Safety Of Dovitinib Research Articles

Efficacy and safety of dovitinib in pretreated advanced squamous non-small cell lung cancer with FGFR1 amplification: A single-arm, phase II study

PRESENTED BY ATTENDEES Efficacy and safety of dovitinib in pretreated advanced squamous non-small cell lung cancer with FGFR1 amplification: A single-arm, phase II study Myung-Ju Ahn, Sung Hee Lim, Jong-Mu Sun, Yoon-La Choi, Hye Ryun Kim, Soo-min Ahn, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Joo Hang Kim, Byoung Chul Cho Samsung Medical Center, Seoul, Korea, Yunsei University, Seoul, Korea Purpose: FGFR1 amplification is one of the most common potential driving oncogenes in squamous cell carcinoma (SCC), which accounts for 20% of non-small cell lung cancer (NSCLC). This phase II study evaluated the efficacy and toxicity profile of dovitinib, an orally active fibroblast growth factor receptor (FGFR) inhibitor, in advanced lung SCC patients. Experimental Design: Patients with histological confirmed advanced squamous cell NSCLC and previously treated with at least one cytotoxic chemotherapy were enrolled. All patients had FGFR1 gene amplification more than 5 copies by fluorescent in situ hybridization (FISH). Each 7-day treatment cycle consisted of dovitinib 500mg orally administration on days 1 to 5 and 2 days off. Primary endpoint was overall response rate and secondary endpoints included PFS, OS and toxicity. Exploratory analysis for FGFR1-3 mRNA expression was performed. The mRNA in situ hybridization (ISH) assay was performed using the RNA scope 2.0 assay system and the FGFR1 probe provided by Advanced Cell Diagnostics. Results: All 26 patients were male with the median age of 68 years (range, 52–80). Most patients were ever smokers (96%) and had good ECOG (0-1) performance status (85%). The median number of dovitinib treatment cycles administered was 2.5 (range, 1-12). The overall response rate (ORR) was 11.5% (95% CI, 0.8–23.8) and disease control rate (DCR) was 50% (95% CI, 30.8– 69.2). There were 3 partial responses (PR) and 10 stable diseases (SD). Duration of response in 3 patients who achieved PR was 4.5þ, 5.1þ and 6.1 months, respectively. After the median follow-up duration of 15.7 months (range, 1.2–25.6), the median overall survival (OS) was 5.0 months (95% Confidential Interval, 3.61– 6.39) and progression-free survival (PFS) was 2.9 Journal of Thoracic Oncology Vol. 11 No. 2S: S16-S55 months (95% CI, 1.54–4.26). The most common grade 3 or higher AEs suspected to be related to dovitinib treatment were fatigue (19.2%), anorexia (11.5%), and hyponatremia (11.5%) and 12 patients (46%) required dose reduction of dovitinib. Further analysis for FGFR1 mRNA, only modest overlap (31.2%) of FGFR1 expression at the mRNA level with FGFR1 amplification was found. The expression of FGFR1 mRNA was not associated with degree of FGFR1 gene amplification nor FGFR2 or FGFR3 mRNA expression. Conclusion: Dovitinib treatment showed modest efficacy in advanced squamous cell lung cancer patients with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in SCC should be warranted. A novel patient-derived cell line originated at the time of crizotinib resistance displays a mesenchymal phenotype Karinna Almodovar-Garcia, Yingjun Yan, Yuanyuan Wang, Zhongming Zhao, Xingyi Guo, Yaomin Xu, Christine M. Lovly Vanderbilt University School of Medicine, Nashville, TN Lung cancers that harbor genomic ALK alterations are clinically responsive to pharmacologic ALK inhibition. Crizotinib, an orally available small-molecule inhibitor of the ALK tyrosine kinase, was approved for the treatment of ALKþ lung cancer patients. Unfortunately, as seen with other tyrosine kinases inhibitors (TKIs) in clinical use, most patients whose disease initially responds to crizotinib eventually develop progressive disease. To elucidate mechanisms of acquired resistance to ALK TKIs, we established and characterized novel ALKþ cell lines from patients with acquired resistance to ALK TKI therapy. In particular, we developed a cell line (designated STM) from a patient with an EML4-ALK (E6;A20, variant 3) fusion that developed acquired resistance to crizotinib. Fluorescence in situ hybridization confirmed that the cell line retained the ALK rearrangement. STM cells had decreased sensitivity to crizotinib and secondgeneration ALK inhibitors, including ceritinib, alectinib, and X-396. Morphologic changes were observed in this patient-derived cell line, the tumor cells had a spindle form, characteristic of the epithelial-mesenchymal transition (EMT). Loss of expression of the epithelial marker, E-cadherin, was accompanied by strong expression of the

An open label, multicenter, phase II study of dovitinib in advanced thyroid cancer

BackgroundThis phase 2 study investigated the efficacy and safety of dovitinib (TKI258), a receptor tyrosine kinase inhibitor with potent activity against fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR), in locally advanced or metastatic thyroid cancer patients. Patients and methodsPatients with advanced thyroid cancer that was refractory or not appropriate for 131I received dovitinib orally, 500mg once daily for five consecutive days, followed by a 2-day rest every week. The primary end-point was objective response rate. Secondary end-points were progression-free survival (PFS), overall survival (OS), duration of response, changes in tumour markers and safety. ResultsBetween January 2013 and October 2014, a total of 40 patients were enrolled. There were 23 (57.5%) papillary thyroid cancer, 12 (30%) medullary thyroid cancer and 5 (12.5%) follicular thyroid cancer patients. One patient had withdrawn consent before the administration of dovitinib. The overall response rate was 20.5% (8/39) and disease control rate was 69.1% (26/39). Median PFS was 5.4months (95% confidence interval (CI), 2.0–8.8) and median OS was not reached with 8.4months follow-up duration. Common treatment-related adverse events were diarrhoea (53.8%), anorexia (35.8%), vomiting (25.6%), fatigue (23%) and nausea (20.5%), most of which were grade 1 or 2. There were no grade 4 events or treatment-related deaths. Dose interruption occurred in 12 (30.7%) patients, and 19 (48.7%) patients experienced dose reduction due to adverse events. ConclusionsDovitinib has a modest activity with manageable toxicity in locally advanced or metastatic thyroid cancer.

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

BackgroundSecond-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. MethodsForty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3MUT; n=12), wild-type (FGFR3WT; n=31), or unknown (n=1) FGFR3 status. Patients received 500mg 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). ResultsMost of the patients were men (75%) and over half of the patients were aged ⩾65years (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 FGFR3MUT (0%; 95% confidence interval [CI], 0.0–26.5) and FGFR3WT (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%). ConclusionAlthough 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 2 Trial to Evaluate the Efficacy and Safety of Dovitinib in Patients (Pts) with Gastrointestinal Stromal Tumor (Gist) Refractory and/or Intolerant to Imatinib (Im)

ABSTRACT Aim: Sunitinib is approved for advanced GIST resistant/refractory to IM; however, disease control rate (DCR) at 12 wk was only ≈ 40%. Thus, novel therapeutic second-line strategies are needed to improve outcomes. Dovitinib inhibits several tyrosine kinases (eg, FGFR, VEGFR, PDGFRb, KIT). DOVIGIST (NCT01478373) is a multicenter, single-arm study to evaluate the efficacy and safety of second-line dovitinib in GIST. Methods: Eligible pts (≥ 18 y) had histologically confirmed GIST; pts had advanced/metastatic GIST refractory/intolerant to IM ≥ 400 mg/day or recurrent GIST after adjuvant IM. All pts had ≥ 1 measurable lesion at baseline. Prior tyrosine kinase inhibitors other than IM were not allowed. Pts received dovitinib 500 mg/day (5 days on/2 days off) until progressive disease (PD), unacceptable toxicity, death, or discontinuation. The primary endpoint was DCR (per RECIST 1.1) at 12 wk. Based on prior trials, DCR ≥45% was deemed clinically meaningful. Key secondary endpoints were progression-free survival (PFS), overall response rate (ORR), and safety. Results: Of 39 pts who received ≥1 dose of dovitinib, 1 had unconfirmed GIST histology; thus, the efficacy analysis included 38 pts (median age, 60 y). The median time from diagnosis to first dose of dovitinib was 46.3 mo; 81.6% had PD on IM, 13.2% discontinued IM due to intolerance, and 5.2% had intolerance and PD. The most common grade 3/4 dovitinib-related adverse events (AEs) were fatigue (12.8%), diarrhea, vomiting, and hypertriglyceridemia (7.7% each); 21.1% discontinued due to AEs. One pt died of a heart attack (suspected drug related). The median PFS was 20.1 wk (90% CI, 12.3-32.1). DCR at 12 wk was 52.6% (Table). Conclusions: DOVIGIST met its primary endpoint. The DCR of 52.6% compares favorably with that of other second-line treatments. Dovitinib had promising efficacy and a manageable safety profile, warranting further studies in GIST. Best Response at 12 Wk, n = 38 n % 90% CI Partial response (PR) 1 2.6 Stable disease (SD) 19 50.0 PD 5 13.2 Unknowna 13 34.2 ORR (≥ PR) 1 2.6 0.1-11.9 DCR (≥ SD) 20 52.6 38.2-66.7 a Not all baseline lesions evaluated during follow-up; no PD detected ≤12 wk on dovitinib. Disclosure: H. Joensuu: The Clinical Research Institute of Helsinki University Hospital has received financial support from Novartis and Bayer AG because HJ participated in advisory group meetings or speaking events; J-Y. Blay: Received research support and honoraria from Novartis, GSK, Roche, Pharmamar, Bayer, MSD, JNJ; E. Fumagalli: Founds for studies and research activities: Amgen Dompe, Bayer, Glaxo SK, Merck SD, Novartis, Pfizer, PharmaMar, Sanofi-Aventis, ImClone, Infinity, Janssen Cilag, Lilly, Molmed, Merck SD, Schering Plough Travel for medical meetings: Novartis; G.E. Grignani: Received travel reimbursement from PharmaMar. Expert opinion for Bayer and Glaxo-Welcome; O. Bouche: Received research support and honoraria from Novartis; S. Bauer: received honoraria by Novartis, Pfizer, Bayer and have received a research grant by Novartis (for a clinical trial). Advisory board for Pfizer; C. Barone: Received honoraria as a speaker and chairman; C. Weiss, S. Crippa, M. Camozzi and R. Castellana: Novartis employee; A. Le Cesne: Received honoraria from GSK, Novartis, Pharmamar and Pfizer for advisory board. All other authors have declared no conflicts of interest.

Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib

Background:This prospective, phase II trial evaluated the efficacy and safety of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours (GISTs) after failure of at least imatinib and sunitinib.Methods:Patients received oral dovitinib, 500 mg once daily, for 5 consecutive days, followed by a 2-day rest, every 28 days. The primary endpoint was disease control rate (DCR; objective response+stable disease (SD)) at 24 weeks, assessed by computed tomography (CT) scan according to RECIST v1.0. Metabolic response was evaluated by positron emission tomography (PET)–CT scans performed at baseline and after 4 weeks of treatment.Results:Between September 2011 and April 2012, 30 patients were enroled. DCR at 24 weeks by RECIST v1.0 was 13% and one patient (3%) had a partial response. Based on the European Organization for Research and Treatment of Cancer PET response criteria, four patients (13%) had a metabolic partial response after 4 weeks of treatment. At a median follow-up of 8.3 months (range, 6.3–12.2 months), median progression-free survival (PFS) was 3.6 months (95% confidence interval (CI), 3.5–3.7 months) and median overall survival was 9.7 months (95% CI, 6.0–13.4 months). Metabolic progressive disease at Week 4 was significantly associated with shorter PFS (P=0.03). Grade 3/4 adverse events included asthenia (20%), neutropenia (13%), thrombocytopenia (10%), and hypertriglyceridaemia (10%). Most toxicities were manageable by dose modification.Conclusion:Dovitinib showed modest antitumour activity with manageable toxicities in heavily pretreated patients with advanced GISTs.

A Phase 2, Multicenter, Nonrandomized, Open-Label Study of Dovitinib (TKI258) in Patients with Relapsed or Refractory Multiple Myeloma with or without t(4;14) Translocation

A Phase 2, Multicenter, Nonrandomized, Open-Label Study of Dovitinib (TKI258) in Patients with Relapsed or Refractory Multiple Myeloma with or without t(4;14) Translocation

1481PD - A Phase II Study of Dovitinib in Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors After Failure of Two or More Tyrosine Kinase Inhibitors

ABSTRACT Objectives This prospective, phase 2 study evaluated the efficacy and safety of dovitinib in patients (pts) with advanced gastrointestinal stromal tumors (GISTs) who failed previous standard tyrosine kinase inhibitors (TKI). Methods Thirty pts with pathologically proven metastatic or unresectable GIST who failed a minimum of both imatinib and sunitinib were accrued between Sep 2011 and Apr 2012. Dovitinib was administered orally at 500 mg qd for 5 consecutive days followed by a 2 day rest period. Results The median age was 57.5 years (range, 35-76). All had metastatic disease in the peritoneum (n = 22), liver (n = 20), lung (n = 4), or bone (n = 4). Thirteen pts (43%) also failed nilotinib (n = 8), regorafenib (n = 2) or both nilotinib and regorafenib (n = 3) after failure of imatinib and sunitinib. By RECIST criteria, there were no objective responses, 19 (63.3%) had stable disease (SD), 5 (16.7%) progressive disease (PD), and 6 (20.0%) were not evaluable. By EORTC PET criteria (at 4 weeks), 3 pts (10.0%) achieved a partial response, 15 (50.0%) had SD, 10 (33.3) showed PD, and 2 were not evaluable. With a median follow-up of 4.8 months (range, 0.8-7.5), the medi an progression-free survival (PFS) and overall survival were 3.6 months (95% CI, 2.7-4.4) and 6.2 months (95% CI, 4.9-7.5), respectively. PFS could be predicted by PET response (PD vs no PD) at 4 weeks (p = 0.003). Grade 3 or 4 adverse events of dovitinib with frequency > 5% pts included asthenia (16.7%), leucopenia (6.7%), thrombocytopenia (6.7%), and hypertension (6.7%). Those toxicities were manageable with dose modification, and there were no treatment-related deaths. Conclusions Dovitinib showed antitumor activity with manageable toxicities in this heavily pretreated cohort of GIST patients. Disclosure Y. Kang: Honoraria, consultant, and research fund from Novartis. All other authors have declared no conflicts of interest.

A multicenter, open-label phase II trial of dovitinib, a fibroblast growth factor receptor 1 (FGFR1) inhibitor, in FGFR1-amplified and nonamplified metastatic breast cancer (BC).

289 Background: Amplification of the FGFR1 gene occurs in ≈ 10% of BC, correlates with FGFR1 overexpression, and is mainly observed in estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)- BCs. Dovitinib (TKI258) is a multitargeted tyrosine kinase inhibitor that demonstrated potent antitumor activities in FGFR1-amplified tumor cell lines. This phase 2 study evaluated the efficacy and safety of dovitinib in metastatic HER2- BC. Methods: Patients were stratified into 4 groups based on FGFR1 and hormone receptor (HR) tumor subtype: 1) FGFR1+, HR+; 2) FGFR1+, HR-; 3) FGFR1-, HR+; 4) FGFR1-, HR-. Screening for FGFR1 status was performed by fluorescence/chromogenic in situ hybridization (cutoff ≥ 6 gene copies). Dovitinib (500 mg) was administered once daily on a 5-day-on/ 2-day-off schedule. The primary endpoint was RECIST best overall response rate in patients with measurable disease per external radiology review. Results: Data from 77 of 81 treated patients were available as of January 2011 (n=21, n=34, n=22 in groups 1, 3, 4, respectively). Median number of prior therapies in the metastatic setting was 2 chemotherapy lines (all patients) and 2 endocrine therapy lines (HR+ patients). Liver metastases were present in 58% of patients (81%, 50%, 50% in groups 1, 3, 4, respectively). Most common adverse events included vomiting (75%; grade 3 [g3]: 6%), diarrhea (72%; g3: 6%), nausea (62%; g3: 5%), and asthenia (61%; g3: 17%). Median dovitinib exposure was 1.7 (range, 0-8.2) months, including 8 patients with > 4 months of therapy. Of patients with measurable disease at baseline, in group 1, 13% had unconfirmed partial responses and 44% had stable disease ≥ 4 months (SD4). In groups 3 and 4, 29% and 11% had SD4. Conclusions: This is the first trial reporting efficacy of an FGFR1 inhibitor in patients with FGFR1-amplified BC. Dovitinib showed antitumor activity in patients with HR+, FGFR1- amplified BC and disease stabilization in other subgroups. FGFR1 is likely a relevant target in BC, and FGFR1 amplification may define a segment of dovitinib-sensitive disease. Further evaluation of dovitinib in patients with HR+ BC is planned.

A multicenter, open-label phase II trial of dovitinib, an FGFR1 inhibitor, in FGFR1 amplified and non-amplified metastatic breast cancer.

508 Background: Amplification of the FGFR1 gene occurs in ≈ 10% of breast cancers (BC), correlates with FGFR1 overexpression, and is mainly observed in ER+/Her2− BCs. Preclinical (pc) studies suggest that FGFR1 is a candidate therapeutic target in BC. Dovitinib (TKI258) is a tyrosine kinase inhibitor that targets FGFR, VEGFR, and PDGFR. In pc models, dovitinib demonstrated potent antitumor activities in FGFR1−amplified tumor cell lines. Methods: A 2-stage, phase 2 study to determine the efficacy and safety of dovitinib in 4 groups (gps) of metastatic BC patients (pts): (gp 1: FGFR1+, HR+), (gp 2: FGFR1+, HR−) (gp 3: FGFR1−, HR+), (gp 4: FGFR1−, HR−). Pt selection was performed according to FISH/CISH for FGFR1 (cut-off ≥ 6 gene copies). Dovitinib (500 mg) was administered once daily on a 5-day on/ 2-day off schedule. The primary endpoint was RECIST best overall response rate in pts with measurable disease per external radiology review. Results: As of January 2011, 81 pts were treated, with data for 77 pts available (gp 1 = 21, gp 3 = 34, gp 4 = 22). Prior therapy in the metastatic setting: a median of 2 chemotherapy lines (all pts) and 2 endocrine therapy lines (HR+ pts). 58% of pts had liver metastases (gp1: 81%; gps 3,4: 50%). Most common adverse events included: vomiting (75%; grade 3 [g3]: 6%), diarrhea (72%; g3: 6%), nausea (62%; g3: 5%), and asthenia (61%; g3: 17%). Median exposure was 1.7 (range, 0-8.2) months (mos), including 8 pts who received > 4 mos of therapy. For pts with measurable disease at baseline: gp 1, 2 (13%) had unconfirmed partial responses, and 7 (44%) pts had stable disease ≥ 4 mos (SD4); gps 3 and 4, SD4 was respectively noted in 8 (29%) and 2 (11%) pts. Conclusions: This is the first trial reporting efficacy of an FGFR1 inhibitor in pts with FGFR1−amplified BCs. Dovitinib showed antitumor activity in this heavily pretreated BC population with extensive visceral involvement. Activity was observed in HR+ pts with FGFR1−amplified disease with disease stabilization observed in other subgroups. FGFR1 is likely a relevant target in BC and FGFR1 amplification may define a molecular segment of dovitinib-sensitive disease. Further evaluation of dovitinib in pts with HR+ BC is planned.

Study CTKI258A2202: A multicenter, open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancer.

TPS122 Background: Dovitinib (TKI258) is an oral investigational drug that inhibits fibroblast growth factor (FGF), platelet-derived growth factor-β, and vascular endothelial growth factor (VEGF) receptor kinases with in vitro IC50 values of ∼10 nM. Dovitinib causes antitumor responses ranging from growth inhibition to regression in xenograft tumor models. Amplification of FGFR1 occurs in approximately 10% of breast tumors, and is an independent predictor of overall survival. FGFR1 amplification is uncommon in human epidermal growth factor receptor 2 (HER2) amplified BCs and is predominantly found in estrogen receptor (ER) positive, luminal type BCs. These data support testing dovitinib in women with HER2-negative (HER2-), FGFR1-amplified (FGFR1+) BC. In addition, the antiangiogenic activity of dovitinib may elicit antitumor activity in women with FGFR1-unamplified (FGFR1-) BC. Methods: This multicenter, open-label, 2-stage, phase II trial of dovitinib in FGFR1+ and FGFR1- metastatic HER2- breast cancer will determine the efficacy and safety of dovitinib in 4 groups of female patients (pts): (FGFR1+, HR+), (FGFR1+, HR-) (FGFR1-, HR+), (FGFR1-, HR-) where HR+ is defined as ER and/or progesterone receptor-positive BC. Pts must have received 1-3 prior therapies in the metastatic setting. Pts receive dovitinib 500 mg orally, once daily, on a 5 day on/2 day off schedule, on a 28 day cycle until disease progression or occurrence of unacceptable toxicity. The primary objective is overall response rate. Secondary objectives include disease control rate, progression-free survival, safety/tolerability and pharmacokinetics. The pharmacodynamic effect of dovitinib on plasma/serum biomarkers and the effect of FGFR and VEGF polymorphisms on response will be explored. Pts must have tumor tissue available for FGFR1 amplification screening by FISH/CISH. Analysis for the primary objective will include 20 pts with measurable disease at baseline in each stage for each group. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis Novartis