[Show abstract][Hide abstract] ABSTRACT: Purpose:
A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma.
Patients and methods:
RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end points included combined PFS for each sequence, overall survival (OS), and safety.
Of 471 enrolled patients, 238 were randomly assigned to first-line everolimus followed by sunitinib, and 233 were randomly assigned to first-line sunitinib followed by everolimus. The primary end point was not met; the median PFS was 7.9 months for first-line everolimus and 10.7 months for first-line sunitinib (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.8). Among patients who discontinued first-line, 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus. The median combined PFS was 21.1 months for sequential everolimus then sunitinib and was 25.8 months for sequential sunitinib then everolimus (HR, 1.3; 95% CI, 0.9 to 1.7). The median OS was 22.4 months for sequential everolimus and then sunitinib and 32.0 months for sequential sunitinib and then everolimus (HR, 1.2; 95% CI, 0.9 to 1.6). Common treatment-emergent adverse events during first-line everolimus or sunitinib were stomatitis (53% and 57%, respectively), fatigue (45% and 51%, respectively), and diarrhea (38% and 57%, respectively).
Everolimus did not demonstrate noninferiority compared with sunitinib as a first-line therapy. The trial results support the standard treatment paradigm of first-line sunitinib followed by everolimus at progression.
[Show abstract][Hide abstract] ABSTRACT: Background: Sequential SUN (tyrosine kinase inhibitor, TKI) until progression of disease (PD) followed by EVE (mTOR inhibitor) is standard therapy for patients with mRCC. This open-label, multicenter, phase II trial compared 1st-line EVE to 1st-line SUN (NCT00903175). Sequential EVE→SUN was also compared with standard SUN→EVE. Methods: Patients with mRCC (clear or non-clear cell) naive to prior systemic therapy were randomized 1:1 to either 1st-line EVE 10 mg/day or SUN 50 mg/day (4 weeks on, 2 weeks off) until PD. Patients then crossed over and continued on the alternate drug until PD. Primary objective was to assess PFS noninferiority of 1st-line EVE to 1st-line SUN; defined as an observed hazard ratio (HR)1st EVE/SUN ≤1.1. Overall survival (OS), combined 1st-line and 2nd-line PFS, and safety were secondary end points. Results: From10/09 to 6/11, 471 patients enrolled (EVE→SUN, n = 238; SUN→EVE, n = 233). Median age was 62 years, 85.4% had clear-cell RCC, and MSKCC favorable/intermediate/poor risk was 30/56/14%. Median follow-up was 22.7 months. A total of 53.7% of patients who discontinued 1st-line EVE entered into 2nd-line SUN and 51.6% of patients who discontinued 1st-line SUN entered into 2nd-line EVE. Median PFS (95% CI) was 7.9 (5.6-8.2) months for 1st-line EVE and 10.7 (8.2-11.5) months for 1st-line SUN. HR1st EVE/1st SUN (95% CI) was 1.43 (1.15-1.77). Median OS (95% CI) was 22.4 (19.7-NA) months for EVE→SUN and 32.0 (20.5-NA) months for SUN→EVE; HREVE-SUN/SUN-EVE (95% CI) was 1.24 (0.94-1.64). A trend in favor of SUN→EVE for OS was observed, but will need to be confirmed with final OS analysis. Additional efficacy results for secondary end points are forthcoming. Common treatment-emergent adverse events for 1st-line EVE vs SUN, respectively, were stomatitis (53% vs 57%), fatigue (45% vs 51%), and diarrhea (38% vs 57%). Conclusions: Noninferiority of PFS for 1st-line EVE compared with SUN was not achieved in this randomized phase II trial of mRCC patients. The treatment paradigm remains SUN→EVE since the sequence achieved optimal clinical benefit.
[Show abstract][Hide abstract] ABSTRACT: Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting.
Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence.
At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P < .0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P = .3803) and Kaplan-Meier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0-10.3]; delayed, 10.5 [95% CI, 6.6-14.4]; P = .6283) were similar at month 61.
Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long-term coadministration of letrozole and zoledronic acid is well tolerated.
Cancer 03/2012; 118(5):1192-201. · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment with aromatase inhibitors decreases bone mineral density (BMD) and may increase the risk of fractures in postmenopausal women with early-stage breast cancer. The addition of zoledronic acid to adjuvant letrozole therapy may protect against bone loss.
Patients receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months). The delayed group received zoledronic acid when lumbar spine (LS) or total hip (TH) T score decreased to less than -2.0 or when a nontraumatic fracture occurred. The primary end point of this study was to compare the change in LS BMD at month 12 between the groups. Secondary end points included change in TH BMD and changes in serum bone turnover markers at month 12.
The upfront and delayed groups each included 301 patients. At month 12, LS BMD was 4.4% higher in the upfront group than in the delayed group (95% CI, 3.7% to 5.0%; P < .0001), and TH BMD was 3.3% higher (95% CI, 2.8% to 3.8%; P < .0001). In the upfront group, mean serum N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 15.1% (P < .0001) and 8.8% (P = .0006), respectively, at month 12, whereas concentrations increased significantly in the delayed group by 19.9% (P = .013) and 24.3% (P < .0001), respectively.
With 1 year of follow-up, results of the primary end point of the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) indicate that upfront zoledronic acid therapy prevents bone loss in the LS in postmenopausal women receiving adjuvant letrozole for early-stage breast cancer.