Robust activity of avapritinib, potent and highly selective inhibitor of mutated KIT, in patient-derived xenograft models of gastrointestinal stromal tumors
Purpose: Gastrointestinal stromal tumors (GIST) are commonly treated with tyrosine kinase inhibitors (TKI). The majority of patients with advanced GIST ultimately become resistant to TKI due to acquisition of secondary KIT mutations, while primary resistance is mainly caused by PDGFRA p.D842V mutation. We tested the activity of avapritinib, potent and highly selective inhibitor of mutated KIT and PDGFRA, in three patient-derived xenograft (PDX) GIST models carrying different KIT mutations, with differential sensitivity to standard TKI. Experimental Design: NMRI nu/nu mice (n=93) were transplanted with human GIST xenografts with KIT exon 11+17 (UZLX-GIST9KIT11+17), exon 11 (UZLX-GIST3KIT11) or exon 9 (UZLX-GIST2BKIT9) mutations, respectively. We compared avapritinib (10 and 30 mg/kg/qd) vs. vehicle, imatinib (50 mg/kg/bid) or regorafenib (30 mg/kg/qd) [UZLX-GIST9KIT11+17]; avapritinib (10, 30, 100 mg/kg/qd) vs. vehicle or imatinib [UZLX-GIST3KIT11]; and avapritinib (10, 30, 60 mg/kg/qd) vs. vehicle, imatinib (50, 100 mg/kg/bid) or sunitinib (40 mg/kg/qd) [UZLX-GIST2BKIT9].Results: In all models avapritinib resulted in reduction of tumor volume, significant inhibition of proliferation and reduced KIT signaling. In two models, avapritinib led to remarkable histologic responses, increase in apoptosis and inhibition of MAPK-phosphorylation. Avapritinib showed superior (UZLX-GIST9KIT 11+17 and -GIST2BKIT9) or equal (UZLX-GIST3KIT11) anti-tumor activity to standard dose of imatinib. In UZLX-GIST9KIT11+17, the anti-tumor effects of avapritinib were significantly better than with imatinib or regorafenib. Conclusions: Avapritinib has significant anti-tumor activity in GIST PDX models characterized by different KIT mutations and sensitivity to established TKI. These data provide strong support for ongoing clinical trials with avapritinib in patients with GIST (NCT02508532, NCT03465722). Gebreyohannes YK, Wozniak A, Zhai ME, Wellens J, Cornillie J, Vanleeuw U, Evans EK, Gardino AK, Lengauer C, Debiec-Rychter M, Sciot R, Schöffski P. Robust activity of avapritinib, potent and highly selective inhibitor of mutated KIT, in patient-derived xenograft models of gastrointestinal stromal tumors (October 1, 2018). Clinical Cancer Research. 10.1158/1078-0432.CCR-18-1858.
Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion
We present a cohort of 41 patients with osimertinib resistance biopsies, including two with an acquired CCDC6-RET fusion. While RET fusions have been identified in resistant EGFR-mutant NSCLC, their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of RET fusions in an EGFR-mutant cancer, we expressed CCDC6-RET in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR-TKIs. The selective RET inhibitors BLU-667 or cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition. Finally, we treated two patients with EGFR-mutant NSCLC and RET-mediated resistance with osimertinib and BLU-667. The combination was well-tolerated and led to rapid radiographic response in both patients. This study provides proof-of-concept that RET fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients. Piotrowska Z, Isozaki H, Lennerz JK, Gainor JF, Lennes IT, Zhu VW, Marcoux N, Banwait MK, Digumarthy SR, Su W, Yoda S, Riley AK, Nangia V, Lin JJ, Nagy RJ, Lanman RB, Dias-Santagata D, Mino-Kenudson M, Iafrate AJ, Heist RS, Shaw AT, Evans EK, Clifford C, Ou SI, Wolf B, Hata AN, Sequist LV. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion (September 26, 2018). Cancer Discovery. 10.1158/2159-8290.CD-18-1022.
Precision targeted therapy with BLU-667 for RET-driven cancers
The receptor tyrosine kinase, rearranged during transfection (RET), is an oncogenic driver activated in multiple cancers including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC). No approved therapies have been designed to target RET; treatment has been limited to multi-kinase inhibitors (MKIs) which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off target toxicity, providing clinical validation for selective RET targeting. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP, Wilson D, Wilson KJ, DiPietro L, Fleming P, Palmer M, Hu MI, Wirth L, Brose MS, Ou SI, Taylor M, Garralda E, Miller S, Wolf B, Lengauer C, Guzi T, Evans EK. Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discovery. 2018; 8(7):836-849.
A precision therapy against cancers driven by KIT/PDGFRA mutations
Targeting oncogenic kinase drivers with small molecule inhibitors can have dramatic therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored, highly selective drugs. This rationale is presented for BLU-285, a clinical stage inhibitor of oncogenic KIT and PDGFRA alterations, including activation loop mutants that are ineffectively treated by current therapies. BLU-285, designed to preferentially interact with the active conformation of KIT and PDGFRA, potently inhibits activation loop mutants KIT D816V and PDGFRA D842V with subnanomolar potency and also inhibits other well-characterized disease-driving KIT mutants both in vitro and in vivo in preclinical models. Early clinical evaluation of BLU-285 in a phase I study has demonstrated marked activity in patients with diseases associated with KIT (aggressive systemic mastocytosis and gastrointestinal stromal tumor) and PDGFRA (gastrointestinal stromal tumor) activation loop mutations. Evans E, Gardino A, Kim JL, Hodous B, Shutes A, Davis A, Xing JZ Schmidt-Kittler O, Wilson D, Wilson K, DiPietro L, Zhang Y, Brooijmans N, LaBranche TP, Wozniak A, Yemarshet GK, Schöffski P, Heinrich M, DeAngelo DJ, Miller S, Wolf B, Kohl N, Guzi T, Lydon N, Boral A, Lengauer C. Science Translational Medicine. 2017 Nov 1.
First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway
Aberrant signaling through the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β (KLB) could potentially respond to treatment with an FGFR4 inhibitor. These findings are the first demonstration of a therapeutic strategy that targets a subset of patients with HCC. Hagel M, Miduturu C, Sheets M, Rubin N, Weng W, Stransky N, Bifulco N, Kim JL, Hodous B, Brooijmans N, Shutes A, Winter C, Lengauer C, Kohl NE, Guzi T. Cancer Discovery 2015; 5:424-437.
Targeting cancer with kinase inhibitors
Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next-generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology. Gross S, Rahal R, Stransky N, Lengauer C, Hoeflich KP. Journal of Clinical Investigation 2015; 125:1780-1789.
The landscape of kinase fusions in cancer
Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been characterized as extensively. Here we develop heuristics for reliably detecting gene fusion events in RNA-seq data and apply them to nearly 7,000 samples from The Cancer Genome Atlas. We thereby are able to discover several novel and recurrent fusions involving kinases. These findings have immediate clinical implications and expand the therapeutic options for cancer patients, as approved or exploratory drugs exist for many of these kinases. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. Nature Communications 2014 Sept 10; 5:4846.
Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes
Malignant mixed Müllerian tumours, also known as carcinosarcomas, are rare tumours of gynaecological origin. Here we perform whole-exome analyses of 22 tumours using massively parallel sequencing to determine the mutational landscape of this tumour type. On average, we identify 43 mutations per tumour, excluding four cases with a mutator phenotype that harboured inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromatin remodelling genes, ARID1A and ARID1B, in histone methyltransferase MLL3, in histone deacetylase modifier SPOP and in chromatin assembly factor BAZ1A, in nearly two thirds of cases. Alterations in genes with potential clinical utility are observed in more than three quarters of the cases and included members of the PI3-kinase and homologous DNA repair pathways. These findings highlight the importance of the dysregulation of chromatin remodelling in carcinosarcoma tumorigenesis and suggest new avenues for personalized therapy. Jones S, Stransky N, McCord CL, Cerami E, Lagowski J, Kelly D, Angiuoli SV, Sausen M, Kann L, Shukla M, Makar R, Wood LD, Diaz LA Jr, Lengauer C, Velculescu VE. Nature Communications 2014 Sept 19; 5:5006.