GSK2849330 / GSK - LARVOL DELTA

Novel preclinical patient-derived lung cancer models reveal inhibition of HER3 and MTOR signaling as therapeutic strategies for NRG1 fusion-positive cancers. (PubMed, J Thorac Oncol) - "We identify the MTOR pathway as a candidate vulnerability in NRG1 fusion-positive lung adenocarcinoma that may warrant further pre-clinical evaluation, with the eventual goal of finding additional therapeutic options for patients in whom ERBB-directed therapy fails. Moreover, our results uncover heterogeneity in downstream oncogenic signaling among NRG1-rearranged cancers, possibly histology-dependent, the therapeutic significance of which requires additional investigation."

Journal • Preclinical • Breast Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EIF4EBP1 • ERBB3 • NRG1 • SLC3A2

Lack of Targeted Therapies for NRG1 Fusion-Positive Advanced Solid Tumors Comes to Attention (Targeted Oncology) - "The standard strategies for treating patients with advanced solid tumors that are NRG1 fusion–positive are chemoimmunotherapy or novel anti–PD-1 or anti–PD-L1 agents, according to David R. Spigel, MD...Next, Spigel analyzed the durability of response to novel and developing therapies, including anti-HER3 antibodies and pan-ERBB TKIs."

Media quote

ImmunoPET imaging to assess target engagement: Experience from Zr-anti-HER3 mAb (GSK2849330) in patients with solid tumors. (PubMed, J Nucl Med) - " In this immunoPET study, dose-dependent inhibition of tumor uptake of Zr-GSK2849330 by unlabeled mAb confirmed target engagement of mAb to the HER3 receptor. This study further validates the use of immunoPET to directly visualize tissue drug disposition in patients with a non-invasive approach and to measure target engagement at the site of action, offering the potential for dose selection."

Clinical • Journal

Generation and Characterization of Novel Preclinical Disease Models of NSCLC with NRG1 Rearrangements to Improve Therapy (IASLC-WCLC 2019) - "...Activating NRG1 fusions have been identified in a variety of cancers including lung, pancreatic, breast, head and neck, etc, and previous work by our group has shown that anti-HER3 antibody (GSK2849330) therapy was effective at inducing a durable response in a NSCLC patient with a CD74/NRG1-fusion...Treatment of NRG1-fusion positive cells with small molecule inhibitors of HER2 (afatinib, neratinib, sapitinib) or trastuzumab inhibited growth, induced caspase 3/7 activity and blocked activation of PI3K and ERK signaling...The PI3K inhibitor pictilisib inhibited growth of NRG1 fusion-positive cells as a single agent with little effect on non-tumor control cells... We generated novel NSCLC PDX and cell line models with verified NRG1 chromosomal rearrangements. In vitro studies show that targeting HER2 and PI3K effectively inhibits growth and induces apoptosis. Studies exploring the efficacy of additional agents targeting HER2, HER3 and PI3K alone or in combination using..."

Preclinical

Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers. (PubMed, Cancer Discov) - P1; "In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). While in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound anti-tumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and endometrial cancers."

Journal

Clinicopathologic characteristics of NRG1fusion-positive cancers:A single-institution study. (ASCO 2019) - "A durable response was achieved with anti-HER3 antibody therapy (GSK2849330) in a patient with a CD74-NRG1-rearranged invasive mucinous adenocarcinoma (previously reported). NRG1 fusions occur in several tumor types and may be amenable to targeting with HER3-directed therapy."

Clinical