pexmetinib (ARRY-614) / Pfizer - LARVOL DELTA

Phase Ib study of the p38 inhibitor ARRY-614 with nivolumab, ipilimumab or nivolumab+ipilimumab in advanced solid tumors (SITC 2022) - P1/2 | "Conclusions Inhibition of the p38 MAPK pathway with ARRY-614 is well tolerated at 200mg in combination with ICB, eliciting durable responses and disease control in poor risk and PD(L)1-refractory subjects. Trial Registration NCT04074967"

P1 data • Lung Cancer • Melanoma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • IL2

Clinical and translational study of p38 inhibitor pexmetinib plus nivolumab following anti–PD-1/L1 failure in advanced solid tumors. (ASCO 2026) - P1/2 | "In patients with PD1-refractory HN cancer and lung cancers, pexmetinib plus nivolumab demonstrated an acceptable safety profile and durable clinical benefit. Multimodal translational profiling revealed increased inflammatory cytokine signaling and radiomic and molecular features consistent with enhanced CD8⁺ T-cell engagement in responders. These findings suggest that targeting tumor-intrinsic p38 MAPK may represent a mechanistically informed strategy to overcome immunotherapy resistance."

Clinical • Metastases • Head and Neck Cancer • Immune Modulation • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CD8 • PD-1

Resistance to VEGFR inhibitors converges from molecular diversity in angiosarcoma cells (AACR 2025) - "However, therapeutic antibodies, such as bevacizumab (Avastin), and chemical inhibitors targeting VEGF pathways have shown limited clinical benefits in angiosarcomas...Then, we examined cellular response to VEGFR2 (Regorafenib, Sorafenib) and Tie2 inhibitors (Rebastinib, Pexmetinib) using cell growth inhibition assays...Furthermore, our results suggest angiosarcoma cells establish a functional convergence that potentiates the signaling activation of VEGF and Tie2 pathways, despite their molecular divergence. Our ongoing work aims to explore the molecular mechanisms promoting resistance to VEGF and Tie2 inhibitors."

Angiosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD31 • PECAM1

A succinylation-related prognostic model for predicting lung adenocarcinoma prognosis and guiding immunotherapy. (PubMed, Clin Proteomics) - "The above results indicated that the prognostic model established using SRGs can be a predictive marker for LUAD prognosis, offering references for LUAD treatment and evaluation."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab (clinicaltrials.gov) - P1/2 | N=70 | Active, not recruiting | Sponsor: Dan Zandberg | Trial completion date: Oct 2025 ➔ Dec 2025

Trial completion date • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4

Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab (clinicaltrials.gov) - P1/2 | N=70 | Active, not recruiting | Sponsor: Jason J. Luke, MD | Trial completion date: Nov 2027 ➔ Oct 2025 | Trial primary completion date: Nov 2027 ➔ Oct 2024

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4

Repurposing pexmetinib as an inhibitor of TKI-resistant BCR::ABL1. (PubMed, Leukemia) - No abstract available

Journal • ABL1

Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab (clinicaltrials.gov) - P1/2 | N=70 | Active, not recruiting | Sponsor: Jason J. Luke, MD | N=144 ➔ 70 | Trial completion date: Jun 2027 ➔ Nov 2027 | Trial primary completion date: Mar 2026 ➔ Nov 2027 | Recruiting ➔ Active, not recruiting

Enrollment change • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4

Screening of potent RIPK3 inhibitors to attenuate necroptosis and inflammation in mouse traumatic brain injury models. (PubMed, Exp Neurol) - "We found four compounds:1D6-Foretinib GSK1363089; 15F6-Poziotinib (HM781-36B); 15F9-Dasatinib monohydrate; 15A10-Pexmetinib (ARRY-614); acts as potent inhibitors of necroptosis (Necroptosis Blocking Compounds, NBCs) by blocking the RIPK3 kinase activity. In our study, we explored the role of NBCs in neuroprotection after traumatic brain injury. It's effectiveness in traumatic brain injury animal models and favorable safety profiles make it a potential candidate for the advances of new therapies for necroptosis-associated neuroinflammatory disorders."

IO biomarker • Journal • Preclinical • CNS Disorders • Infectious Disease • Inflammation • Oncology • Vascular Neurology • RIPK1

In silico screening combined with bioactivity evaluation to identify AMI-1 as a novel anticancer compound by targeting AXL. (PubMed, J Biomol Struct Dyn) - "Next, four compounds (ARRY614, AMI-1, NG25, and Butein) were selected for bioactivity evaluation after hydrogen bond and cluster analysis...Finally, further MM/PBSA prediction showed that AMI-1 is more sensitive to mutant protein 3IKA than wildtype protein 1M17, which means that the AMI-1 may be helpful to overcome the resistance of EGFR mutations. In conclusion, this work successfully discovered a novel compound with moderate inhibitory activity against AXL by a drug discovery workflow, which also could be applied to discover active compounds for other targets quickly.Communicated by Ramaswamy H. Sarma."

Journal • Oncology • AXL • EGFR • LY6G6D

Inhibition of tumor cell-autonomous p38 MAPK suppresses IL1α-mediated inflammatory tumor-stromal crosstalk in pancreatic adenocarcinoma (AACR 2023) - "PKT mice were treated daily with pexmetinib, gemcitabine and paclitaxel chemotherapy, or combination therapy for downstream analysis and survival studies. Both pharmacologic and genetic inhibition of p38α significantly reduced IL1A transcription and protein levels in human and murine PDAC tumor cell lines. These findings provide a new therapeutic opportunity to target the p38α MAPK pathway for suppression of IL1α-mediated stromal activation and combination with chemotherapy to overcome therapeutic resistance by modulating the stromal and immune microenvironment in PDAC."

Stroma • Tumor cell • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CAFs • IL1A • KRAS • NF-κβ

Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab (clinicaltrials.gov) - P1/2 | N=144 | Recruiting | Sponsor: Jason J. Luke, MD | Trial completion date: Jun 2024 ➔ Jun 2027 | Trial primary completion date: Mar 2023 ➔ Mar 2026

Metastases • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4

p38 MAPK inhibition reprograms the inflammatory stroma to overcome the immunosuppressive tumor microenvironment in pancreatic cancer (SSO 2023) - "Ptf1acre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice were treated with vehicle control, the p38 inhibitor, pexmetinib (30mg/kg, daily PO), gemcitabine (30mg/kg IP) and paclitaxel (10mg/kg, IP), or combined chemotherapy and pexmetinib, for 2.5 weeks prior to sacrifice. These findings elucidate a novel mechanism of IL-1/p38 pathway inhibition in reprogramming the inflammatory stroma and overcomes the immunosuppressive TME of PDAC resulting in overcoming therapeutic resistance and improving survival in a genetic mouse model of PDAC. These data provides preclinical evidence to pursue targeted p38 MAPK inhibition to improve outcomes in PDAC."

Biomarker • Stroma • Tumor microenvironment • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • CD8 • IL1A • ITGAM • KRAS

ARRY-614 Plus Immune Checkpoint Inhibition Can Induce Durable Responses in Advanced Solid Tumors (OncLive) - P1b/2 | N=144 | NCT04074967 | "The combination of the p38 MAPK inhibitor ARRY-614 plus nivolumab (Opdivo) with or without ipilimumab (Yervoy) was well tolerated and elicited disease control in high-risk, PD-(L)1–refractory patients with advanced solid tumors, according to data from a phase 1/2 trial (NCT04074967) presented at the 2022 Society for Immunotherapy of Cancer Annual Meeting. Of the 20 evaluable patients, 3 had partial responses (PRs), 7 achieved stable disease (SD), 2 patients had immune-related SD (irSD), and the remaining 8 patients experienced disease progression. The median duration of response was not reached with PRs ongoing in 2 patients. Moreover, 6 additional patients reached 6-month progression-free survival, which included 2 patients who had SD/irSD for longer than 1 year and 3 with ongoing benefit despite early drug cessation because of toxicities."

P1/2 data • Cutaneous Melanoma • Gastroesophageal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Kidney Cancer • Lung Cancer • Melanoma • Mesothelioma • Non Small Cell Lung Cancer • Ocular Melanoma • Oncology • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Thoracic Cancer • Uveal Melanoma

Pexmetinib suppresses osteoclast formation and breast cancer induced osteolysis via P38/STAT3 signal pathway. (PubMed, J Bone Oncol) - "Furthermore, Pexmetinib suppressed breast cancer-associated osteolysis in vivo. These results suggest that Pexmetinib may be a promising drug for the treatment of breast cancer-induced osteolysis."

Journal • Breast Cancer • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Solid Tumor • NFATC1 • STAT3

Targeting stromal-specific p38 MAPK signaling to stifle inflammatory reprogramming of cancer-associated fibroblasts in pancreatic cancer (AACR 2022) - "For survival studies, PKT mice were treated with vehicle, gemcitabine (20 μg/twice weekly), pexmetinib, or combination until moribund. Inhibition of p38 MAPK in PSCs prevented activation into an inflammatory fibroblast in vitro when stimulated with IL-1 or tumor cell cocultures. These findings provide important mechanistic data to explore p38 MAPK inhibition to target the fibrotic stroma and reduce immunosuppressive myeloid levels in tumors and provide compelling preclinical evidence to combine pexmetinib with chemotherapy to improve overall survival in PDAC."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • ITGAM • KRAS

Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab (clinicaltrials.gov) - P1/2; N=144; Recruiting; Sponsor: Jason J. Luke, MD; Trial completion date: Nov 2021 ➔ Jun 2024; Trial primary completion date: Nov 2021 ➔ Mar 2023

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4

Angiopoietin 2 stimulates trophoblast invasion via a mechanism associated with JNK signaling. (PubMed, Mol Hum Reprod) - "Inhibition of p-JNK (using SP600125) blocked the Ang-2 induced invasion of HTR-8/SVneo cells. In addition, inhibition of Tie2 (pexmetinib) and integrin signaling (RGDS and ATN-161) also blocked Ang-2 induced invasion. In conclusion, we demonstrate that Ang-2 can stimulate EVT invasion via a mechanism associated with activation of both the Tie2 receptor and integrins, which appear to work through different pathways; Tie2 through the JNK/c-JUN pathway and integrins through an as yet unidentified pathway(s). We therefore propose that any alterations in Ang-2 expression in the decidua would lead to an imbalance in pro- and anti-invasive factors, disrupting regulation of EVT invasion and spiral artery remodeling and thereby contribute to the aetiology of several complications of pregnancy."

Journal • Oncology • MMP2 • MMP9

Study of ARRY-614 Plus Either Nivolumab or Ipilimumab (clinicaltrials.gov) - P1/2; N=144; Recruiting; Sponsor: Jason J. Luke, MD; Not yet recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Genito-urinary Cancer • Melanoma • Neutropenia • Oncology • Renal Cell Carcinoma • Solid Tumor

Roth Capital Partners OC Growth Stock Conference (Array Biopharma , Inc) - ARRY-614 / Array; Expected to complete & report P1 trial in MDS patients in 2011;

Aniticipated P1 results • Anticipated P1 completion • Oncology

Q1 2013 Results (Array Biopharma) - Anticipated data from P1 trial for myelodysplastic syndrome at ASH 2012 / H1 2013; Anticipated FDA meeting by Dec 2013; Anticipated initiation of registration trial for myelodysplastic syndrome by Dec 2013; Anticipated reporting of dose escalation trial with improved formulation in myelodysplastic syndrome by Dec 2013; Anticipated decision of P3 / pivotal trial for cancer in 2013

Anticipated FDA event • Anticipated new P3 trial • Anticipated new trial • Anticipated P1 data • Oncology

A Phase 1 Study of Oral ARRY-614, a p38 MAPK/Tie2 Dual Inhibitor, in Patients with Low or Intermediate 1 Risk Myelodysplastic Syndromes. (PubMed) - "We recommend 1200 mg QD as the optimal dose for further study. This study was registered at http://www.clinicaltrials.gov as NCT00916227."

Biomarker • Acute Coronary Syndrome • Biosimilar • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Barclays Capital Healthcare Conference (Array Biopharma , Inc) - ARRY-614 / Array; Expected to complete & report P1 trial in MDS patients in 2011;

Aniticipated P1 results • Anticipated P1 completion • Oncology

Jefferies Global Healthcare Conference (Array Biopharma) - P1 data release

P1 data • Oncology