Shi, Michael

Abstract Abstract 4055 Introduction: Approximately 15% of patients (pts) with multiple myeloma (MM) exhibit a t(4;14) translocation that results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3) in the absence of ligand. This translocation has been strongly linked with a poor prognosis and short survival compared with pts without this translocation. Dovitinib (TKI258) is an RTK inhibitor that has demonstrated in vitro inhibitory activity against FGFR (including FGFR3), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), with IC50values of approximately 10 nM. Tumor growth inhibition was observed in xenograft tumor models of MM treated with dovitinib. This study was designed to evaluate the efficacy and safety of dovitinib in pts with relapsed or refractory MM that is either t(4;14) positive or negative. Patients and Methods: Adult pts who had received at least 2 prior antimyeloma regimens and who had relapsed or were refractory to their last treatment regimen were enrolled in this multicenter, open-label, 2-stage, phase 2 trial. Pts were evaluated for t(4;14) status at the baseline visit and classified according to the result into either a t(4;14)-positive or a t(4;14)-negative group. Dovitinib was administered at a dose of 500 mg/day on a 5-days-on/2-days-off schedule. Response was characterized as per the International Myeloma Working Group (IMWG) criteria. The primary endpoint was extended overall response rate as defined by the rate of pts with best overall response of complete response, very good partial response, partial response, or minor response. Secondary endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. After disease progression, pts had the option to continue treatment with the addition of low-dose dexamethasone (40 mg every 7 days) with M-protein levels at the time of progression considered as the new baseline. Results: A total of 43 pts were enrolled in this study; 26 pts were t(4;14) negative, 13 were t(4;14) positive, and 4 pts had unknown/indeterminate t(4;14) status. Median age was 63 years. Most pts (86%; n = 37) had received ≥ 3 prior lines of therapy. No objective responses were observed in either group of pts. Due to the apparent lack of efficacy, the study did not proceed to stage 2. The following observations are based on the preliminary data. In the t(4;14)-negative group, median duration of exposure to the study drug was 4.0 weeks, and 9 of the 26 pts (35%) had stable disease, 13 (50.0%) had progressive disease, and 4 (15%) were not evaluable. Due to slow enrollment and lack of efficacy among the earlier enrolled t(4;14)-positive pts, enrollment for the t(4;14)-positive group was closed prematurely. Among the 13 enrolled t(4;14)-positive pts, median duration of exposure to the study drug was 8.7 weeks. Best responses were stable disease for 8 pts (62%), disease progression for 3 pts (23%), and unknown for 2 pts (15%). Among both groups, the most common adverse events of any grade, regardless of study drug, were nausea (67%), diarrhea (58%), vomiting (51%), fatigue (47%), thrombocytopenia (33%), and anemia (28%). Most of the nonhematologic events were mild. The most common grade 3/4 adverse events were thrombocytopenia (26%) and anemia (23%). The principal reasons for discontinuation of dovitinib monotherapy were disease progression (72%) and adverse events (19%). Six pts continued on the dovitinib plus dexamethasone regimen; 1 pt is ongoing, and 5 pts discontinued due to disease progression (n = 4) and adverse events (n = 1). Conclusion: Dovitinib was found to have no or minimal single-agent activity in relapsed/refractory myeloma irrespective of t(4;14) status. Although the patient numbers are small, the rate of patients with stable disease during study treatment who may have had a clinical benefit was higher in the t(4;14)-positive group, suggesting that this subgroup may be a candidate to explore combination treatment of dovitinib with other agents, such as proteasome inhibitors. Gastrointestinal toxicity, while mostly mild, remains a challenge, and timely monitoring and supportive care during dovitinib treatment may alleviate these symptoms. Dovitinib may be a promising agent for combination therapies to improve prognosis of patients with t(4;14)-positive MM. Disclosures: Scheid: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Reece:Millennium Pharmaceuticals: Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Spencer:Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria. Callander:Millennium Pharmaceuticals: Research Funding. Sonneveld:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding. Kalimi:Novartis Pharmaceuticals: Employment. Cai:Novartis: Employment. Shi:Novartis: Employment, Equity Ownership. Scott:Novartis: Employment. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

AbstractObjectivesApproximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14) translocation.MethodsAdult patients with relapsed or refractory MM who had received ≥2 prior regimens were enrolled in this multicenter, 2‐stage, phase 2 trial. Patients were grouped based on their t(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5‐days‐on/2‐days‐off schedule. The primary endpoint was overall response rate by local investigator review (per International Myeloma Working Group criteria). In non‐responding patients, treatment could continue with the addition of low‐dose dexamethasone.ResultsIn total, 43 patients (median age, 63 years) were enrolled (13 t(4;14) positive, 26 t(4;14) negative, and 4 t(4;14) status non‐interpretable). Patients had received a median of 5 prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)‐positive group and 3.7 weeks in the t(4;14)‐negative group. None of the patients on dovitinib had objective responses. The stable disease rate was 61.5% in the t(4;14)‐positive group and 34.6% in the t(4;14)‐negative group. Overall, 39 patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%).ConclusionDovitinib showed no single‐agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)‐positive patients.

Abstract The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P = 0.073 and P = 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection. Mol Cancer Ther; 12(5); 632–42. ©2013 AACR.

Abstract Background: Endometrial carcinoma is the most common gynecological malignancy in the western world. Activating mutations of the fibroblast growth factor receptor 2 (FGFR2) have been described in 12-16% of endometrial cancers. Moreover, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their receptors are involved in the neovascularization, invasiveness, and metastatic potential of endometrial cancer. Therefore, suppression of FGFR/VEGFR/PDGFR signaling by TKI258 may represent a novel approach for treatment of endometrial cancer. Experimental Design: The aims of this study were 1.) to assess the effect of TKI258 on tumor cell growth in two-dimensional (2D) and three-dimensional (3D) culture assays using a panel of 20 human endometrial cancer cell lines, 2.) to identify candidate molecular markers predicting sensitivity using baseline gene expression profiling and mutational analyses, and 3.) to determine the in vivo antineoplastic activity of TKI258 in endometrial cancer xenograft models. In addition, we screened 200 fresh frozen endometrial cancer specimens to comprehensively assess the distribution pattern of PI3K, PTEN, and FGFR mutations in endometrial cancer. Results: Concentration-dependent anti-proliferative effects of TKI285 using 2D assays were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC50 range: 0.42µM – 3.06 µM). The three most sensitive endometrial cancer cell lines demonstrated activating FGFR2 mutations (MFE296: N549K, IC50 0.42µM; AN3CA: N549K and K310R, IC50 0.50µM; MFE280: S252W, IC50 0.66µM). Assessment of TKI258 responses in 3D assays demonstrated similar results to those observed in 2D culture assays in that the 3 cell lines harboring FGFR2 mutations were the most sensitive to TKI258 achieving 100% growth inhibition at a concentration of 1µM. AN3CA and MFE296 endometrial cancer cells formed xenografts in nude mice and antitumor activity was studied in both models. Inhibition of p-FGFR, p-PDGFR, p-VEGFR-2, pAKT and p-ERK1/2 were observed. Comprehensive data on the pattern of PI3K, PTEN and FGFR mutations in endometrial cancer will be provided. Conclusion: TKI258 demonstrates significant antitumor activity in endometrial cancer cells with FGFR2 mutations. This study provides a strong rationale for the clinical evaluation of TKI258 in patients with endometrial cancer, specifically in those harboring FGFR2 mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3589. doi:10.1158/1538-7445.AM2011-3589