Lenvatinib – A multikinase inhibitor for radioiodine-refractory differentiated thyroid cancer

2016 ◽  
Vol 24 (1) ◽  
pp. 28-32 ◽  
Author(s):  
Yvonne Hewett ◽  
Subash Ghimire ◽  
Bilal Farooqi ◽  
Binay K Shah
Keyword(s):  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
Pivotal Phase ◽  
Multikinase Inhibitor ◽  
The Us ◽  
Phase Iii Study ◽  
New Treatment

Lenvatinib, an oral multikinase inhibitor, was approved by the US Food and Drug Administration in February 2015. In a pivotal phase III study of 392 patients with progressive radioiodine-refractory thyroid cancer, the overall response rate of patients receiving lenvatinib was 64.8%, with complete response in four patients. The median progression-free survival was 18.3 months in the lenvatinib arm versus 3.6 months in patients receiving placebo. Median overall survival was not reached in either arm. Lenvatinib is a promising new treatment for patients with radioiodine (iodine-131)-refractory differentiated thyroid cancer.

scholarly journals Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

2017 ◽  
Vol 35 (29) ◽  
pp. 3315-3321 ◽  
Author(s):  
Maria E. Cabanillas ◽  
Jonas A. de Souza ◽  
Susan Geyer ◽  
Lori J. Wirth ◽  
Michael E. Menefee ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

scholarly journals Defibrotide – A New Treatment Approach for Severe Veno-occlusive Disease

2015 ◽  
Vol 11 (1) ◽  
pp. 11
Author(s):  
Katrina Mountfort ◽  
Mohamad Mohty ◽  
Elisabeth Wallhult ◽  
◽  
◽  
...  
Keyword(s):  
Standard Of Care ◽  
Complete Response ◽  
Occlusive Disease ◽  
Phase Iii ◽  
Haematopoietic Stem Cell ◽  
Large Patient ◽  
Improved Outcomes ◽  
Life Threatening ◽  
Phase Iii Study ◽  
New Treatment

Severe veno-occlusive disease (VOD) is a serious and life-threatening complication of haematopoietic stem cell transplantation (HSCT), for which the standard of care has until recently been supportive care. VOD is the result of a primary injury to sinusoidal endothelial cells and severe VOD is characterised by sinusoidal narrowing and occlusion, which leads to portal hypertension, multi-organ failure (MOF) and, ultimately, death. Defibrotide regulates multiple pathways involved in the pathological processes underlying VOD and is the first drug to be approved in Europe for the treatment of severe VOD. Defibrotide is indicated for the treatment of severe hepatic VOD in HSCT therapy in adults and infants aged over 1 month. A phase III study found significant increases in complete response (CR) and survival with defibrotide compared with historical controls. These data together with earlier studies and an ongoing expanded access protocol in a large patient cohort demonstrate improved outcomes with defibrotide in severe VOD and highlight the importance of treatment with defibrotide

Pharmacodynamic biomarkers of outcomes in the phase III study of lenvatinib in 131I-refractory differentiated thyroid cancer (SELECT).

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 6014-6014 ◽  
Author(s):  
Makoto Tahara ◽  
Martin Schlumberger ◽  
Rossella Elisei ◽  
Mouhammed Amir Habra ◽  
Naomi Kiyota ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Pharmacodynamic Biomarkers

Use of Bendamustine in Chronic Lymphocytic Leukaemia Patients with Co-morbidities

2012 ◽  
Vol 08 (01) ◽  
pp. 52 ◽  
Author(s):  
Véronique Leblond ◽  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Response Rate ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Best Supportive Care ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Study

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia and mainly affects older patients. First-line treatments for 'fit' (go go) and 'unfit' (no go) CLL patients are well defined, in the form of fludarabine–cyclophosphamide–rituximab (FCR) combination chemoimmunotherapy and best supportive care, respectively. However, the majority of CLL patients fall between these two extremes (slow go patients), nevertheless the standard of care for these patients is not well defined. Recent data suggest that bendamustine chemotherapy may be a good option in this group. In a recent Phase III study, significant improvements in overall response rate, complete response and progression-free survival were reported with bendamustine compared with chlorambucil. Chlorambucil plus rituximab has been shown to induce high responses in elderly CLL patients with a relatively low complete response rate. Bendamustine plus rituximab, and reduced-dose fludarabine plus cyclophosphamide plus high-dose rituximab have demonstrated promising efficacy, but have not been evaluated in elderly CLL patients. Several trials are also ongoing evaluating novel cytostatic agents, combination chemotherapy and chemoimmunotherapy regimens in elderly patients.

The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Long-term outcomes in first-line patients (pts)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5096-5096 ◽  
Author(s):  
C. W. Ryan ◽  
R. M. Bukowski ◽  
R. A. Figlin ◽  
J. J. Knox ◽  
T. E. Hutson ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Treatment Protocol ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
The Us ◽  
Phase Iii Study

5096 Background: Sorafenib (SOR) doubled median progression-free survival (PFS) versus placebo in a phase III study (TARGETs) for previously treated pts with clear cell renal cell carcinoma (RCC). We report on pts who had not received any prior systemic anti- cancer therapy (1st line) for advanced RCC from the ARCCS program in the US and Canada, which enrolled a broad range of pts. Methods: Pts received SOR 400 mg bid in the ARCCS open-label, nonrandomized treatment protocol if they were =15 years old with advanced (unresectable, recurrent or metastatic) RCC and had ECOG PS 0–2. In the US, ARCCS enrollment ended with SOR approval in 12/05, and pts were transitioned to commercial drug with 1st line pts being eligible for an additional 6-mo follow-up in an extension protocol (EP); Canadian enrollment completed in 8/06. Response evaluation (baseline and =1 post-baseline radiologic assessment) was conducted every 4 wks in the main study and every 8 wks during the EP. Pts without a confirmatory scan were classified as unconfirmed PR. The primary efficacy analysis on PFS was pre-specified to be performed only on the EP-enrolled pts. Results: Of the 2,488 pts valid for safety in ARCCS, nearly 50% were 1st line (n=1239) of which 69% were male with median age 65 yrs; 77% had prior nephrectomy and 29% had prior radiotherapy. Time from diagnoses to treatment was <1 yr for 52% and =1 yr 36% in these 1st line pts. Grade 3 and 4 adverse events with >2% incidence included hand-foot skin reaction 7.7%, fatigue 4.7%, hypertension 3.8%, rash/desquamation 5.2%, dehydration 2.9, diarrhea and dyspnea 2.6%. Confirmed responses are reported in the table ; 15% had unconfirmed PRs. For the 224 1st line pts enrolled in the EP, median PFS was 35.1 wks (95% CI; 32.7, 41.9). Conclusions: SOR toxicity in 1st line pts appeared similar to that in both overall and 2nd line populations previously reported in the phase III study. The PFS among patients enrolled in the EP is encouraging, but may be biased by low enrollment and selection for non-progressors. [Table: see text] [Table: see text]

scholarly journals Nivolumab in Renal Cell Carcinoma: Current Trends and Future Perspectives

2018 ◽  
Vol 5 (1) ◽  
pp. 15-18 ◽  
Author(s):  
Cesar E Ochoa ◽  
Richard W Joseph
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Novel Therapy ◽  
Pivotal Phase ◽  
Angiogenic Therapy ◽  
Phase Iii Study

Targeted agents form the backbone of most therapeutic strategies in advanced renal cell carcinoma (aRCC) but ultimately resistance develops, and toxicity often leads to discontinuation of treatment, limiting the clinical benefits of these treatments. Nivolumab, a fully human IgG4 anti-PD-1 antibody, selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 and provides a novel therapy option for patients with aRCC. In 2015, the pivotal phase III study CheckMate 025 led to the Food and Drug Administration approval of nivolumab in patients with aRCC who had received prior anti-angiogenic therapy, and in 2017, the phase III study CheckMate 214 showed that combined immunotherapy with nivolumab plus ipilimumab resulted in greater objective response rate and prolonged progression-free survival when compared with sunitinib in intermediate- and poor-risk patients with previously untreated aRCC. Early studies of nivolumab in association with anti-angiogenic therapy have generated enthusiasm and multiple combination trials are ongoing.

A phase II study of ziv-aflibercept (Z) + FOLFIRI in Japanese patients (pts) with metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 707-707 ◽  
Author(s):  
Taroh Satoh ◽  
Tadamichi Denda ◽  
Tetsuya Hamaguchi ◽  
Naotoshi Sugimoto ◽  
Takashi Ura ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Complete Response ◽  
Japanese Patients ◽  
Phase Iii ◽  
Open Label ◽  
Secondary Endpoints ◽  
Phase Iii Study

707 Background: VEGF promotes tumor angiogenesis and metastasis. Z blocks the activity of VEGF-A/-B, and placental growth factor and was shown in the VELOUR phase III study (NCT00561470) outside of Japan to significantly improve overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in mCRC pts as a second-line treatment given with FOLFIRI. Goals of the current open-label, multicenter phase II study were to assess the efficacy and safety of Z + FOLFIRI in a post-oxaliplatin setting in mCRC pts in Japan. Methods: Pts received Z (4 mg/kg) + FOLFIRI (400 mg/m2 bolus 5-fluorouracil [FU]; 2400 mg/m2 continuous infusion 5-FU; 200 mg/m2 levofolinate; 180 mg/m2 irinotecan) every 2 weeks until progression, unacceptable toxicity, or study withdrawal. Primary endpoint: ORR (required 60 pts in order to obtain a 95% CI width of 16–20%, assuming an ORR of 10–20%). Secondary endpoints: PFS, OS, and safety. Tumors were assessed by independent reviewers every 6 ± 1 weeks until progression. Results: Study enrolled 62 pts; 50 pts (83.3%) had received prior bevacizumab. Of 60 pts evaluable for response, 5 had a partial response and none had a complete response, resulting in an ORR of 8.3% (95% CI: 1.3–15.3%). The median PFS was 5.42 months (95% CI: 4.140–6.702), and the median OS was 15.59 months (range 11.20–19.81). Forty-one pts (66.1%) died due to progression; none died due to study treatment. Pts underwent a median of 8 treatment cycles (range 1–31) lasting a median of 21.8 weeks (range 2–73). The median relative dose intensity was 0.99 (range 0.2–1.0) for Z, 0.87 (range 0.4–1.0) for irinotecan, and 0.96 (range 0.7–1.0) for 5-FU. All pts had ≥1 treatment emergent adverse event (TEAE; see table). Conclusions: The ORR was 8.3% (95% CI: 1.3–15.3%), and the median OS was 15.59 months. The safety profile was consistent with that reported previously. Registered as NCT01882868. Clinical trial information: NCT01882868. [Table: see text]

Effect of Age on the Efficacy and Safety of Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial

2017 ◽  
Vol 35 (23) ◽  
pp. 2692-2699 ◽  
Author(s):  
Marcia S. Brose ◽  
Francis P. Worden ◽  
Kate L. Newbold ◽  
Matthew Guo ◽  
Arti Hurria
Keyword(s):  
Thyroid Cancer ◽  
Older Patients ◽  
Differentiated Thyroid Cancer ◽  
Objective Response ◽  
Age Groups ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Effect Of Age

Purpose In the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). This prespecified subanalysis investigated the effect of age on the efficacy and safety of lenvatinib. Patients and Methods This randomized, double-blind, phase III study enrolled patients with histologically confirmed RR-DTC stratified by age (≤ 65 or > 65 years). Patients (N = 392) received lenvatinib 24 mg/day (n = 261) or placebo (n = 131). The primary end point was PFS; secondary end points included overall survival (OS), objective response rate, and safety. Results In both treatment arms, median ages were 56 (younger group) and 71 years (older group). PFS benefit was maintained with lenvatinib versus placebo in the younger and older age groups, with median PFS of 20.2 versus 3.2 months (hazard ratio [HR], 0.19; 95% CI, 0.13 to 0.27; P < .001) and 16.7 versus 3.7 months (HR, 0.27; 95% CI, 0.17 to 0.43; P < .001), respectively. PFS did not differ with age in either treatment arm. OS was improved in older lenvatinib-treated patients versus placebo (HR, 0.53; 95% CI, 0.31 to 0.91; P = .020). Younger lenvatinib-treated patients showed significantly higher ORR (72% v 55%; P = .0038), longer time to first dose reduction (3.7 v 1.5 months), and lower proportion of grade ≥ 3 treatment-related adverse events (67% v 89%; P < .001) compared with older patients. Conclusion This subanalysis demonstrated improved PFS with lenvatinib treatment versus placebo in both age groups, although higher toxicity was observed in older patients. Despite the allowance of crossover after disease progression, the OS benefit was observed in older patients, suggesting that lenvatinib should be considered for treatment of patients of any age with RR-DTC.

scholarly journals Pain Progression at Initiation of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Post Hoc Analysis of the PROSELICA Study

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1284
Author(s):  
Nicolas Delanoy ◽  
Debbie Robbrecht ◽  
Mario Eisenberger ◽  
Oliver Sartor ◽  
Ronald de Wit ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Radiological Progression ◽  
Post Hoc Analysis ◽  
Psa Response ◽  
Phase Iii Study ◽  
Psa Progression ◽  
Previously Treated ◽  
Post Hoc

Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m2 (CABA20) was non-inferior to cabazitaxel 25 mg/m2 (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes. Methods: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (RADIO-p), no pain), RADIO-p (±PSA-p, no pain), or pain progression (PAIN-p, ±PSA-p, ±RADIO-p). Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed. Results: All randomized patients (n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients (PSA-p = 24.4%, RADIO-p = 20.8%, PAIN-p = 54.8%). Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups (12.0 versus 16.8 and 18.4 months, respectively, p < 0.001). In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS (HR = 1.44, p < 0.001). PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p. Conclusions: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise.

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