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 Subgroup analysis by prior anti-VEGF or anti-EGFR target therapy in FRESCO, a randomized, double-blind, Phase III tri1al

2020 ◽  
Author(s):  
Ruihua Xu ◽  
Shukui Qin ◽  
Weijian Guo ◽  
Yuxian Bai ◽  
Yanhong Deng ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Target Therapy ◽  
Objective Response ◽  
Progression Free Survival ◽  
Placebo Treatment ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Colorectal Cancer Patients

Background: FRESCO study demonstrated efficacy and safety of fruquintinib in metastatic colorectal cancer patients. Impact of prior targeted therapy (PTT) on efficacy and safety of fruquintinib was evaluated. Materials & methods: In this subgroup analysis of FRESCO trial, patients were divided into PTT and non-PTT subgroups, and efficacy and safety of fruquintinib were assessed, respectively. Results: In non-PTT subgroup, fruquintinib significantly prolonged overall survival (OS) and progression free survival (PFS) of patients compared with placebo. In PTT subgroup, the median OS and PFS of patients in fruquintinib arm was significantly higher than those in placebo. Treatment-emergent adverse events (TEAEs) rates were similar in both subgroups. Conclusion: Fruquintinib demonstrated clinically meaningful improvement in OS, PFS, objective response rate, and disease control rate with manageable TEAEs in both subgroups. ClinicalTrial Registration: NCT02314819 ( ClinicalTrials.gov )

scholarly journals Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial

2020 ◽  
Vol 38 (24) ◽  
pp. 2773-2781 ◽  
Author(s):  
Michael C. Kreissl ◽  
Lars Bastholt ◽  
Rossella Elisei ◽  
Robert Haddad ◽  
Ole Hauch ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Medullary Thyroid ◽  
Post Hoc Analysis ◽  
Post Hoc

PURPOSE We conducted a post hoc analysis of the vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of vandetanib in patients with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients. PATIENTS AND METHODS Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated. RESULTS Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64; P < .0001), OS (HR, 1.08; 95% CI, 0.72 to 1.61; P = .71), and TWP (HR, 0.67; 95% CI, 0.43 to 1.04; P = .07), and the observed adverse events were consistent with the known safety profile of vandetanib. In this subgroup, the ORR was 37% in the treatment arm versus 2% in the placebo arm. CONCLUSION Vandetanib demonstrated clinical benefit—specifically, increased PFS—in patients with symptomatic and progressive MTC.

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.

Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: A randomized, double-blind phase III trial (ZEST)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8009-8009
Author(s):  
R. B. Natale ◽  
S. Thongprasert ◽  
F. A. Greco ◽  
M. Thomas ◽  
C. M. Tsai ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Double Blind ◽  
Equivalent Efficacy ◽  
Secondary Endpoints ◽  
Previously Treated ◽  
Grade 3 ◽  
To Receive

8009 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. This phase III study compared the efficacy of vandetanib vs erlotinib in patients (pts) with advanced, previously treated NSCLC. Methods: Eligible pts (stage IIIB/IV NSCLC, PS 0–2, 1–2 prior chemotherapies; all histologies permitted) were randomized 1:1 to receive vandetanib 300 mg/day or erlotinib 150 mg/day until progression/toxicity. The primary objective was to show superiority in progression-free survival (PFS) for vandetanib vs erlotinib. Secondary endpoints included overall survival (OS), objective response rate (ORR), time to deterioration of symptoms (TDS; EORTC QoL Questionnaire) and safety. Results: Between Oct 06-Nov 07, 1240 pts (mean age 61 yrs; 38% female; 22% squamous) were randomized to receive vandetanib (n=623) or erlotinib (n=617). Baseline characteristics were similar in both arms. Median duration of follow-up was 14 months, with 88% pts progressed and 67% dead. There was no difference in PFS for pts treated with vandetanib vs erlotinib (hazard ratio [HR] 0.98, 95.22% CI 0.87–1.10; P=0.721), and no difference in the secondary endpoints of OS (HR 1.01, 95.08% CI 0.89–1.16; P=0.830), ORR (both 12%) and TDS (pain: HR 0.92, P=0.289; dyspnea: HR 1.07, P=0.407; cough: HR 0.94, P=0.455). A preplanned non-inferiority analysis for PFS and OS demonstrated equivalent efficacy for vandetanib and erlotinib. The adverse events (AEs) observed for vandetanib were generally consistent with previous NSCLC studies with vandetanib 300 mg. There was a higher incidence of some AEs (any grade) with vandetanib vs erlotinib, including diarrhea (50% vs 38%) and hypertension (16% vs 2%); rash was more frequent with erlotinib (38% vs 28%). The overall incidence of CTCAE grade ≥3 AEs was also higher with vandetanib (50% vs 40%). The incidence of protocol-defined QTc prolongation in the vandetanib arm was 5%. Conclusions: The study did not meet its primary objective of demonstrating PFS prolongation with vandetanib vs erlotinib in pts with previously treated advanced NSCLC. However, vandetanib and erlotinib showed equivalent efficacy for PFS and OS in a preplanned non-inferiority analysis. [Table: see text]

An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC).

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA7512-LBA7512 ◽  
Author(s):  
G. Scagliotti ◽  
I. Vynnychenko ◽  
Y. Ichinose ◽  
K. Park ◽  
K. Kubota ◽  
...  
Keyword(s):  
Cox Model ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
High Rate ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Grade 3 ◽  
Nonsquamous Nsclc

LBA7512 Background: This study evaluated whether motesanib (a selective oral inhibitor of VEGFR 1, 2 and 3; PDGFR and Kit) plus C/P improved overall survival (OS) compared with placebo + C/P in patients (pts) with nonsquamous NSCLC and in a subset of pts with adenocarcinoma. Methods: Pts had stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC. The study initially enrolled all histologies but was amended to exclude pts with squamous NSCLC owing to a high rate of hemoptysis. Pts were randomized 1:1 to receive up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), adverse events (AEs), objective response rate (ORR) and association between placental growth factor (PLGF) change and OS. OS was evaluated using a stratified Cox model and 2-sided log-rank test (α=0.03 for nonsquamous pts and α=0.02 for adenocarcinoma pts). Results: 1090 pts with nonsquamous NSCLC were randomized (Arm A/B, n=541/549); 890 had adenocarcinoma (n=448/442). 61% were men; median age was 60 years (range 21–87); 83% had stage IV disease. At the time of analysis, 753 pts had died (608 pts with adenocarcinoma). Median follow-up was 10.6 mo. OS was not significantly improved in Arm A compared with Arm B (Table). In Arm A, PLGF analysis did not show an association with OS. The incidence of grade ≥3 AEs in Arms A/B was 73/59%. Grade ≥3 AEs occurring more frequently in Arm A than B included neutropenia (22/15%), diarrhea (9/1%), hypertension (7/1%) and cholecystitis (3/0%). The incidence of grade 5 AEs was 14/9% in Arms A/B. Conclusions: In pts with advanced nonsquamous NSCLC, treatment with motesanib + C/P did not significantly improve OS compared with C/P alone. [Table: see text]

REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA8006-LBA8006 ◽  
Author(s):  
Maurice Perol ◽  
Tudor-Eliade Ciuleanu ◽  
Oscar Arrieta ◽  
Kumar Prabhash ◽  
Konstantinos N. Syrigos ◽  
...  
Keyword(s):  
Disease Progression ◽  
Primary Endpoint ◽  
Objective Response ◽  
Pulmonary Hemorrhage ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
Double Blind

LBA8006^ Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. Methods: Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m2 in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). Results: Between Dec 2010 and Feb 2013, 1,253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P<0.001). The hazard ratio (HR) for PFS was 0.762 (P<0.0001); median PFS was 4.5 months (m) for RAM+DOC vs. 3.0m for DOC. REVEL met its primary endpoint; the OS HR was 0.857 (95% CI 0.751, 0.98; P=0.0235); median OS was 10.5m for RAM+DOC vs. 9.1m for DOC. OS was longer for RAM+DOC in most pt subgroups, including SQ and NSQ histology. Grade ≥3 adverse events (AEs) occurring in >5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). Conclusions: REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. Clinical trial information: NCT01168973.

ENGOT-EN6/NSGO-RUBY: A phase III, randomized, double-blind, multicenter study of dostarlimab + carboplatin-paclitaxel versus placebo + carboplatin-paclitaxel in recurrent or primary advanced endometrial cancer (EC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6107-TPS6107
Author(s):  
Mansoor Raza Mirza ◽  
Robert L. Coleman ◽  
Lars Christian Hanker ◽  
Brian M. Slomovitz ◽  
Giorgio Valabrega ◽  
...  
Keyword(s):  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Disease Status ◽  
Phase Iii ◽  
Stage Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Primary Stage ◽  
Patient Reported

TPS6107 Background: Carboplatin-paclitaxel is considered standard systemic anticancer therapy for recurrent or advanced EC for which surgery and/or radiation are not curative. Dostarlimab (TSR-042) is an anti-programmed cell death (PD)-1 humanized monoclonal antibody that has demonstrated antitumor activity and an acceptable safety profile in patients (pts) with recurrent or advanced EC in the GARNET trial. The RUBY trial was designed to evaluate the efficacy and safety of dostarlimab in combination with carboplatin-paclitaxel in recurrent or primary advanced EC compared with carboplatin-paclitaxel alone. Methods: This is a global, randomized, double-blind, multicenter, placebo-controlled study. Eligible pts must have first recurrent or primary stage III or stage IV EC with a low potential for cure by radiation therapy or surgery alone or in combination. Pts with carcinosarcoma are eligible for enrollment. 470 pts will be enrolled from approximately 160 sites in the ENGOT countries, United States, and Canada. Stratification factors are microsatellite instability (MSI) status (MSI-high [MSI-H] or microsatellite stable [MSS]), prior external pelvic radiotherapy (yes or no), and disease status (recurrent, primary stage III, or primary stage IV). Pts will be randomized 1:1 to receive combination dostarlimab 500 mg or placebo + carboplatin AUC 5 + paclitaxel 175 mg/m2 every 3 weeks for 6 cycles followed by dostarlimab 1000 mg or placebo monotherapy every 6 weeks for up to 3 years in the absence of progressive disease, death, unacceptable toxicity, or patient/physician decision to withdraw from the study. The primary endpoint is progression-free survival (PFS) as assessed by the investigator in the all-comers population and the MSI-H population per RECIST version 1.1. Secondary efficacy endpoints are PFS assessed by blinded independent central review per RECIST version 1.1, overall survival, objective response rate, duration of response, disease control rate, safety and tolerability, and patient-reported outcomes. Clinical trial information: NCT03981796.

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