Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations.

Summary Background An unmet medical need exists for patients with metastatic renal cell carcinoma (RCC) who have progressed on a vascular endothelial growth factor (VEGF)–targeted therapy plus a mammalian target of rapamycin (mTOR) inhibitor. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine kinase inhibitor that inhibits VEGF and FGF receptors. This open-label, multicenter phase 3 study compared dovitinib with sorafenib as a third-line targeted therapy in metastatic RCC. Methods Patients (N = 570) with clear cell metastatic RCC who received one prior VEGF-targeted therapy and one prior mTOR inhibitor were randomized 1:1 to receive dovitinib (500 mg orally on a 5-days-on/2-days-off schedule) or sorafenib (400 mg orally twice daily). Randomization was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) by central review. Secondary endpoints included overall survival (OS) and safety. Biomarker studies were an exploratory endpoint. Findings The median PFS was 3·7 months for dovitinib (n = 284) and 3·6 months for sorafenib (n = 286) (hazard ratio [HR], 0·86; 95% CI, 0·72-1·04; one-sided P = 0·063). Median OS was 11·1 months for dovitinib and 11·0 months for sorafenib (HR, 0·96; 95% CI, 0·75-1·22). Diarrhea, nausea, and vomiting were more common with dovitinib, whereas palmar-plantar erythrodysesthesia, hypertension, and alopecia were more common with sorafenib. In both arms, prolonged OS was observed in patients with low baseline plasma levels of FGF2, hepatocyte growth factor, and VEGFA. Interpretation Dovitinib demonstrated activity but not superior efficacy compared with sorafenib in patients who progressed on prior VEGF-targeted therapies and mTOR inhibitors. This trial provides landmark outcome data for future studies in this third-line setting. Funding Novartis Pharmaceuticals Corporation

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Cyclin-dependent kinases (CDK), and their regulatory cyclin partners, play a central role in eukaryotic cell growth, division, and death. This key role in cell cycle progression, as well as their deregulation in several human cancers, makes them attractive therapeutic targets in oncology. A series of CDK inhibitors was developed using Astex's fragment-based medicinal chemistry approach, linked to high-throughput X-ray crystallography. A compound from this series, designated AT7519, is currently in early-phase clinical development. We describe here the biological characterization of AT7519, a potent inhibitor of several CDK family members. AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines, and the mechanism of action was shown here to be consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. Tumor regression was observed following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer xenograft models. We show that these biological effects are linked to inhibition of CDKs in vivo and that AT7519 induces tumor cell apoptosis in these xenograft models. AT7519 has an attractive biological profile for development as a clinical candidate, and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development. Studies described here formed the biological rationale for investigating the potential therapeutic benefit of AT7519 in cancer patients. [Mol Cancer Ther 2009;8(2):324 -32]

Background Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAF V600 -mutant, stage III melanoma in the phase 3 COMBI-AD trial. This prespecified exploratory biomarker analysis aimed to evaluate potential prognostic or predictive factors and mechanisms of resistance to adjuvant targeted therapy.Methods COMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAF V600E or BRAF V600K mutation. Patients were randomly assigned (1:1) to the two treatment groups by an interactive voice response system, stratified by mutation type and disease stage. Patients, physicians, and the investigators who analysed data were masked to treatment allocation. The primary outcome was relapse-free survival, defined as the time from randomisation to disease recurrence or death from any cause. Biomarker assessment was a prespecified exploratory outcome of the trial. We assessed intrinsic tumour genomic features by use of next-generation DNA sequencing and characteristics of the tumour microenvironment by use of a NanoString RNA assay, which might provide prognostic and predictive information. This trial is registered with ClinicalTrials.gov, number NCT01682083, and is ongoing but no longer recruiting participants. FindingsBetween Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB, top third; hazard ratio [HR] 0•56, 95% CI 0•37-0•85, p=0•0056), but not in the dabrafenib plus trametinib group (0•83, 95% CI 0•53-1•32, p=0•44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0•49, 95% CI 0•35-0•68, p<0•0001). However, patients with high tumour mutational burden seem to have a less pronounced benefit with targeted therapy (HR [versus placebo] 0•75, 95% CI 0•44-1•26, p=0•27), especially if they had an IFNγ signature lower than the median (HR 0•88 [95% CI 0•40-1•93], p=0•74). Interpretation Tumour mutationa...