Hirbe, Angela C.

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.

Abstract BACKGROUND PN in patients (pts) with NF1 can cause pain, disfigurement, impaired quality of life (QoL), and it can undergo malignant transformation. ReNeu (NCT03962543), a multicenter, open-label, phase 2b study, evaluated efficacy and safety of the highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in adults (≥18 y) and children (2-17 y) with inoperable NF1 PN causing significant morbidities. MATERIAL AND METHODS Mirdametinib was administered as a capsule or dispersible tablet (2 mg/m2 BID, max 4 mg BID) without regard to food in 3 wk on/1 wk off 28-d cycles. The primary endpoint was confirmed objective response rate (ORR; percentage of pts with confirmed MRI-assessed ≥20% reduction of target PN volume by blinded independent central review [BICR] within the 24-cycle treatment phase). The minimum clinically relevant ORR (null) was defined as 23% for adults and 20% for children. Pts could continue treatment in an optional long-term follow-up (LTFU) phase. Additional key endpoints were duration of response (DoR), time to response (TTR), change from baseline in target PN volume, worst pain severity (Numerical Rating Scale-11 [NRS-11]), pain interference (Pain Interference Index [PII]), health-related (HR) QoL (PedsQL), and safety. RESULTS All 114 pts (58 adult, 56 children) received mirdametinib. As of the 20 Sept 2023 data cutoff (DCO), BICR-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P<.001 vs null) in adults and 52% (95% CI, 38-65; P<.001 vs null) in children. Two adults and 1 child had a confirmed response in the ongoing LTFU. Median (range) target PN volumetric best response from baseline was -41% (-90, 13) and -42% (-91, 48) in adult and children, respectively. As of the DCO, median treatment duration was 22 mo for each cohort, and median DoR was not reached. Median (range) TTR was 7.8 (4-19) mo in adults and 7.9 (4-19) mo in children. Adults and children had statistically significant improvements from baseline to Cycle 13 in NRS-11, PII, and key PedsQL measures. Most frequent (≥35% pts) treatment-emergent adverse events (TEAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults and diarrhea, dermatitis acneiform, and vomiting in children. 16% and 25% of adults and children, respectively, had grade ≥3 treatment-related AEs, and 22% and 9%, respectively, discontinued due to TEAEs. CONCLUSIONS In ReNeu, the largest multicenter NF1 PN trial reported to date, mirdametinib demonstrated a statistically significant ORR by BICR, with deep and durable PN volume reductions, significant improvements in pain severity, pain interference, and HRQoL, and a manageable safety profile in both adults and children. Together with a dispersible tablet formulation, these results underscore the potential of mirdametinib to become an important new treatment option for NF1 PN pts across all ages.

Abstract Purpose: Early detection of neurofibromatosis type 1 (NF1)–associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. In this study, we describe a cell-free DNA (cfDNA) fragmentomic approach that distinguishes nonmalignant, premalignant, and malignant forms of PNST in the cancer predisposition syndrome, NF1. Experimental Design: cfDNA was isolated from plasma samples of a novel cohort of 101 patients with NF1 and 21 healthy controls and underwent whole-genome sequencing. We investigated diagnosis-specific signatures of copy-number alterations with in silico size selection as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end motifs, and fragment non-negative matrix factorization signatures. Results: The novel cohort of patients with NF1 validated that our previous cfDNA copy-number alteration–based approach identifies malignant PNST (MPNST) but cannot distinguish between benign and premalignant states. Fragmentomic methods were able to differentiate premalignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Conclusions: Novel cfDNA fragmentomic signatures distinguish AN from benign plexiform neurofibromas and MPNST, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant PNST in NF1 and provides a blueprint for decentralizing noninvasive cancer surveillance in hereditary cancer predisposition syndromes.

3016 Background: PN in patients (pts) with NF1 can cause pain, disfigurement, impaired quality of life (QoL), and can undergo malignant transformation. ReNeu (NCT03962543), a multicenter, open-label, Phase 2b study, evaluated efficacy and safety of the highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in adult (≥18 y) and pediatric (2-17 y) pts with inoperable NF1 PN causing significant morbidities. Methods: Mirdametinib was administered as a capsule or dispersible tablet (2 mg/m 2 BID, max 4 mg BID) without regard to food in 3 wk on/1 wk off 28-d cycles. The primary endpoint was confirmed objective response rate (ORR; percentage of pts with MRI-assessed ≥20% reduction of target PN volume by blinded independent central review [BICR] within the 24-cycle treatment phase). The minimum clinically relevant ORR (null) was defined as 23% for adults and 20% for pediatrics. Ptscould continue treatment in an optional long-term follow-up (LTFU) phase. Additional key endpoints were duration of response (DoR), time to response (TTR), change from baseline (BL) in target PN volume, pain severity (Numerical Rating Scale-11 [NRS-11]), pain interference (Pain Interference Index [PII]), health-related (HR) QoL (PedsQL), and safety. Results: All114 pts (58 adult, 56 pediatric) received mirdametinib. As of the 20 Sept 2023 data cutoff (DCO), BICR-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P<.001 vs null) in adults and 52% (95% CI, 38-65; P<.001 vs null) in pediatric pts. Two adult pts and 1 pediatric pt also had a confirmed response in the ongoing LTFU. Median (min, max) target PN volumetric best response from BL was -41% (-90, 13) and -42% (-91, 48) in adult and pediatric pts, respectively. As of the DCO, median treatment duration was 22 mo for each cohort and median DoR was not reached. Median (range) TTR was 7.8 (4-19) mo in adult pts and 7.9 (4-19) mo in pediatric pts. Adult and pediatric pts had statistically significant improvements from BL to cycle 13 in NRS-11, PII, and key PedsQL measures. Most frequent (≥35% pts) treatment-emergent adverse events (TEAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults and diarrhea, dermatitis acneiform, and vomiting in pediatric pts. 16% and 25% of adult and pediatric pts, respectively, had grade ≥3 treatment-related AEs, and 22% and 9%, respectively, discontinued due to TEAEs. Conclusions: In ReNeu, the largest multicenter NF1 PN trial reported to date, mirdametinib demonstrated a statistically significant ORR by BICR, with deep and durable PN volume reductions, significant improvements in pain severity, pain interference, and HRQoL, and a manageable safety profile in both adults and children. Together with a dispersible tablet formulation, these results underscore mirdametinib’s potential to become an important new treatment option for NF1 PN pts across all ages. Clinical trial information: NCT03962543 .

Abstract Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ–CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ– CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. Results: 44 patients enrolled and 42 started trametinib. TAZ– CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094–19.0], median PFS was 10.4 months (95%CI, 7.1–NA), and 2-year OS rate was 33.3%(95%CI, 19.1–58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib. Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552

11505 Background: Potentiation of chemotherapy, without increased toxicity, to improve outcome is an area of interest. Preclinical and clinical evidence shows simultaneous utilization of antiangiogenic agents and chemotherapy have a synergistic effect. We hypothesized that the dual targeting of VEGF and c-MET pathways with cabozantinib (CAB) would result in clinical benefit for patients with soft tissue sarcoma (STS) when combined with temozolomide (TMZ), an alkylating agent. Utilization of CAB/TMZ is anticipated to produce a synergistic antitumor effect worthwhile to explore in STS. Methods: A multicenter phase II study of CAB/TMZ in patients with unresectable/metastatic leiomyosarcoma (LMS) and other STS was conducted by the Midwest Sarcoma Trials Partnership. Age ≥ 18, adequate performance status, organ function, measurable disease (RECIST 1.1), and 0-5 prior chemotherapy regimens were required. CAB 40 mg PO daily plus TMZ 150-200 mg/m2 PO 1-5 days were given in 28-day cycles until disease progression or unacceptable toxicity. Patients enrolled in 2 cohorts: 1. Uterine and non-uterine LMS 2. Other STS. The first 14 subjects to be enrolled in the study in either cohort served as a safety lead in. The primary endpoint was progression-free rate (PFR) at 12 weeks for cohort 1. Secondary endpoints include overall response rate (ORR), clinical benefit rate, median progression-free survival (PFS), overall survival, and safety and tolerability. The exploratory endpoint was to estimate the correlation of PFR and OS to expression levels of VEGF, amongst others. A Simon 2-stage design was used. Results: A total of 42 patients were enrolled in Cohort 1, and 30 in Cohort 2, across 5 sites. For Cohort 1, median age was 59 years (range 35-86), 85.7% were non-Hispanic, 73.8% were female, 61.9% had ECOG of 0. The PFR at 12 weeks was 45.9% (for 37 evaluable patient) with a median PFS of 6.4 months (95% CI 4.6-6.7). Five PR were observed for an ORR of 13.5%. For Cohort 2, median age was 63 (20-86), 83.3% were non-Hispanic, 36.7% were female, 53.3% had ECOG of 0. The PFR at 12 weeks was 50% (for 28 evaluable patients) with a median PFS of 3.2 months (95% CI 1.4-4.6). One PR was observed. Reported grade 3-4 adverse events attributed to one or both intervention drugs affecting ≥10% of patients (n = 70) included hypertension (10%), decreased neutrophils (18.7%), decreased platelets (31%). Conclusions: The combination therapy of CAB/TMZ in patients with unresectable or metastatic LMS exceeded its primary endpoint with a PFR at 12 weeks > 39%. The PFS of 6.4 months in Cohort 1 exceeds rates achieved with second line tyrosine kinase inhibitors (TKIs) and alkylators in LMS patients. Treatment was feasible and did not reveal any previously unreported toxicities. The combination with CAB with TMZ demonstrated meaningful clinical benefit and is worth further exploration in LMS. Clinical trial information: NCT04200443 .