Matthew Squires

Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial

BACKGROUND An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. 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. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. METHODS In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. FINDINGS 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). INTERPRETATION Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. FUNDING Novartis Pharmaceuticals Corporation.

Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study.

The JAK1/JAK2 inhibitor ruxolitinib produced significant reductions in splenomegaly and symptomatic burden and improved survival in patients with myelofibrosis (MF), irrespective of their JAK2 mutation status, in 2 phase III studies against placebo (COMFORT-I) and best available therapy (COMFORT-II). We performed a comprehensive mutation analysis to evaluate the impact of 14 MF-associated mutations on clinical outcomes in 166 patients included in COMFORT-II. We found that responses in splenomegaly and symptoms, as well as the risk of developing ruxolitinib-associated anemia and thrombocytopenia, occurred at similar frequencies across different mutation profiles. Ruxolitinib improved survival independent of mutation profile and reduced the risk of death in patients harboring a set of prognostically detrimental mutations (ASXL1, EZH2, SRSF2, IDH1/2) with an hazard ratio of 0.57 (95% confidence interval: 0.30-1.08) vs best available therapy. These data indicate that clinical efficacy and survival improvement may occur across different molecular subsets of patients with MF treated with ruxolitinib.

Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma

BACKGROUND Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. METHODS Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n=12), wild-type (FGFR3(WT); n=31), or unknown (n=1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). RESULTS Most of the patients were men (75%) and over half of the patients were aged ⩾65 years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). CONCLUSION Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426.

Phase II Results of Dovitinib (TKI258) in Patients with Metastatic Renal Cell Cancer

Purpose: Fibroblast growth factor (FGF) signaling regulates tumor growth and vascularization and partly mediates antiangiogenic escape from VEGF receptor (VEGFR) inhibitors. Dovitinib (TKI258) is a tyrosine kinase inhibitor (TKI) that inhibits FGF receptor (FGFR), VEGFR, and platelet-derived growth factor receptor, which are known drivers of antiangiogenic escape, angiogenesis, and tumor growth in renal cell carcinoma (RCC). Experimental Design: Patients with advanced or metastatic RCC were treated with oral dovitinib 500 mg/day (5-days-on/2-days-off schedule). The study population was enriched for patients previously treated with a VEGFR TKI and an mTOR inhibitor. Results: Of 67 patients enrolled, 55 patients (82.1%) were previously treated with ≥1 VEGFR TKI and ≥1 mTOR inhibitor (per-protocol efficacy set). The 8-week overall response rate and disease control rate in this population were 1.8% and 52.7%, respectively. Disease control rate during the entire study period was 56.4% (50.9% ≥4 months). Median progression-free survival and overall survival in the entire population were 3.7 and 11.8 months, respectively. Pharmacodynamic analyses demonstrated dovitinib-induced inhibition of VEGFR (as determined by increased levels of placental growth factor and decreased levels of soluble VEGFR2) and FGFR (as determined by increased FGF23 serum measures). The most frequently reported treatment-related adverse events of all grades included nausea (65.7%), diarrhea (62.7%), vomiting (61.2%), decreased appetite (47.8%), and fatigue (32.8%). Conclusion: Dovitinib was shown to be an effective and tolerable therapy for patients with metastatic RCC who had progressed following treatment with VEGFR TKIs and mTOR inhibitors. Clin Cancer Res; 20(11); 3012–22. ©2014 AACR.

Final results of a multicenter, open-label phase II trial of dovitinib (TKI258) in patients with advanced urothelial carcinoma with either mutated or nonmutated FGFR3.

255 Background: Increased signaling through mutational activation of fibroblast growth factor receptor 3 (FGFR3) contributes to tumor development and vascularization of urothelial carcinoma (UC). Dovitinib (TKI258), an oral investigational inhibitor of angiogenic factors including FGFR3, has demonstrated inhibition of tumor growth and proliferation in preclinical UC models with FGFR3-activating mutations or protein overexpression. METHODS Advanced UC patients (pts) with 1-3 prior regimens received dovitinib 500 mg/day on a 5-days-on/2-days-off schedule. Pts were stratified into 2 groups based on presence (mut) or absence (non-mut) of FGFR3 gene mutation in archival tissue (initially analyzed by SNaPshot; later by Sanger sequencing for screening and confirmation). The primary objective was overall response rate (ORR) in each group using a Simons 2-stage design (20 pts planned for stage 1 and 20 for stage 2 if ≥ 2 responses seen in stage 1). RESULTS A total of 44 pts (median age, 67 years) were treated in stage 1: 12 FGFR3 mut, 31 FGFR3 non-mut, and 1 unknown mutation status. Over-recruitment of non-mut pts was due to rapid enrollment of non-mut pts with invasive bladder tumors and some tumors initially classified as mut by SNaPshot but reclassified as non-mut after sequencing. Most pts (77%) had metastases in ≥ 2 organs. ORR (local review) was 0% in the FGFR3 mut group and 3% in the FGFR3 non-mut group (1 partial response). Median progression-free survival was 3 months in the FGFR3 mut group and 1.8 months in the FGFR3 non-mut group. There were insufficient non-mut responders to proceed to stage 2. Since most pts in the mut group did not receive > 6 months of treatment and meeting the response threshold to proceed to stage 2 was highly unlikely, the study was terminated. Common adverse events were diarrhea (73%), nausea (61%), and asthenia (50%) and were similar in both groups. CONCLUSIONS Although there were difficulties in evaluating mutation status, dovitinib had limited single-agent activity in pts with advanced bladder cancer regardless of FGFR3 mutation status. Further studies are needed to understand the role of FGFR3 inhibition in advanced UC treatment. CLINICAL TRIAL INFORMATION NCT00790426.

Ruxolitinib is an effective treatment for CALR-positive patients with myelofibrosis

Approximately 60–65% of patients with myelofibrosis carry mutations in the Janus kinase 2 gene (JAK2) and 5–10% carry mutations in the thrombopoietin receptor gene, MPL (Vainchenker et al, 2011). Recently, somatic mutations in the calreticulin gene (CALR) were identified in most patients lacking JAK2 or MPL mutations (Klampfl et al, 2013; Nangalia et al, 2013). In preclinical models, overexpression of CALR mutations resulted in cytokine-independent proliferation of Ba/F3 cells and activation of signal transducer and activator of transcription 5 (STAT5) (Klampfl et al, 2013). Fedratinib, a JAK2 inhibitor, suppressed these effects in vitro (Klampfl et al, 2013) and reduced palpable spleen length and symptoms in two patients with myelofibrosis (Passamonti et al, 2014). These results suggest that inhibition of abnormal JAK/STAT signalling represents a therapeutic option for CALR-mutated patients.

MINI01.03: Phase (Ph) I Study of the Safety and Efficacy of the cMET Inhibitor Capmatinib (INC280) in Patients with Advanced cMET+ NSCLC: Topic: Medical Oncology

Background: Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report data on the ALK TKI-naïve and crizotinib (C)-resistant NSCLC pts treated with ensartinib. Clinical trial information: NCT01625234 Methods: In this multicenter expansion study, pts with ALK+NSCLCwere treatedwith ensartinib 225mgdaily on a 28-day schedule. Pts had measurable disease, ECOG PS 0-1, and adequate organ function. Untreated brain metastases (CNS) and leptomeningeal disease were allowed. Next Generation Sequencing (NGS) was performed on plasma samples collected at baseline and on study and compared with central tissue results (FISH/IHC). All pts were assessed for response to therapy using RECIST 1.1 and for adverse events (AEs) using CTCAE version 4.03. Results: 83 pts (51% female) have been enrolled. Median age 54 (20-79) years, 64% ECOG PS 1. Of 42 ALK+ NSCLC pts evaluable for response; partial response (PR) was achieved in 25 pts (60%) and stable disease (SD) in 6 pts (14%). In the C-naïve pts (n 1⁄4 9), PRs were observed in 7 pts (77%). In the 22 pts with prior C but no other ALK TKI, 16 pts (73%) achieved PR and 4 (18%) SD. In the 10 pts who had received two or more prior ALK TKIs, there were 2 PR, 2 SD (40% DCR). CNS responses (53% PR) have been observed in both C-naïve and C-resistant pts. Plasma and tissue genotyping were available on 27 pts (26 ALK+ and 1 ALK-). ALK was detected in plasma in 16 pts, all of whom had a response to therapy. 2 pts with PD were tissue +ve and plasma -ve. 9 plasma samples were unevaluable. Serial sequencing demonstrated a decrease in ALK in pts responding and an increase at the time of progression. The most common drug-related AEs ( 20% of pts) included rash (53%), nausea (33%), vomiting (27%), fatigue (22%), and pruritus (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs in 2 pts were rash (9 pts), pruritus (3 pts), and fatigue (2 pts). Conclusion: Ensartinib is generally well-tolerated and induces response in both C-naïve and C-resistant ALK+ NSCLC pts, as well as pts with CNS disease. Plasma sequencing appears to be promising to select pts for therapy and monitor for response and development of resistance. MINI01.03 Phase (Ph) I Study of the Safety and Efficacy of the cMET Inhibitor Capmatinib (INC280) in Patients with Advanced cMET+ NSCLC

The identification and characterization of a STAT5 gene signature in hematologic malignancies

BACKGROUND The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies. OBJECTIVE Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors. METHODS We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. RESULTS Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5-positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5-negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment. CONCLUSIONS The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib.

Abstract OT2-6-04: Dovitinib, a receptor tyrosine kinase inhibitor in combination with fulvestrant in postmenopausal endocrine resistant human epidermal growth factor receptor 2 negative (HER2-) / hormone receptor-positive (HR+) breast cancer: A phase II, randomized, double blind, placebo-controlled study

Background: Overcoming endocrine resistance is a critical goal in the treatment of HR+ breast cancer. Emerging in vitro evidence suggests that amplification and overexpression of fibroblast growth factor receptor 1 (FGFR1) is associated with endocrine resistance. Up to 8% of patients with HER2–/HR+ breast cancer have amplification of the FGFR1 gene. Dovitinib, a potent inhibitor of FGFR, as well as vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, demonstrated antitumor activity in heavily pretreated breast cancer patients with FGF-pathway amplification. The objective of this study is to determine if dovitinib in combination with fulvestrant can improve outcomes in postmenopausal patients with endocrine resistant HER2-/HR+ breast cancer. Trial design: This multicenter, randomized, double-blind, placebo-controlled, phase II trial (NCT01528345) will enroll postmenopausal patients with HER2–/HR+ locally advanced or metastatic breast cancer. Patients are randomized 1:1 (stratified by FGF amplification [FGFR1, FGFR2, or FGF3] and presence of visceral disease) to receive intramuscular fulvestrant (500 mg q4w [with an additional dose 2 weeks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or matching placebo until disease progression, unacceptable toxicity, death, or discontinuation (any reason). Crossover is not permitted. Eligibility criteria: Postmenopausal women with HER2-/HR+ breast cancer (N = 150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting are eligible. Other key inclusion criteria are: ECOG performance status ≤1; and adequate bone marrow and organ function; measurable disease as per RECIST 1.1 or ≥ 1 nonmeasurable lytic or mixed bone lesions in the absence of measurable disease. Patients with current or past evidence of CNS or leptomeningeal metastases, HER2 overexpression, and those who received previous treatment with fulvestrant or FGFR inhibitors are excluded. Specific aims: The primary endpoint is progression free survival (central review). Secondary endpoints include overall response rate, duration of response, overall survival, time to deterioration of ECOG performance status, patient-reported outcome scores, safety, and assessment of plasma pharmacokinetic concentrations of fulvestrant and dovitinib. Additionally, the pharmacodynamics of dovitinib on FGFR-associated angiogenic pathways and potential predictive biomarkers of response will be explored. Statistical methods: Analysis of primary endpoint will be carried out in FGF amplified subpopulation, FGF non-amplified subpopulation and the full population, using Bayesian methodology. Target accrual: Enrollment is ongoing. Target accrual is 150 patients (90 FGF amplified patients and 60 FGF non-amplified patients). Contact: For further information about the study please contact Gogov Sven (sven.gogov@novartis.com)/ Stephanie Deudon (stephanie.deudon@novartis.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-04.

PS01.60: Ph Ib/II, Trial of INC280 ± Erlotinib vs Platinum + Pemetrexed in Adult pts with EGFR-Mutated, cMET amplified, EGFR TKI Resistant, Advanced NSCLC: Topic: Medical Oncology

George Blumenschein Jr., Jason Chandler, Edward B. Garon, David Waterhouse, Jonathan W. Goldman, Vijay K. Gunuganti, Ralph Boccia, David Spigel, John Glaspy, Donald A. Berry, Beata Korytowsky, Jin Zhu, Wen Hong Lin, Kelly Bennett, Craig Reynolds The University of Texas MD Anderson Cancer Center, Houston, TX/United States of America, The West Clinic, PC, Memphis, TN/United States of America, David Geffen School of Medicine at UCLA/TRIO-US Network, Santa Monica, CA/United States of America, OncologyHematology Care (OHC), Cincinnati, OH/United States of America, US Oncology Research, Texas Oncology, Austin, TX/United States of America, Center for Cancer and Blood Disorders, Bethesda, MD/United States of America, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN/United States of America, Berry Consultants, LLC, Austin, TX/United States of America, Bristol-Myers Squibb, Princeton, NJ/United States of America, Ocala Oncology Center, Ocala, FL/United States of America