Koselugo (selumetinib) / Merck (MSD), AstraZeneca, Pfizer - LARVOL DELTA

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=2316 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2027 ➔ Jun 2025 | Trial primary completion date: Sep 2027 ➔ Jun 2025

Biomarker • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

AMC team proves new neurofibromatosis drug selumetinib’s effects in adult patients for 1st time worldwide (Korea Biomedical Review) - P=NA | N=89 | "Asan Medical Center (AMC) said Thursday that a research team analyzed the outcomes of 89 patients treated with selumetinib for neurofibromatosis type 1 and plexiform neurofibromas between May 2019 and December 2021, up to 104 weeks after treatment, and found that plexiform neurofibromas decreased in size by an average of about 41 percent....Eighty-eight of 89 patients (98.9 percent) had an average reduction of 40.8 percent in their plexiform neurofibromas. One patient did not respond to treatment. Eighty-one (91 percent) patients had a “partial response,” meaning a reduction in tumor size of 20 percent or more. Of the 89 patients, 59 pediatric patients under 19 had an average reduction of about 39 percent in the size of their plexiform neurofibromas, and 30 adults over 19 had a reduction of about 42 percent."

Clinical data • Neurofibromatosis • Oncology

A Mixed Methods Study of Medication Adherence in Adults with Neurofibromatosis Type 1 (NF1) on a Clinical Trial of Selumetinib. (PubMed, Cancers (Basel)) - "This study highlights patient characteristics that may be related to increased risk for nonadherence, as well as challenges with electronic pill caps that should be considered in future clinical trials for NF1-related PN. Results can inform future adherence interventions for adults with NF1 and PNs. Future research with larger samples is needed to fully explore factors related to long-term medication adherence among individuals with NF1."

Journal • CNS Disorders • Depression • Genetic Disorders • Neurofibromatosis • Oncology • Psychiatry • Solid Tumor • NF1

AZD6244 (ARRY-142886) Solid Oral Dosage Formulation in Participants With Advanced Solid Malignancies (clinicaltrials.gov) - P1 | N=58 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Oncology • Solid Tumor

A Phase I, Open-Label, Multi-center Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD6244 (ARRY-142886) (clinicaltrials.gov) - P1 | N=140 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Breast Cancer • Colon Cancer • Colorectal Cancer • Genito-urinary Cancer • Kidney Cancer • Lung Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor

Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma (clinicaltrials.gov) - P1/2 | N=220 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Jul 2026 | Trial primary completion date: Dec 2025 ➔ Jul 2026

Trial completion date • Trial primary completion date • Astrocytoma • Brain Cancer • CNS Tumor • Genetic Disorders • Glioma • Neurofibromatosis • Oncology • Pediatrics • Pilocytic Astrocytoma • Solid Tumor • BRAF

Disproportionate adverse event signals of selumetinib in neurofibromatosis type I: insights from FAERS. (PubMed, Front Pharmacol) - "The study underscores the importance of early detection and management of adverse reactions associated with Selumetinib, particularly within the initial month of treatment. These findings provide valuable insights for clinicians and regulators to ensure the safe and effective use of Selumetinib in NF1 patients."

Adverse events • Journal • Dermatitis • Dermatology • Genetic Disorders • Immunology • Neurofibromatosis • Ophthalmology • Rare Diseases • Solid Tumor • NF1

Selumetinib in adults with NF1 and inoperable plexiform neurofibroma: a phase 2 trial. (PubMed, Nat Med) - P2 | "The sustained PN volume decreases, associated improvement in pain and manageable AE profile indicate that selumetinib provides benefit to adults with NF1 and inoperable PNs. ClinicalTrials.gov identifier: NCT02407405 ."

Journal • P2 data • Genetic Disorders • Neurofibromatosis • Oncology • Pain • Pediatrics • Solid Tumor • AKT1 • NF1

Selumetinib for children with neurofibromatosis type 1 and plexiform neurofibromas that can't be removed by surgery, and impact on how the condition affects caregivers: a plain language summary. (PubMed, J Comp Eff Res) - "Caring for a child with NF1 and symptomatic, inoperable plexiform neurofibromas has a significant impact on family members and others providing daily care. This highlights the importance of improving treatment and quality of life for both children with the condition and their caregivers."

Journal • Review • Genetic Disorders • Neurofibromatosis • Oncology • Otorhinolaryngology • Pain • Solid Tumor • NF1

N6-Methylandenosine-related lncRNAs as potential biomarkers for predicting prognosis and the immunotherapy response in pancreatic cancer. (PubMed, Cell Mol Life Sci) - "Drugs such as WZ8040, selumetinib, and bortezomib were also identified as more effective for high-risk patients. Our results indicate that the m6A-related lncRNA risk model could be an independent prognostic indicator, which may provide valuable insights for identifying therapeutic approaches for PaCa."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • TMB

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Active, not recruiting | Sponsor: UNICANCER | Trial completion date: Dec 2024 ➔ Dec 2025

IO biomarker • Trial completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

TATTON: AZD9291 in Combination With Ascending Doses of Novel Therapeutics (clinicaltrials.gov) - P1 | N=344 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Koselugo showed statistically significant and clinically meaningful objective response rate vs. placebo in adults with neurofibromatosis type 1 in global KOMET Phase III trial (AstraZeneca Press Release) - P3 | N=146 | KOMET (NCT04924608) | Sponsor: AstraZeneca | "Positive high-level results of KOMET...showed that Koselugo (selumetinib), an oral, selective MEK inhibitor, met its primary endpoint, demonstrating a statistically significant and clinically meaningful objective response rate (ORR) versus placebo in these adult patients....In the trial, ORR was defined as the percentage of patients with confirmed complete response (disappearance of PNs) or partial response (at least 20% reduction in tumour volume) by cycle 16 (28 days per cycle) as determined by independent central review (ICR) per response evaluation in neurofibromatosis and schwannomatosis (REiNS) criteria. The safety profile of Koselugo in this study was consistent with that observed in clinical trials among children and adolescents. No new safety signals were identified."

P3 data • Neurofibromatosis

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=455 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Aug 2027 ➔ Feb 2031 | Trial primary completion date: Aug 2027 ➔ Feb 2031

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2024 ➔ Mar 2025

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CD8 • CDKN2A • FGFR • HRD • IFNG • IL10 • IL2 • IL6 • MYCL • MYCN • RB1

ZP3 Expression in Pancreatic Adenocarcinoma: Its Implications for the Prognosis and Therapy. (PubMed, Protein Pept Lett) - "ZP3 has the potential to serve as a prognostic biomarker and therapeutic target for patients with PAAD."

Journal • Tumor mutational burden • Immunology • Microsatellite Instability • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Primary Immunodeficiency • MSI • TMB

LS-NF1PNs: Low-dose Selumetinib for the Treatment of Plexiform Neurofibromas in Chinese Children (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: West China Hospital

New P2 trial • Genetic Disorders • Neurofibromatosis • Solid Tumor

Selumetinib in adults with NF1 and inoperable plexiform neurofibroma: a phase 2 trial (Nature, Nat Med) - P2 | N=36 | NCT02407405 | "The objective response rate was 63.6% (21/33 participants). Median maximal PN volume decrease was 23.6% (range: −48.1% to 5.5%). No disease progression relative to baseline PN volumes occurred before data cutoff, with a median of 28 cycles completed (range: 1–78, 28 d per cycle). Participants experienced decreased tumor pain intensity and pain interference. Adverse events (AEs) were similar to those of the pediatric trial; acneiform rash was the most prevalent AE. Phosphorylation ratios of ERK1/2 decreased significantly (ERK1 median change: −64.6% (range: −99.5% to 90.7%), ERK2 median change: −57.3% (range: −99.9% to 84.4%)) in paired PN biopsies (P ≤ 0.001 for both isoforms) without compensatory phosphorylation of AKT1/2/3."

P2 data • Neurofibromatosis • Oncology

Selumetinib in adults with NF1 and inoperable plexiform neurofibroma: a phase 2 trial (Nature, Nat Med) - P2 | N=36 | NCT02407405 | "The objective response rate was 63.6% (21/33 participants). Median maximal PN volume decrease was 23.6% (range: −48.1% to 5.5%). No disease progression relative to baseline PN volumes occurred before data cutoff, with a median of 28 cycles completed (range: 1–78, 28 d per cycle). Participants experienced decreased tumor pain intensity and pain interference. Adverse events (AEs) were similar to those of the pediatric trial; acneiform rash was the most prevalent AE. Phosphorylation ratios of ERK1/2 decreased significantly (ERK1 median change: −64.6% (range: −99.5% to 90.7%), ERK2 median change: −57.3% (range: −99.9% to 84.4%)) in paired PN biopsies (P ≤ 0.001 for both isoforms) without compensatory phosphorylation of AKT1/2/3."

P2 data • Neurofibromatosis • Oncology

Trial of Selumetinib and Bromodomain Inhibitor With Durvalumab for Sarcomas (clinicaltrials.gov) - P2 | N=41 | Not yet recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: Dec 2030 ➔ Jun 2031 | Trial primary completion date: Dec 2029 ➔ Jun 2030

Trial completion date • Trial primary completion date • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor

Investigates the Role of PANoptosis in Idiopathic Pulmonary Fibrosis and Potential Therapeutic Targets. (PubMed, J Inflamm Res) - "Additionally, potential therapeutic drugs, including Metergoline, Candesartan, and Selumetinib, were identified based on four prognostic genes. Molecular docking shows that these drugs have good binding ability with their targets. Importantly, our findings provide scientific evidence for the diagnosis and prognostic biomarkers of IPF patients, as well as small molecule therapeutic drugs."

Journal • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • AKT1 • PDCD4 • PSMA2 • TNFRSF12A • TNFRSF25

NF114: Selumetinib for the Prevention of Plexiform Neurofibroma Growth in NF Type 1 (clinicaltrials.gov) - P2 | N=200 | Not yet recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: Dec 2031 ➔ Mar 2032 | Trial primary completion date: Dec 2030 ➔ Mar 2031

Trial completion date • Trial primary completion date • Genetic Disorders • Neurofibromatosis • Solid Tumor

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=2316 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

Combined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer. (PubMed, Cancers (Basel)) - "The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted."

Journal • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Psychiatry • Solid Tumor • EGFR • KRAS

Alexion, AstraZeneca Rare Disease reaches an agreement with the pan-Canadian Pharmaceutical Alliance (pCPA) for Koselugo (selumetinib) for the treatment of paediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) (Canada Newswire) - "Alexion Pharma Canada Corp...has entered into a Letter of Intent (LOI) with the pan-Canadian Pharmaceutical Alliance (pCPA) for Koselugo for the treatment of paediatric patients aged two years and above with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). With the agreement in place with the pCPA, individual provinces and territories may now initiate the process to list Koselugo on their formularies, the timing of which will vary by province and territory. Following the agreement, the Province of Quebec was the first to list Koselugo and provide public reimbursement of the only approved therapy for eligible children living with NF1 PN."

Commercial • Reimbursement • Neurofibromatosis