Ghulam Warsi

Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results.

BACKGROUND Postmenopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures. The ongoing Zometa-Femara Adjuvant Synergy Trial (Z-FAST) is evaluating the efficacy and safety of zoledronic acid in preventing such bone loss. PATIENTS AND METHODS In this multicenter study, postmenopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole were randomized to receive up-front or delayed-start zoledronic acid (ZA; 4 mg intravenously every 6 months) for 5 years. Delayed-start ZA was administered if the lumbar spine (LS) or total hip (TH) T score fell below -2.0 or a nontraumatic fracture occurred. The primary endpoint was to compare the change from baseline in LS bone mineral density (BMD) between groups at month 12; secondary endpoints, measured at other predetermined timepoints, included comparing changes in TH BMD, LS BMD, and markers of bone turnover, fracture incidence, and time to disease recurrence. Herein, we report the results of the 36-month interim analysis. RESULTS Overall, 301 patients were randomized to each group. At month 36, the absolute difference in mean LS and TH BMDs between the up-front and delayed groups was 6.7% and 5.2%, respectively (P < .0001 for both). Although this study was not designed to show antifracture efficacy, the incidence of fractures was slightly higher in the delayed group (up-front, 17 [5.7%] vs. delayed, 19 [6.3%]) but not statistically significant (P = .8638). Pyrexia (27 [9%] vs. 6 [2%]; P = .0002) and bone pain (39 [13%] vs. 20 [6.7%]; P = .01) were more common in up-front patients; cough (13 [4.3%] vs. 27 [9%]; P = .03) was more common in delayed patients. No severe renal dysfunction or confirmed cases of osteonecrosis of the jaw were reported. Disease recurrence was reported in 9 up-front (3.0%) and 16 delayed (5.3%) patients (Kaplan-Meier analysis, P = .127), with an absolute decrease of 2.3%. CONCLUSION Up-front ZA more effectively prevents AI-associated bone loss in postmenopausal women with early breast cancer than delaying therapy until substantial bone loss or fracture occurs.

Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole.

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.

The Effect of Zoledronic Acid on Aromatase Inhibitor-Associated Bone Loss in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole: The Z-FAST Study 5-Year Final Follow-Up.

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 -1), and no U pts as compared to 4.9%(4) D pts became severely osteopenic (T Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4083.

Prospective assessment of effects on iron-overload parameters of deferasirox therapy in patients with myelodysplastic syndromes

We report the first prospective study evaluating the effects of deferasirox on liver iron concentration (LIC), labile plasma iron (LPI) and pharmacokinetics (PK) along with serum ferritin values in patients with IPSS Low- and Intermediate-1 risk myelodysplastic syndromes (MDS) and evidence of iron overload. Twenty-four heavily transfused MDS patients were enrolled in a planned 52 weeks of therapy. PK studies showed dose-proportional total drug exposure. Data demonstrated that deferasirox was well tolerated and effectively reduced LIC, LPI and serum ferritin in the iron-overloaded patients with MDS who completed 24 and 52 weeks of therapy despite ongoing receipt of red blood cell transfusions.

Multicenter, randomized, phase 2 study of zoledronic acid in combination with docetaxel and carboplatin in patients with unresectable stage IIIB or stage IV non-small cell lung cancer

This study was designed to evaluate the efficacy and safety of combined zoledronic acid and docetaxel/carboplatin in patients with non-small cell lung cancer (NSCLC) as preclinical studies showed synergistic antitumoral activity with bisphosphonates and docetaxel. Patients with inoperable stage IIIB or stage IV NSCLC were randomized 2:1 to receive docetaxel 75mg/m(2) and carboplatin area under the concentration time curve 6 with (Arm A) or without (Arm B) zoledronic acid 4mg every 3 weeks for 6 cycles. Patients responding in Arm A were rerandomized to receive monthly zoledronic acid (maximum: 12 months [Arm A1] or no zoledronic acid [Arm A2]). Patients responding in Arm B entered Arm B1 for follow-up evaluation only. The primary endpoint was the proportion of patients without disease progression; secondary endpoints were time to disease progression (TTP), TTP in bone, best overall response rate, 1-year overall survival (OS) time, and safety; study not powered to detect endpoint differences. Of 150 patients, 98 were randomized to Arm A and 52 to Arm B. In the treatment phase, results were similar between groups in the proportion of patients without disease progression (40.9% vs 38.8%; P=.8096) and median TTP (132d vs 132d; P=.9622). One-year OS times and best overall response rates were 266d vs 206d (P=.4855) and 64.1% vs 72% (P=.3423), respectively; the study was not powered to detect differences. In the follow-up phase, TTP and OS time were similar. Adding zoledronic acid to docetaxel/carboplatin in advanced stage NSCLC patients was well tolerated, but provided little to no effect on disease progression endpoints.

Bone Marker–Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Results of the Z-MARK Study

Purpose: Zoledronic acid (ZOL) given every 3 to 4 weeks can reduce skeletal-related events (SRE) in patients with bone lesions from multiple myeloma. This study evaluated efficacy and safety of less-frequent ZOL dosing based on bone turnover markers in patients with 1 to 2 years of prior bisphosphonate therapy. Experimental Design: Patients received ZOL (4 mg) every 4 or 12 weeks based on urinary N-telopeptide of type 1 collagen (uNTX) levels (every 4 weeks if uNTX ≥50 nmol/mmol creatinine, every 12 weeks if uNTX < 50). Results: Of 121 patients enrolled (mean age, 63.8 years; median follow-up, 21 months), 4 patients started ZOL every 4 weeks and 117 received ZOL every 12 weeks based on uNTX at study entry. All 4 patients who initiated ZOL every 4 weeks switched to every 12 weeks due to decreased uNTX. Thirty-eight of 117 patients who initiated ZOL every 12 weeks switched to ZOL every 4 weeks due to disease progression (n = 20), increased uNTX (n = 14), and SREs (n = 4). Overall SRE incidence was low; 7 (5.8%) and 5 (4.9%) patients experienced an SRE during years 1 and 2, respectively. Mean (SD) SRE rate at year 2 was 0.01 (0.03) per person-year. The 2-year incidence rate for osteonecrosis of jaw was 3.3%. Four deaths were reported, none related to ZOL. Conclusions: Less frequent ZOL dosing (every 12 weeks over 2 years) maintains a low SRE rate and can be safely administered for up to 4 years. Clin Cancer Res; 22(6); 1378–84. ©2015 AACR. See related commentary by Fonseca and Jain, p. 1301

Prevention of everolimus/exemestane (EVE/EXE) stomatitis in postmenopausal (PM) women with hormone receptor-positive (HR+) metastatic breast cancer (MBC) using a dexamethasone-based mouthwash (MW): Results of the SWISH trial.

189 Background: Stomatitis is a frequent adverse event (AE) associated with mTOR inhibition. In BOLERO-2 patients (pts) receiving EVE/EXE, all grade (Gr) stomatitis was 67%; 33% had Gr ≥ 2 and 8% Gr 3. Median time to ≥ Gr 2 onset was 15.5 days; incidence of new stomatitis (Gr ≥ 2) plateaued at 6 wks. In a meta-analysis, 89% of first stomatitis events occurred within 8 wks. Topical steroids are used to treat aphthous ulcers; anecdotal use as prophylaxis has been reported. METHODS Eligibility included PM women with HR+ MBC prescribed EVE/EXE. Treatment included EVE 10 mg and EXE 25 mg QD, with 10 mL of commercially available 0.5 mg/5 mL dexamethasone oral solution to swish x 2 min and spit QID for 8 wks starting day 1. Pts completed a daily adherence log, including an oral pain (range 0-10) and normalcy of diet score. The primary endpoint was to compare the incidence of Gr ≥ 2 stomatitis at 8 wks with BOLERO-2 results. Secondary endpoints included MW use by average times/day, EVE/EXE dose intensity, incidence of all Gr stomatitis and time to resolution to Gr ≤ 1. RESULTS 92 women were enrolled; 86 were evaluable for efficacy. Median age was 61 yrs (range 34-87); median dose intensity was 10 (range 3-10) and 25 mg (range 8-25) for EVE and EXE, respectively. 95% of pts used the MW 3-4 times/day (median MW use/day = 3.95, range 1.9-4). At 8 wks, the rate of ≥ Gr 2 stomatitis was 2.4% (2 pts) with a Gr 1 rate of 18.8%. A comparison of stomatitis incidence by grade between BOLERO-2 and SWISH is shown in the table. In the 75 patients with complete ECOG scores, 88% maintained/improved ECOG status. Mean pain scale score was < 1 at all visits; 88% of pts reported a normal diet at 8 wks. 13% discontinued EVE/EXE due to suspected related AEs (most common: rash, 2%; hyperglycemia, 2%; stomatitis, 2%; and pneumonitis, 1%). CONCLUSIONS Prophylactic use of 0.5 mg/5 mL dexamethasone oral solution markedly decreases the incidence and severity of stomatitis in patients receiving EVE/EXE for MBC and should be considered a new standard of oral care in this setting. CLINICAL TRIAL INFORMATION NCT02069093. [Table: see text].

Correlations Between Cytogenetic and Molecular Monitoring Among Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: Post Hoc Analyses of the Rationale and Insight for Gleevec High-Dose Therapy Study

CONTEXT Although bone marrow (BM) karyotyping has been the standard in monitoring patients with chronic myeloid leukemia, peripheral blood (PB) monitoring methods may be more convenient. OBJECTIVE To conduct post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study to evaluate correlations between results of cytogenetic testing and molecular monitoring from BM and PB during the first 18 months of high-dose imatinib therapy, and between early and late molecular responses. DESIGN Newly diagnosed patients with chronic-phase chronic myeloid leukemia received imatinib 400 mg twice daily and were monitored quarterly for up to 18 months. Cytogenetic testing was performed by karyotyping using BM or by fluorescence in situ hybridization using PB. Molecular testing was performed by quantitative reverse transcriptase polymerase chain reaction using BM and PB. RESULTS Significant pairwise correlations were found between results obtained by karyotyping, fluorescence in situ hybridization, and quantitative reverse transcriptase polymerase chain reaction using PB or BM (all pairwise correlations >0.8; P < .001). At 12 months, cytogenetic response by karyotyping correlated well with response by fluorescence in situ hybridization. A median 2.579-log reduction in BCR-ABL1 level from a standardized baseline correlated with fluorescence in situ hybridization-negative status. Patients with greater than 2-log reduction in BCR-ABL1 level at 3, 6, and 9 months were more likely to achieve major molecular response at 18 months than those with 2-log reduction or less. CONCLUSIONS Our findings support the feasibility of molecular monitoring using PB and suggest that molecular monitoring conducted at a single reliable reference laboratory can adequately track response without invasive BM testing. Our findings are consistent with other work indicating that early response to imatinib predicts favorable long-term outcome.

Bone-specific alkaline phosphatase (BSAP) and serum N-telopeptide (sNTX) as predictors of bone loss in postmenopausal women with early breast cancer receiving letrozole as adjuvant therapy: a 5-year study (Z-FAST).

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #2067 Background : Changes in biochemical markers of bone turnover are expected to be predictors of long-term changes in bone mineral density (BMD). We studied the potential of bone-specific alkaline phosphatase (BSAP) and serum N-telopeptide (sNTX) at 6 and 12 months (mo) in predicting BMD of the lumber spine (LS) and total hip (TH) at 48 mo in Z-FAST study. Methods: Postmenopausal women with ER+ and/or PR+ early stage breast cancer were randomized 1:1 into Up-front (U) or Delayed (D) arms (N=301 in each). Patients (pts) in U received zoledronic acid (ZOL) 4 mg IV q6 mo starting at baseline; pts in D started ZOL q6 mo when their LS or TH T-score fell below -2. All pts started Letrozole 2.5 mg/day for 5 years. Levels of BSAP and sNTX were assessed at screening and every 6 mo on a subset of pts. LS and TH BMD were assessed by dual-energy x-ray absorptiometry (DEXA) at screening, 6 mo and every 12 mo thereafter for all available pts. This is an exploratory analysis to investigate the correlation between short-term % changes from baseline in BSAP and sNTX and long-term % changes from baseline in BMD. Pearson correlations and Receiver Operating Characteristics (ROC) analysis were performed. We report the results based on 48 mo data. Results: The Pearson correlations between % change in BSAP at 6 mo and LS BMD at 48 mo were -0.13 [(N=38, not significant (NS)] and -0.17 (N=39, NS) in arms U and D respectively. The correlations between % change in BSAP at 12 mo and LS BMD at 48 mo were -0.15 (N=39, NS) in U and -0.43 (N=38, p=0.0077) in D. Very similar correlations were obtained for % change in sNTX at 6, 12 mo and LS BMD at 48 mo in D, but in U the correlations were smaller and positive. The correlations between % change of both markers at 6, 12 mo and TH BMD at 48 mo were all NS at 0.05. ROC analysis showed that at best performance (maximum of sensitivity plus specificity), for any increase in sNTX at 12 mo, the sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) to predict LS BMD loss at 48 mo was 74%, 77%, 85% and 63% in D. For BSAP change of 3%, the four ROC parameters were 71%, 71%, 81% and 59% respectively. For prediction of TH BMD loss, the SE, SP and NPV were lower for both markers with higher PPV. In U, the SE, SP and PPV were all much lower with very high NPV for both markers and BMD loss. Conclusion: Interim results of Z-FAST data show that short-term changes in BSAP and sNTX have the potential for predicting long-term bone loss. The weaker correlations in U also suggest that zoledronic acid may have a direct preventive effect on bone loss independent of changes in the markers. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2067.

Exploratory study on the impact of switching to nilotinib in 18 patients with chronic myeloid leukemia in chronic phase with suboptimal response to imatinib

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.