Ericson, Solveig G.

Background: The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. Methods: Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy ( N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. Results: At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. Conclusions: Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.

Abstract Background: Aromatase inhibitor (AI) therapy effectively increases disease-free survival in postmenopausal women (PMW) with ER+ and/or PR+ breast cancer (BCa). However, the use of AIs results in nearly complete ablation of estrogen production which can lead to accelerated bone loss and increased fracture risk. The Z-FAST study evaluated the efficacy and safety of zoledronic acid (ZOL) in preventing AI associated bone loss in PMW with early breast cancer (EBC) who received adjuvant letrozole (LET).Material and Methods: 602 PMW with stage I-IIIa ER+ and/or PR+ BCa starting LET (2.5 mg qd x 5 yrs) were randomized (1:1) to upfront ZOL (4 mg IV q 6 mos) vs delayed ZOL. The delayed arm (D) received ZOL when either the post-baseline T-score decreased to <-2 or a clinical fracture occurred. All patients (pts) were treated with calcium and vitamin D. The primary endpoint, the percent change in lumbar spine (LS) bone mineral density (BMD) at 12 mos, was previously reported (JCO; 25:829, 2007). The 5 year (5y) final study results are reported here.Discussion: Baseline characteristics were similar between groups. 180 pts in upfront ZOL arm (U) and 175 pts in D completed full 5y study. Of pts with BMD data available, U (n=140) showed a mean increase of 6.2% in LS BMD while D (n=132) showed a mean decrease of 2.4%, resulting in an absolute difference of 8.6% (p<0.001). U (n=141) showed a mean increase of 2.6% in total hip (TH) BMD while D (n=132) showed a mean decrease of 4.1%, resulting in an absolute difference of 6.7% (p<0.001). When BMD data in D was excluded after pts started ZOL (censored analysis), the absolute difference in LS and TH BMD between the two arms was 11.3% and 8.7%, respectively. Among pts with baseline LS T-score between -1 and -2, 27.9% (19) U pts [8.6% (7) D pts] returned to normal T-score (T-score >-1), and no U pts as compared to 4.9%(4) D pts became severely osteopenic (T <-2). 17.7% (53) D pts met criteria that required initiation of ZOL. Although the study was not designed to detect a significant difference in the fracture rate between treatment arms, fractures occurred in 10.7% (29) U pts and 12.4% (33) D pts. Administration of ZOL q 6 mos for up to 5y was safe and well tolerated. No serious renal adverse events suspected related to ZOL and no confirmed osteonecrosis of the jaw cases (ONJ) were reported. Disease recurrence including death due to disease progression was reported in 7.0%, 95% C.I. (3.7%-10.3%) from K-M (16) pts in U, and 8.8%, 95% C.I. (5.2%-12.5%) (21) pts in D.Conclusion: The 5y follow-up of the Z-FAST trial show that the overall difference in the percentage change in BMD between U and D, at both LS and TH, progressively increased from baseline through 5y. These data demonstrate that ZOL 4mg IV q 6 mos is effective in preventing bone loss associated with adjuvant AI therapy in PMW with EBC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4083.

Abstract Learning Objectives After reading this article, the reader should be able to: Monitor for and treat to prevent bone loss in postmenopausal breast cancer patients receiving an aromatase inhibitor.Describe the methodology of the Z-FAST and ZO-FAST clinical trials.Discuss the effectiveness and tolerability of zoledronic acid when administrated to prevent bone loss associated with aromatase inhibitors. CME This article is available for continuing medical education credit at CME.TheOncologist.com Background. The interim (12-month) results of two similarly designed, ongoing studies (the Zometa®-Femara® Adjuvant Synergy Trials [Z-FAST and ZO-FAST]) suggest that zoledronic acid (4 mg intravenously every 6 months) when initiated with adjuvant letrozole increases bone mineral density (BMD) of the lumbar spine (LS) in postmenopausal women with early-stage breast cancer compared with patients who receive zoledronic acid only when bone loss became clinically significant or a fragility fracture occurred. Methods. An integrated analysis was performed to maximize the value of the large pool of data from the two studies in answering clinically relevant questions. The primary objective was to compare the change in LS BMD at month 12. Secondary objectives included comparing (a) the change in total hip (TH) BMD, (b) changes in bone turnover marker concentrations, (c) time to disease recurrence, and (d) safety at month 12. Findings. The integrated analysis included 1,667 patients. At month 12, LS BMD was 5.2% higher in the upfront group than in the delayed group; TH BMD was 3.5% higher. N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 21.3% and 12.8% in the upfront group and increased by 21.7% and 24.9% in the delayed group, respectively (p < .0001 for intergroup comparisons). Fewer patients receiving upfront zoledronic acid experienced disease recurrence than patients in the delayed group—seven patients (0.84%) versus 17 patients (1.9%) (p = .0401). Fracture rates were similar. No confirmed osteonecrosis of the jaw was reported. Conclusions. The results of this analysis strengthen the statistical validity of the preliminary results of the Z-FAST and ZO-FAST studies, showing that upfront zoledronic acid prevents aromatase inhibitor–associated bone loss more effectively than delayed-start zoledronic acid in postmenopausal women with early-stage breast cancer receiving letrozole. Additionally, disease recurrence appears to be lower with upfront zoledronic acid, but further follow-up is needed to confirm these interim results.