform, 9 (2, 73) for diarrhea, and 29 (1, 264) for vomiting. For older adults, median day (range) of onset was 4 (1, 286) for diarrhea, 9 (2, 15) for nausea, and 13 (2, 38) for dermatitis acneiform. Time to resolution was variable between TRAEs and among patients in all age groups; 90% resolved completely by DCO. Among all patients, 18 had a TRAE of asymptomatic ejection fraction decrease, with all but one resolving by DCO. CONCLUSIONS Overall, common TRAEs arose before treatment benefits and were generally resoluble by DCO. Proactively managing TRAEs may improve treatment experience and adherence.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2 years) with NF1 who have symptomatic PN not amenable to complete resection. We report updated results from the LTFU phase of the pivotal, phase 2b ReNeu trial (NCT03962543) evaluating the efficacy and safety of mirdametinib. MATERIALS AND METHODS In ReNeu, mirdametinib capsules or tablets for oral suspension (2 mg/m2 BID, max 4 mg BID) are administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle (~2 years) treatment phase, patients could continue mirdametinib in an optional LTFU phase. These analyses are inclusive of the treatment and LTFU phases (data cutoff: June 12, 2024; an additional 9 months of cumulative data following the primary analysis). Exploratory analyses reported here included confirmed objective response rate (ORR; proportion of patients with ≥20% reduction of target PN volume from baseline on consecutive MRI scans within 2 to 6 months, assessed by blinded independent central review), duration of response (DoR), change from baseline in target PN volume, and safety. RESULTS Fifty-eight adults and 56 children were dosed with mirdametinib. Median (range) duration of mirdametinib treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered the LTFU. Confirmed ORR was 47% (27/58; 95% CI, 33%, 60%) in adults and 55% (31/56; 95% CI, 42%, 69%) in children. Of patients with a confirmed objective response, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of >50%). Median (range) best percentage change from baseline in target PN volume was -41% (-90%, 13%) in adults and -43% (-98%, 48%) in children. Median DoR was not reached. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhoea, nausea, and vomiting in adults, and diarrhoea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and in 14%, 14%, and 9%, respectively, of children. CONCLUSIONS An increase in confirmed ORR was observed with longer duration of mirdametinib treatment, with additional deep responses achieved in both adults and children with NF1-PN. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals identified in the LTFU phase. SUPPORTED BY SpringWorks Therapeutics, Inc.

Abstract Patients with NF1-PN experience pain and other symptoms that negatively impact functioning and quality-of-life. We present patient- and parent proxy-reported HRQoL outcomes from ReNeu (NCT03962543), a pivotal, phase 2b trial of mirdametinib, an investigational MEK1/2 inhibitor, in adults and children (≥2 y) with NF1-PN causing morbidities. Fifty-eight adults and 56 children received mirdametinib (2 mg/m2 BID; 3-weeks-on/1-week-off, 28-d cycles). Change in HRQoL was assessed by Pediatric QoL Inventory (PedsQL) 4.0 Generic Core Scales from baseline across the 24-cycle treatment phase; change from baseline at Cycle 13 (C13) was a prespecified secondary endpoint. PedsQL is a HRQoL measure for adults and children with a Total Score (TS) and 4 subscales: physical, emotional, social, and school/work. Items are reported on a 0-100 scale (higher scores=better HRQoL). Clinically meaningful improvement was defined as change from baseline >9.7 points for adults, >8.5 points for child self-report, and >9.0 points for parent proxy-report. PedsQL-TS improvement (least-squares mean, LSM [SE] change) from baseline at C13 was 3.9 (1.6; P=.018; n=34) for adults, 4.0 (2.4; P=.096; n=38) for children by self-report, and 5.6 (1.9; P=.005; n=43) by parent proxy-report. PedsQL-TS improvements for adults and children by parent proxy-report (not by children self-report) were observed early (at C5 and C3, respectively) and sustained through C24. Clinically meaningful improvement in PedsQL-TS from baseline at C13 was achieved by 37% (10/27) adults, 45% (13/29) children by self-report, and 47% (15/32) children by parent proxy-report (among patients who could have achieved a clinically meaningful change from baseline). Significant (P<.05) improvement from baseline to C13 was reported for physical (adults, children, and parent proxy-report), school/work (adults), and emotional and social (parent proxy-report) subscales. Adults and children (by parent proxy-report) with NF1-PN had clinically meaningful, early, and sustained improvement in HRQoL over the course of mirdametinib treatment.

Abstract ReNeu (NCT03962543) is a trial of the investigational, oral, selective MEK1/2 inhibitor (MEKi) mirdametinib in adults (≥18 years) and children (2-17 years) with NF1-PN. Skin adverse events (AEs) were common in ReNeu, and some discontinuations were noted with low-grade AEs. A multidisciplinary team retrospectively reviewed skincare practices at one high-enrolling site (n=12) with no discontinuations due to skin AEs; these were incorporated into ReNeu trial recommendations and recently updated. The purpose was to prevent/manage skin AEs and maintain protocol treatment adherence. MEKi skin AEs vary by pubertal status, therefore recommendations also vary by pubertal status. All patients were counseled to adopt hygienic skincare practices, including bathing daily, and using mild cleansers and hypoallergenic skin moisturizers (cream or ointment-based emollient; minimum BID) to prevent dry skin. Prepubescent patients were advised to incorporate diluted bleach baths (3-4 times/week) when initiating mirdametinib or after rash development. Treatments recommended for mild-to-severe dermatitis were hydrocortisone cream (2.5% BID) on face/skinfold areas and triamcinolone ointment (0.1% BID) on trunk/extremities. Treatments for mild acneiform eruptions included topical clindamycin lotion (1.0% BID) until resolution, with optional hydrocortisone cream (2.5% BID). For moderate-to-severe acneiform eruptions, cephalexin (20 mg/kg/day divided BID, max 500 mg, ≤6 weeks), amoxicillin (25 mg/kg/day divided BID, max 875 mg, ≤6 weeks), or oral fluconazole (20 mg/kg/day, max 100 mg, 5 days then once weekly for 3 months) were suggested. Postpubescent patients were advised to initiate topical 1.0% clindamycin lotion and oral doxycycline or minocycline (50-mg daily, 3 months) with mirdametinib initiation. Patients with subsequent mild-to-severe acneiform eruptions were advised to apply hydrocortisone cream (2.5% BID) or triamcinolone ointment (0.1% BID). Referral to a dermatologist was suggested for all patients with uncontrolled dermatitis, worsening acneiform eruptions, or infection. Proactive skincare practices appeared effective at this site, but prospective validation is necessary before making clinical recommendations.

Abstract BACKGROUND Patients with NF1-PN in the phase 2b ReNeu trial (NCT03962543) of mirdametinib in adults (N=58, ≥18y) and children (N=56, 2-17y) had a deeper median (range) best reduction (adults: -41% [-90% to 13%]; children: -42%, [-91% to 48%]) from baseline in target PN volume than previously published in trials of other agents in NF1-PN. METHODS In the 24-cycle (1-cycle=28d) treatment phase, objective response rate (ORR) was the percentage with confirmed objective responses (OR) of ≥20% target PN volume reduction from baseline on consecutive MRIs (by blinded independent central review). This analysis includes patients achieving deep response (>50% best reduction from baseline in target PN volume) regardless of OR and inclusive of patients in the long-term follow-up. Exploratory analysis of baseline characteristics compared patients with deep response and patients with ≤50% volume reduction. RESULTS ORR was 41% (24/58) in adults and 52% (29/56) in children treated with mirdametinib. 62% (15/24) of adults and 52% (15/29) of children who achieved OR had deep response. To further characterize deep response, 2 adults and 3 children with deep response without confirmation or in long-term follow-up were included. Of those with a deep response, 35% (6/17) of adults and 72% (13/18) of children were investigator-defined as having progressing PN. Patients achieved deep response regardless of baseline age, sex, target PN volume, tumor location, or progression status. For adults and children, median time to best percent change from baseline in PN volume for patients achieving deep response was 25.4 and 21.8mo; for patients with reductions of ≥20% to ≤50% was 15.3 and 15.2mo; for patients with reductions of <20% was 7.8 and 4.2mo, respectively. CONCLUSIONS Patients had a similar likelihood of achieving deep response across assessed baseline characteristics. A trend between deep response and longer treatment duration suggests a benefit of prolonged therapy with mirdametinib.

PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration–approved for adults. METHODS ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. RESULTS Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was –41% (−90 to 13) in adults and –42% (−91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. CONCLUSION In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.