Cristina Ivanescu

Tivozanib Versus Sorafenib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma: Results From a Phase III Trial

PURPOSE Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review. RESULTS A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%). CONCLUSION Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.

Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial

BACKGROUND Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial. METHODS In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991. FINDINGS Median treatment duration was 16·6 months (IQR 10·1-21·1) in the enzalutamide group and 4·6 months (2·8-9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1-13·9) in the enzalutamide group and 5·6 months (5·5-5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54-0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6-5·7) in the enzalutamide group and 5·6 months (5·4-5·6) in the placebo group (HR 0·62 [95% CI 0·53-0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5-not reached) and 31·3 months (95% CI 23·9-not reached) in the placebo group (HR 0·72 [95% CI 0·61-0·84]; p<0·0001). INTERPRETATION In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer. FUNDING Astellas Pharma and Medivation.

Clinical efficacy of fidaxomicin compared with vancomycin and metronidazole in Clostridium difficile infections: a meta-analysis and indirect treatment comparison

OBJECTIVES To evaluate the efficacy of fidaxomicin treatment, which has a limited effect on the normal gut flora, compared with vancomycin and metronidazole treatment in Clostridium difficile infections (CDIs). METHODS A systematic literature review was conducted in July to August 2011 and updated in July 2013. For fidaxomicin versus vancomycin, efficacy was evaluated using meta-analysis of data from two Phase III direct comparative studies (n = 1164). As there were no studies comparing fidaxomicin and metronidazole, an indirect comparison was made using data from three vancomycin versus metronidazole studies (n = 345), using the methodology of Bucher et al. (J Clin Epidemiol 1997; 50: 683-91). This provides an OR for the indirect comparison of fidaxomicin versus metronidazole when direct evidence of fidaxomicin versus vancomycin and vancomycin versus metronidazole is available. RESULTS Clinical cure rates were similar for fidaxomicin and vancomycin; the OR (95% CI) was 1.17 (0.82, 1.66). Recurrence [0.47 (0.34, 0.65)] was significantly lower and sustained cure rates [1.75 (1.35, 2.27)] significantly higher for fidaxomicin than vancomycin. Similar results were obtained in patient subgroups with severe CDI and with non-severe CDI. From the indirect comparison, the likelihood of recurrence [0.42 (0.18, 0.96)] and sustained cure [2.55 (1.44, 4.51)] were significantly improved for fidaxomicin versus metronidazole. Again, similar results were obtained in those with severe and non-severe CDI. CONCLUSIONS Fidaxomicin provides improved sustained cure rates in patients with CDI compared with vancomycin. An indirect comparison indicates that the same is also true for fidaxomicin versus metronidazole. In view of these data, fidaxomicin may be considered as first-line therapy for CDI.

Impact of Enzalutamide Compared with Bicalutamide on Quality of Life in Men with Metastatic Castration-resistant Prostate Cancer: Additional Analyses from the TERRAIN Randomised Clinical Trial

BACKGROUND Improving health-related quality of life (HRQoL) is an important goal in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE To examine the impact of enzalutamide versus bicalutamide on HRQoL in mCRPC. DESIGN, SETTING, AND PARTICIPANTS TERRAIN is a multinational, phase 2, randomised, double-blind study in asymptomatic/mildly symptomatic men with mCRPC (ClinicalTrials.gov, NCT01288911). Patients were randomised (1:1) via an interactive voice and web response system to enzalutamide 160mg/d (n=184) or bicalutamide 50mg/d (n=191), with androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), European Quality of Life 5-Domain Scale (EQ-5D), and Brief Pain Inventory, Short-form questionnaires every 12 wk. Primary and secondary analyses utilised mixed models for repeated measures and pattern mixture models, respectively. RESULTS AND LIMITATIONS At 61 wk, 84 (46%) enzalutamide and 39 (20%) bicalutamide patients in the study were assessed. At 61 wk, changes from baseline favoured enzalutamide versus bicalutamide on three FACT-P domains in mixed models for repeated measures analyses and seven in pattern mixture models analyses. There were no differences in changes for EQ-5D index/visual analogue scale scores. Risk of first deterioration was lower with enzalutamide for FACT-P total (hazard ratio: 0.64, 95% confidence interval: 0.46-0.89, p=0.007), FACT-G total (hazard ratio: 0.70, 95% confidence interval: 0.50-0.98, p=0.04), PCS pain (hazard ratio: 0.74, 95% confidence interval: 0.54-1.00, p=0.048), and EQ-5D index (hazard ratio: 0.66, 95% confidence interval: 0.47-0.93, p=0.02) scores versus bicalutamide. Brief Pain Inventory, Short-form scores increased in both groups. There was no difference in time-to-pain progression. Study limitations include the exploratory nature of the HRQoL analyses, lack of multiple comparisons corrections, and unknown effects of anxiety/depression on HRQoL. CONCLUSIONS In patients with asymptomatic/mildly symptomatic mCRPC, enzalutamide provides HRQoL benefit versus bicalutamide. PATIENT SUMMARY Enzalutamide treatment was associated with better health-related quality of life in several domains versus bicalutamide in asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer. This likely relates to previously reported lower rates of symptomatic disease progression.

Effect of enzalutamide on health-related quality of life (HRQoL) in men with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel-based therapy: Results from the AFFIRM study.

17 Background: In the AFFIRM trial, enzalutamide (ENZ), an oral androgen receptor inhibitor, was superior to placebo (PBO) in overall survival (HR=0.63 [0.53, 0.75], p<0.001) [Scher et al. NEJM 2012;367:1187]. This analysis focuses on impact of ENZ on HRQoL. METHODS Men with mCRPC previously treated with docetaxel were randomized (2:1) to receive ENZ (160mg/day) or PBO. HRQoL was assessed at baseline (BL), weeks 13, 17, 21, 25 and every subsequent 12 weeks using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Patients with BL and ≥1 post-BL evaluable forms were included in this analysis. Change from BL in FACT-P scores over 25 weeks of treatment was analyzed using linear mixed models. HRQoL improvement/deterioration was defined as a 10-point or higher increase/decrease during the study compared to BL on the FACT-P total score. RESULTS The HRQoL analysis included 938 patients. Changes from BL in FACT-P total score and domains over 25 weeks of treatment were significantly smaller (less decline) with ENZ than PBO (Table). A greater percentage of patients on ENZ reported HRQoL improvement compared to PBO (42.2% vs 14.5%; p<0.001). Median time to first HRQoL deterioration was 9.0 months for ENZ and 3.7 months for PBO (p<0.001). Overall, 46.8% of patients on ENZ and 59.3% on PBO experienced HRQoL deterioration at some point while on treatment (p=0.001). CONCLUSIONS Compared to PBO, therapy with ENZ yields significantly better HRQoL across all domains and delays deterioration. The extent of the HRQoL advantage, along with the previously established overall survival gain of ENZ over PBO, suggest that ENZ confers a significant and meaningful clinical benefit to men with mCRPC. [Table: see text].

Treatment benefit of tivozanib hydrochloride versus sorafenib on health-related quality of life (HRQoL) among patients (pts) with advanced/metastatic renal cell carcinoma (mRCC): TIVO-1 study results.

355 Background: Tivozanib hydrochloride (T) was superior to sorafenib (S) in progression-free survival (medians of 11.9 vs. 9.1 months, respectively; 12.7 vs. 9.1 months, respectively, for metastatic treatment-naïve pts) in the phase III TIVO-1 study in pts with mRCC. T showed a differentiated safety profile with lower rates of dose interruptions/reductions v S (18/12 vs. 35/43, respectively; p<0.001). TIVO-1 also evaluated patient self-reported HRQoL. METHODS Pts with mRCC were randomized 1:1 to receive T (1.5 mg PO once daily for 3 weeks on, 1 week off) or S (400 mg bid, continuously). HRQoL was assessed on Cycle 1/Day1 (baseline [BL]) and at the beginning of each cycle, using the Functional Assessment of Cancer Therapy-General (FACT-G), FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS), and EuroQol 5-dimensional (EQ-5D) questionnaires; EQ-5D scores are not reported here. Pts with BL and ≥1 post-BL evaluable forms were analyzed. Changes from BL in FACT-G and FKSI-DRS scores over 18 treatment cycles were analyzed using repeated measures mixed-effects models. QoL improvement/deterioration was defined as an increase/decrease from BL of ≥3 points for FACT-G subscales and FKSI-DRS total score and 7 points for the FACT-G total score during the study. RESULTS In the mixed effects analyses, no significant differences in HRQoL (FACT-G and FKSI-DRS) were noted between T and S. More pts receiving T vs. S experienced a significant improvement during the study in physical well-being (PWB) (25.7% vs. 16.4%; p=0.011) and a favorable trend in all other FACT-G and FKSI scores (p values: 0.078-0.405). FKSI improvement was greater with T than S in treatment-naïve pts (34.1% vs. 23.6%; p=0.023), pts with ≥2 metastases (32.9% vs. 24.7%; p=0.054), or pts <65 years old (33.0% vs. 22.8%; p=0.022). Median time to QoL deterioration was usually longer with T (3.75-7.66 months) than S (2.04-8.80 months). CONCLUSIONS HRQoL was generally similar for T and S. Non-significant numeric differences usually favored T over S, and PWB improvement occurred significantly more often with T. These results support the previously-reported PFS advantage of T over S. CLINICAL TRIAL INFORMATION NCT01030783.

762PDIMPACT OF ENZALUTAMIDE ON SKELETAL RELATED EVENTS (SRES), PAIN AND QUALITY OF LIFE (QOL) IN THE PREVAIL TRIAL

ABSTRACT Aim: Enzalutamide (ENZ) improved overall survival vs. placebo (PL) in PREVAIL, a phase 3 trial in asymptomatic/mildly symptomatic chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [Beer et al, ASCO GU 2014]. PREVAIL also prospectively evaluated SREs, pain and QoL. Methods: Pts were randomized to ENZ (160mg/day; n = 872) or PL (n = 845). SREs were assessed throughout the study and time to 1st SRE measured. QoL was assessed at baseline (BL) and during treatment (tx) on the FACT-P and EQ-5D; changes from BL over time were compared using repeated measures analyses. Pain was assessed with the BPI-SF at BL, and months (mo) 3 and 6. Pts with BL and ≥1 post-BL score were analyzed using pre-specified criteria for clinically meaningful pain progression (pain severity: increase ≥30% from BL; pain interference: increase ≥50% of BL standard deviation) and QoL deterioration (Cella et al, VIH 2009; Pickard et al, HQOL 2007). Results: Median tx duration was 16.6 (ENZ) and 4.6 (PL) mo; BL pain and QoL scores were similar between arms. Overall, 32% (ENZ) and 37% (PL) of pts reported at least one SRE. Compared to PL, ENZ significantly reduces the risk of 1st SRE occurrence (hazard ratio: 0.72 [0.61, 0.84], p Time to 1st deterioration (mo), median (95% Cl) ENZ (n = 872) PL (n = 845) P-value Hazard ratioa (95% CI) EQ-5D instrument Visual analogue scale 22.14 (19.35;27.66) 13.83 (11.07;16.59) 0.67 (0.56;0.80) FACT-P instrument Physical well-being 10.84 (8.31;11.07) 5.55 (5.49;5.62) 0.74 (0.65;0.85) Functional well-being 8.54 (8.31;11.07) 3.09 (2.86;5.55) 0.72 (0.62;0.82) Emotional well-being 19.48 (16.59;25.07) 11.01 (8.25;11.40) 0.67 (0.57;0.79) Social well-being 24.87 (14.16;NYR) 8.51 (6.01;13.86) 0.74 (0.63;0.86) Prostate Cancer Subscale 5.65 (5.55;8.31) 2.83 (2.79;2.96) 0.69 (0.60;0.78) FACT-P total score 11.30 (11.07;13.86) 5.55 (5.49;5.59) 0.62 (0.54;0.72) Pain progression, n(%) Pain severity 329/802 (41) 317/628 (50) Pain interference 247/788 (31) 255/613 (42) Conclusions: In PREVAIL, in addition to overall survival benefit, ENZ was also associated with clinically significant patient benefits compared to PL, including a delay in time to 1st SRE, superior QoL, a delay in QoL deterioration, and significantly lower proportion of pts with pain. Disclosure: Y. Loriot: Consultant/Advisory: Astellas Research Funding: Astellas Other: Sanofi, Janssen, Bayer, Cellgene; K. Miller: Consulting: Astellas/Medivation Consultancy: Astellas, Amgen, Janssen, Medivation, Novartis, Roche Lectures: Novartis, Janssen, Pierre-Fabre; C.N. Sternberg: Honoraria: Astellas, Johnson & Johnson, Ipsen, Bayer, Millenium; K. Fizazi: Advisory Board: Astellas/Medivation Speaker: Astellas/Medivation; J.S. de Bono: Astellas/Medivation; S. Chowdhury: Advisory Board/Lecture: Astellas, Janssen, Sanofi-Aventis, Dendreon Speaker: GSK; C. Higano: Research funding: Astellas/Medivation, Algeta, Aragon, Dendreon, Sanofi Consultant/Advisory: Astellas/Medivation, Dendreon, Bayer, Johnson & Johnson; S. Noonberg: Employee: Medivation; S. Holmstrom, F.G. Perabo and D. Phung: Employee: Astellas; H. Mansbach: Employee: Medivation; C. Ivanescu: Astellas: payment for writing or reviewing a manuscript, provision of writing assistance or administrative support, consultancy; K. Skaltsa: Astellas: Payment for writing or reviewing a manuscript, provision of writing assistance or administrative support, consultancy; T. Beer: Research Funding: Astellas/Medivation, Janssen Consultant: Janssen; B. Tombal: Advisor: Astellas/Medivation, Ferring Speaker: Astellas, Ferring