Trials In Metastatic Breast Cancer Research Articles

A phase I study of indoximod in combination with docetaxel in metastatic solid tumors.

3026 Background: The indoleamine-2, 3-dioxygenase (IDO) pathway catabolizes tryptophan to create a state of immunosuppression. Indoximod (1-methyl-(D)-tryptophan, D-1MT) is an IDO pathway modulator. Preclinical studies in MMTV-neu mouse models have shown indoximod combined with chemotherapy was more effective in causing tumor regression than either agent alone. Based on this data, a phase IB trial was designed to study the safety of the combination of docetaxel (Doc) and indoximod. The primary goal of this trial was to determine the MTD for the combination of Doc and oral indoximod. Secondary endpoints were PK data and efficacy for indoximod/Doc. Methods: This phase IB study consisted of 5 dose levels (DL). Doc was dosed IV q 3 wks at 60 mg/m2 in DL 1-4 and 75 mg/m2 at DL 5. Indoximod was dosed at 300, 600, 1,000, 2,000, and 1,200 mg PO BID continuously in DL 1-5 respectively. MTD was determined using a 3+3 design. The DLT rule was 1st cycle ≥G3 non-heme AEs or ≥G4 heme AEs despite supportive care or that delay therapy >14d. The PK of indoximod and Doc was analyzed using a HPLC assay. PK was measured on C1D1 and 8. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilumimab. Treatment was continued until disease progression, intolerance, or unacceptable side effects. Results: Total # of patients treated at DL1-5 were 7, 6, 6, 2, and 6 respectively, with 22 total patients evaluable for response. DLTs included: G3 dehydration (at 300 mg), G5 neutropenic colitis (at 600 mg), G3 hypotension (at 2,000 mg) and G3 mucositis (at 2,000 mg). DL 5 was well tolerated and is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 PRs (2 breast, 1 NSCLC, 1 thymic), 9 SD, and 9 PD. There were no drug-drug interactions, and PK was similar to Doc and indoximod single-agent studies. Conclusions: The Doc+ indoximod combination was well tolerated with no increase in expected toxicities or unexpected PK interactions. It was active in a pretreated population of patients with metastatic solid tumors. The RP2D is 75 mg/m2 of Doc with 1,200 mg of indoximod BID for the current phase II metastatic breast cancer trial. NCT01191216 Clinical trial information: NCT01191216.

Treatment Algorithms for Hormone Receptor-Positive Advanced Breast Cancer: Applying the Results from Recent Clinical Trials into Daily Practice—Insights, Limitations, and Moving Forward

Hormone receptor-positive (HR+) breast cancer is the most prevalent subtype of breast cancer in both early- and advanced-stage disease. Thus, the treatment of HR+ breast cancer has had the greatest global influence in improving clinical outcomes overall. Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in translating these findings into clinical practice stems from the influence of prior adjuvant endocrine therapy, particularly the increasing use of adjuvant AIs today, on the choice of endocrine agent in the advanced setting because of the development of acquired resistance. Because the majority of patients enrolled into these studies were either endocrine-treatment naïve or exposed to tamoxifen only, the "real-life" applicability of the evidence is unclear. Because a superior dose of the selective estrogen receptor (ER) downregulator fulvestrant has now been established, its role as first-line therapy is being re-established. We are now starting to see the promise realized with blocking cross-talking growth factor pathways in addition to the ER pathway. The greatest efficacy is seen with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane and, perhaps to a lesser extent, anti-HER2-directed therapy in combination with an AI. Future gains will likely involve a greater understanding of the redundancy and compensation induced by blocking these pathways, trials involving blocking multiple pathways in addition to hormonal agents, and the molecular interrogation of the individual's tumor in search of predictive biomarkers and "actionable" genomic aberrations.

A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs.

The failure rate of randomized phase III oncology clinical trials is extremely high, even when preceded by encouraging preclinical studies and phase II trial results of the same therapy. Thus, there is considerable effort being made to improve the predictive clinical potential of preclinical models, in addition to improving phase II trial design. With respect to the former, preclinical models have historically relied heavily on treatment of primary spontaneous or transplanted tumors rather than the more common and therapeutically challenging clinical trial circumstance of advanced metastatic disease. Here, we show that the oral antiangiogenic tyrosine kinase inhibitor (TKI), sunitinib, which failed to meet primary or secondary survival endpoints in 4 separate phase III metastatic breast cancer (MBC) trials, either alone or with chemotherapy, similarly failed to show monotherapy or combination chemotherapy efficacy in a model of postsurgical advanced MBC using a metastatic variant of the MDA-MB-231 triple-negative human breast cancer. In contrast, the drug was effective when used to treat established orthotopic primary tumors. Similar results were obtained with pazopanib monotherapy, another antiangiogenic oral TKI. However, when an antibody targeting the VEGF pathway (DC101) was tested, it showed a trend in modestly improving the efficacy of paclitaxel therapy, thus resembling to a degree prior phase III clinical results of bevacizumab plus paclitaxel in MBC. Our results suggest the potential value of treating postsurgical advanced metastatic disease as a possible strategy to improve preclinical models for predicting outcomes in patients with metastatic disease.

Abstract 2465: A new polymer conjugated taxane shows improved efficacy in tumor xenograft models.

Abstract Introduction: Microtubule inhibitors are a mainstay of cancer therapy despite limitations in efficacy and tolerability. Such deficiencies are typical of cytotoxic drugs and a variety of strategies have been investigated to improve them, including the use of polymer conjugates. For example, etirinotecan pegol (EP, formerly NKTR-102) is a topoisomerase I inhibitor-polyethylene glycol (PEG) conjugate engineered by attaching irinotecan molecules to PEG using a biodegradable linker. EP has been studied in multiple clinical oncology studies and showed significantly higher response rates and decreased bone marrow toxicity in Phase 2 compared to historical data for irinotecan. EP is currently in a Phase 3 trial (BEACON; NCT01492101) for metastatic breast cancer. We here report a novel PEG-taxane conjugate, PEG-TX1, which exhibits improved tumor growth inhibition compared to a recently approved taxane, cabazitaxel (CBZ). We have explored the basis for the improved preclinical activity, and show increased intratumoral exposure of the released active taxane (TX1) following administration of PEG-TX1, compared with that achieved with CBZ. Methods: Tumor growth inhibition was examined using subcutaneous NCI-H460 tumor xenografts in nu/nu athymic mice. Test articles were administered intravenously via tail vein, q7dx3, at the maximum tolerated dose with a study endpoint of 2000 mm3. In PK/PD experiments to determine tissue and plasma concentrations of CBZ, TX1, and PEG-TX1, a single dose of test article was administered intravenously, and samples were collected at various time points to 14 d. Drug concentrations in tissue and plasma were quantified using LC/MS. Results: In the NCI-H460 xenograft model, PEG-TX1 (administered q7dx3) delayed tumor growth by 336%, producing 90% partial and 10% complete tumor regressions. In comparison, CBZ delayed tumor growth by 213% and produced only 40% partial tumor regressions and 0% complete regressions. Following a single administration of PEG-TX1 vs. CBZ, significantly greater tumor growth inhibition was observed for PEG-TX1. This improved activity correlated well with increased tumor accumulation of PEG-TX1 and TX1 than was achieved for CBZ. Throughout the study, the concentration of TX1 was at least 10-fold higher in tumor tissue than in plasma or all other tissues examined. CBZ did not show such a sustained increase in tumor exposure relative to other tissues. Conclusions: We demonstrate that PEG-TX1, a PEG-taxane prodrug utilizing Nektar's proprietary polymer conjugation technology, achieved superior tumor growth suppression in a murine xenograft model. Tumor growth inhibition is consistent with the enhanced concentration of taxane detected in tumors following administration of PEG-TX1. These data further demonstrate the utility of polymer conjugation to modify the biodistribution of drug conjugates and thereby enhance the therapeutic properties of an active pharmacophore. Citation Format: Dennis G. Fry, Christine Brew, Steve Lee, Ute Hoch, Wen Zhang, Antoni Kozlowski, Fadil Dahhani, Nagabhusan Tangudu, Stephen D. Harrison, Jennifer Riggs-Sauthier. A new polymer conjugated taxane shows improved efficacy in tumor xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2465. doi:10.1158/1538-7445.AM2013-2465

Comparing duration of response and duration of clinical benefit between fulvestrant treatment groups in the CONFIRM trial: application of new methodology

Comparisons of duration of response (DoR) and duration of clinical benefit (DoCB) within clinical trials are prone to biases. To address these biases, we used new methodology to prospectively analyze expected DoR and expected DoCB. Objective response rate and clinical benefit rate were calculated for fulvestrant 500 and 250 mg, and used to calculate expected DoR and expected DoCB for each dose group. The ratios for expected DoR and expected DoCB (expected DoR500/expected DoR250 and expected DoCB500/expected DoCB250) were then calculated, thereby allowing statistical comparisons of these endpoints between each arm of the COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial. Expected DoRs for fulvestrant 500 and 250 mg were 3.2 and 3.6 months, respectively. The expected DoR ratio between fulvestrant 500 and 250 mg was not statistically significant (0.89; 95 % CI, 0.48–1.67, P = 0.724). The expected DoCBs for fulvestrant 500 and 250 mg were 9.8 and 7.2 months, respectively. The expected DoCB ratio showed that the expected DoCB for fulvestrant 500 mg was significantly improved compared with the expected DoCB for fulvestrant 250 mg (1.36; 95 % CI, 1.07–1.73, P = 0.013). Analysis of the expected DoR and expected DoCB showed fulvestrant 500 mg significantly increased expected DoCB compared with fulvestrant 250 mg in the CONFIRM trial.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-012-2395-8) contains supplementary material, which is available to authorized users.

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial

Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens. In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m(2) on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral capecitabine (1000 mg/m(2) twice daily on days 1-14) repeated every 3 weeks (capecitabine group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00600340. Between Sept 10, 2008, and Aug 30, 2010, we randomised 564 patients (paclitaxel group n=285; capecitabine group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; capecitabine group n=265). After median follow-up of 18·6 months (IQR 14·9-24·7), 181 patients in the per-protocol population had died (89 [33%] in the paclitaxel group; 92 [35%] in the capecitabine group). The hazard ratio [HR] for overall survival was 1·04 (97·5% repeated CI -∞ to 1·69; p=0·059); the non-inferiority criterion of the interim analysis (interim α=0·00105) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus capecitabine (125 [44%] of 285 patients vs 76 [27%] of 279; p<0·0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the capecitabine group (median progression-free survival 11·0 months [95% CI 10·4-12·9] vs 8·1 months [7·1-9·2]; HR 1·36 [95% CI 1·09-1·68], p=0·0052). The most common adverse events of grade 3 or higher were neutropenia (51 [18%]), peripheral neuropathy (39 [14%]), and leucopenia (20 [7%]) in the paclitaxel group and hand-foot syndrome (44 [16%]), hypertension (16 [6%]), and diarrhoea (15 [5%]) in the capecitabine group. One treatment-related death occurred in the paclitaxel group; no deaths in the capecitabine group were deemed to be treatment-related. In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 2014. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus capecitabine. Efficacy results in both groups were consistent with previous reports. Central European Cooperative Oncology Group; Roche.

Treatment Algorithms for Hormone Receptor-Positive Advanced Breast Cancer: Applying the Results from Recent Clinical Trials into Daily Practice—Insights, Limitations, and Moving Forward

Hormone receptor-positive (HR+) breast cancer is the most prevalent subtype of breast cancer in both early- and advanced-stage disease. Thus, the treatment of HR+ breast cancer has had the greatest global influence in improving clinical outcomes overall. Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in translating these findings into clinical practice stems from the influence of prior adjuvant endocrine therapy, particularly the increasing use of adjuvant AIs today, on the choice of endocrine agent in the advanced setting because of the development of acquired resistance. Because the majority of patients enrolled into these studies were either endocrine-treatment naïve or exposed to tamoxifen only, the "real-life" applicability of the evidence is unclear. Because a superior dose of the selective estrogen receptor (ER) downregulator fulvestrant has now been established, its role as first-line therapy is being re-established. We are now starting to see the promise realized with blocking cross-talking growth factor pathways in addition to the ER pathway. The greatest efficacy is seen with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane and, perhaps to a lesser extent, anti-HER2-directed therapy in combination with an AI. Future gains will likely involve a greater understanding of the redundancy and compensation induced by blocking these pathways, trials involving blocking multiple pathways in addition to hormonal agents, and the molecular interrogation of the individual's tumor in search of predictive biomarkers and "actionable" genomic aberrations.

Nab-Paclitaxel versus Docetaxel for the First-line Treatment of Metastatic Breast Cancer

Taxane-based treatment regimens are standard first-line therapies for metastatic breast cancer (MBC). The clinical benefit of solvent-based taxanes, including solvent-based paclitaxel and docetaxel, in MBC has been established in large randomized clinical trials. Docetaxel has demonstrated greater efficacy versus solvent-based paclitaxel in at least one trial, but both solvent-based paclitaxel and docetaxel are associated with undesirable dose-limiting toxicities, including neutropenia, sensory neuropathy, and hypersensitivity reactions.nab-Paclitaxel, an albuminbound form of paclitaxel, was developed to improve the therapeutic index of taxane treatment. This review summarizes preclinical experiments and clinical data from MBC trials comparingnab-paclitaxel with docetaxel. In preclinical studies,nab-paclitaxel more effectively suppressed tumor growth than docetaxel (80 versus 29 % inhibition) in breast cancer tumor xenograft models and was associated with less toxicity. Clinical studies confirmed these findings and reported a better therapeutic index with nab-paclitaxel than docetaxel. As such, the clinical experience withnab-paclitaxel supports its role as an important advance in the treatment of MBC with taxane-based regimens.

Abstract P2-12-07: A review of clinical endpoints and use of quality-of-life outcomes in phase III metastatic breast cancer clinical trials

Abstract Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with most interventions intended to relieve disease symptoms, minimize treatment effects and prolong patient survival. The impact of disease and treatment on a patient's functional abilities has led to the emphasis of incorporating quality of life (QoL) measures into clinical trials. The primary objective of this study is to evaluate phase III clinical trials in MBC, and assess the inclusion of QoL as an endpoint, in addition to conventional progression and survival endpoints. Methods: A structured PubMed search was conducted to identify phase III clinical trials published between Jan. 1990 and Aug. 2011, which evaluated systemic treatment in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a particular focus on progression-based (PB), overall survival (OS), and QoL endpoints. The instrument(s) used in evaluating QoL were also noted (when applicable). Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. 14 instruments were identified as QoL measurement tools among these studies, with EORTC QLQ-C30 and FACT-B accounting for 54.7% of the instruments used. While the inclusion of QoL was not associated with the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as a clinical endpoint (p = 0.016). When stratified by treatment arm, it was found that studies favouring standard therapy were more likely to include QoL (75%, p = 0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management and treatment decisions, only one-third of identified phase III clinical trials included an assessment of QoL. About half of these trials showed no statistically significant differences in QoL endpoint; of note, instruments of varying validity were utilized. There needs to be greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-07.

Abstract OT3-3-01: Eniluracil + 5-fluorouracil + leucovorin (EFL) vs. capecitabine phase 2 trial for metastatic breast cancer

Abstract Based on a modified dosing protocol designed to optimize efficacy, an open-label EFL vs. capecitabine (4:3 randomization) Phase 2 trial for metastatic breast cancer is in progress. Eniluracil inactivates dihydropyrimidine dehydrogenase, thereby preventing the formation of α-fluoro-β-alanine, and conferring 100% oral bioavailability and a 5 hr half-life on 5-fluorouracil (5-FU). Study drugs are administered orally for 1st- or 2nd-line treatment for metastatic disease in patients previously treated with an anthracycline and a taxane. Arm 1: eniluracil (40 mg) taken 11–16 hr before 5-FU (30 mg/m2); leucovorin (30 mg) taken with 5-FU and the next day. The regimen is administered once/week for 3 weeks/4 weeks. Arm 2: capecitabine (1000 mg/m2) taken bid for 14 days/21days. Arm 2 patients with disease progression could crossover to take EFL in Arm X. Two sites in the USA and 19 in Russia are enrolling. Currently, 115 patients (21% are 1st-line, 70% had previous 5-FU treatment) are enrolled and 83 have had tumor assessments. EFL was well tolerated with no unexpected toxicities. As of May 2012, there were 11, 7, &amp; 1 partial responses in Arms 1, 2, &amp; X, respectively. The primary endpoint, progression-free survival, will be determined approximately 7.5 months after the trial is enrolled with 140 evaluable patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-01.

Abstract P3-06-34: Plasma (p) VEGF-A and VEGFR-2 biomarker (BM) results from the BEATRICE phase III trial of bevacizumab (BEV) in triple-negative early breast cancer (BC)

Abstract Background: Several candidate BMs have been explored in randomized trials of BEV across tumor types with the aim of identifying patients (pts) deriving the most substantial benefit from BEV therapy. In phase III trials, baseline pVEGF-A and pVEGFR-2 showed potential predictive value in metastatic BC (AVADO, AVEREL), pancreatic cancer (AViTA), and gastric cancer (AVAGAST; VEGF-A only). The randomized phase III BEATRICE trial, evaluating the addition of BEV to adjuvant chemotherapy in pts with triple-negative early BC, includes a comprehensive program to identify potential BMs predicting efficacy and toxicity of BEV therapy. We report results for baseline pVEGF-A and pVEGFR-2. Methods: After selection of chemotherapy (anthracycline and/or taxane), pts with T1a-T3 operable BC were randomized 1:1 to receive ≥4 cycles of chemotherapy either alone or with 1 year of BEV 5 mg/kg/wk equivalent. The primary endpoint is invasive disease-free survival (IDFS). pEDTA samples were collected from consenting pts at baseline (before treatment, after surgery), during study treatment, and at relapse. Pts were dichotomized using the median baseline concentration of each marker as the cut-off between high and low cohorts; further exploratory analyses were also performed by quartile. Results: Between Dec 2007 and Mar 2010, 2591 pts were enrolled. Of these, 1273 (49%) consented to the BM study and 1178 (45%) were included in the BM-evaluable population (BEP). Overall, the BEP was representative of the ITT population except for lower proportions of Asian pts (12% vs 24%). IDFS was similar in the BEP and ITT populations. Baseline characteristics were balanced between arms in the BEP. Baseline pVEGF-A showed neither prognostic nor predictive value using the median as the cut-off, although with a third quartile (Q3) cut-off there was a more pronounced but non-significant differentiation between treatments (HR 0.92 [low] vs 0.64 [high]). High baseline pVEGFR-2 showed potential predictive value for BEV efficacy (HR 1.24 [low] vs 0.61 [high]; p=0.029). Conclusions: Unlike trials in metastatic BC (AVADO, AVEREL), in the adjuvant setting, baseline pVEGF-A concentration did not show predictive value for BEV efficacy with a median cut-off. However, analyses using the Q3 cut-off suggest a trend toward predictive value. High baseline pVEGFR-2 was associated with greater BEV treatment effect, consistent with previous results in AVADO and AVEREL. The impact of differing biology in the adjuvant setting, lower median VEGF-A concentration than in the metastatic setting (77.0 vs 125.0–129.1 pg/mL), and the possible influence of surgery immediately before treatment require further investigation. Additional exploratory analyses are ongoing to provide better understanding of the BEATRICE dataset and the complex biology of angiogenesis, including additional markers, changes over time, and combination signatures. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-34.

Abstract S1-4: Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg

Abstract Background: The COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial (NCT00099437) compared fulvestrant 500 mg with fulvestrant 250 mg in postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer who had recurred or progressed following prior endocrine therapy. Fulvestrant 500 mg was associated with a statistically significant increase in progression-free survival compared with fulvestrant 250 mg (Di Leo A et al. J Clin Oncol 2010; 28: 4594–4600). At the time of the primary analysis approximately 50% of patients had died. Median overall survival was 25.1 months and 22.8 months for fulvestrant 500 mg and 250 mg, respectively (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.69, 1.03; p = 0.091). A follow-up analysis of overall survival was subsequently planned for when 75% of patients had died and the results are presented here. Methods: CONFIRM was a randomized, double-blind, parallel-group, multicenter, Phase III study. Patients were randomized 1:1 to either fulvestrant 500 mg (500 mg i.m. on Days 0, 14 and 28 and every 28 days thereafter) or fulvestrant 250 mg (250 mg i.m. every 28 days). After the primary analysis, patients on fulvestrant 250 mg were permitted to switch to 500 mg and all patients were followed up for overall survival, regardless of treatment discontinuation, unless consent was withdrawn. Overall survival was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) were also reported. Results: In total, 736 women (median age 61.0 years) were randomized between February 2005 and August 2007 from 128 centers in 17 countries (fulvestrant 500 mg: n=362; fulvestrant 250 mg: n=374). At time of follow-up analysis, 63 (9.0%) patients were lost to follow-up, 16 (2.2%) patients had withdrawn consent, 103 (14.0%) patients were still ongoing (21 [2.9%] on treatment and 82 [11.1%] not on treatment), and 554 (75.3%) patients had died. Eight (2.1%) patients crossed over from fulvestrant 250 mg to 500 mg. Median overall survival was 26.4 months for fulvestrant 500 mg and 22.3 months for fulvestrant 250 mg (HR 0.81; 95% CI, 0.69, 0.96; nominal p = 0.016). During the treatment period, a total of 32 (8.9%) patients had at least one SAE in the fulvestrant 500 mg and 25 (6.7%) patients in the fulvestrant 250 mg groups, and SAEs that were causally related to study treatment were reported for 6 (1.7%) and 3 (0.8%) patients, respectively. SAEs with an outcome of death were reported for 5 (1.4%) and 6 (1.6%) patients, respectively, during the treatment period. Overall, there were no clinically important differences in the profiles of SAEs between the treatment groups and no clustering of SAEs could be detected in either treatment group. Conclusions: Overall survival data from CONFIRM demonstrate that, in patients with locally advanced or metastatic ER positive breast cancer, fulvestrant 500 mg is associated with a clinically relevant 4.1 month difference in median overall survival and 19% reduction in risk of death compared with fulvestrant 250 mg. There were no new safety concerns associated with the use of fulvestrant 500 mg. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-4.

Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer

A phase II trial in metastatic breast cancer (MBC) (NO16853) failed to show noninferiority (progression-free survival, PFS) of capecitabine 825 mg/m2 plus docetaxel 75 mg/m2 to the registered capecitabine dose of 1,250 mg/m2 plus docetaxel 75 mg/m2. We developed a modeling framework based on NO16853 and the pivotal phase III MBC study, SO14999, to characterize the link between capecitabine dose, tumor growth, PFS, and survival to simulate response to a range of capecitabine doses and determine a minimum capecitabine dose noninferior to 1,250 mg/m2. Simulation showed NO16853 had little power to demonstrate noninferiority (69%). The power reached 80% with a 1,000 mg/m2 starting dose and an increased number of PFS events. A starting dose of 1,000 mg/m2 could be established as noninferior in terms of efficacy to the registered dose in the second-line MBC setting, with a potentially improved safety, in line with medical practice.

Long Term Survival After High-Dose Chemotherapy with Autologous Hematopoietic Cell Transplantation in Metastatic Breast Cancer.

AbstractAbstract 3072In the 1990s, the most common indication for high dose chemotherapy (HDC) and autologous hematopoietic cell transplantation (AHCT) was breast cancer. Several randomized controlled trials for metastatic breast cancer (MBC), performed to address the role of HDC and AHCT, found no survival benefit over conventional therapy. A recently published meta-analysis confirmed a lack of significant survival benefit and failed to identify any subset of patients that benefited from this approach. Many trials of HDC for MBC, however, demonstrate better than expected 10–15 year progression free and overall survival occurring in 5–15% of patients. These data prompted us to evaluate the long term results of treatment with HDC and AHCT in MBC at our institution.Two-hundred eighty five patients underwent HDC followed by AHCT for metastatic breast cancer from 1984–2000. Preparative regimens included STAMP V (cyclophosphamide [Cy], carboplatin, thiotepa [TT]), n=98; CBT (Cy, carmustine, TT), n=79; busulfan and Cy, n=54; TT, n=27; STAMP I (Cisplatin, Cy, BCNU), n=26; and BCNU, n=1. With a median follow up of 169 months (range 77–283 months) in survivors, 34 (12%) of these patients remain alive. Of the 251 patients who died, 218 (87%) died of relapsed/metastatic disease. Other causes of death included infectious or cardiopulmonary etiologies. Incidence of death from secondary malignancies was less than 1%. Her2 status was unavailable in the majority of the patients, but comparison by age (<50 and >50) and hormonal status did not demonstrate any significant differences in relapse (p=0.33 and p=0.32 respectively) or survival (p=0.13 and p=0.42). Using Cox analysis, we identified three prognostic factors for survival in multivariable analysis: number of prior chemotherapy regimens (HR 1.48 per 1 regimen increase, p<0.001); disease status, (HR 1.34, p=0.029 for partial response and HR 2.66, p=0.008 for relapsed/refractory disease); and source of hematopoietic cells (HR 2.45, p=0.012 for bone marrow compared to peripheral stem cells). Data regarding number and type of metastatic sites was not available for the entire cohort.Of the 34 long term survivors identified, sufficient data was available on 28 patients. In this cohort, 10 patients had metastatic disease at presentation while 18 patients had recurrent metastatic disease. Of the 10 patients with primary metastatic disease, 4 patients had oligometastatic involvement of the ipsilateral supraclavicular lymph node which would now be classified as stage IIIC disease by current AJCC staging guidelines. Three patients had limited bone disease and 3 had oligometastatic disease that had been resected. Of the 18 patients with recurrent metastatic disease, 9 had local recurrence at the site of the incision or chest wall, and 6 had a single site of recurrence primarily in the lung or loco-regional lymph nodes, also classified as primarily oligometastatic disease. Most of these lesions were surgically resected. Of the remaining patients, one had recurrent lesions in the liver, one had bilateral breast recurrence, and one had recurrence in the lung with additional possible bone involvement.This retrospective evaluation of patients who underwent HDC and AHCT for metastatic breast cancer demonstrates long term survival in a small subset of MBC patients, primarily those with primary or recurrent oligometastatic disease. Previous studies have suggested that oligometastatic breast cancer is a distinct subgroup with long-term prognosis that is superior to MBC. While the use of HDC and AHCT has largely been abandoned in the United States, several recent long term follow up studies such as this one questions its role for select populations. The use of HDC in subsets such as oligometastatic breast cancer may be beneficial, and may warrant further study; however, overall there remains no demonstrable benefit to HDC and long term survival is rare in the population of patients with metastatic disease. Disclosures:No relevant conflicts of interest to declare.

Everolimus and Its Role in Hormone-Resistant and Trastuzumab-Resistant Metastatic Breast Cancer

Advances in targeted therapies have improved progression-free and overall survival in women with metastatic breast cancer; however, regardless of efficacy, resistance almost always occurs eventually. Upregulation of the PI3K/AKT/mTOR pathway, which promotes cell growth and proliferation, is a means of escaping responsiveness to hormone therapy in hormone receptor-positive disease, or trastuzumab in HER2-positive disease. Everolimus, an inhibitor of mTOR, has shown promise in early clinical trials in metastatic breast cancer and is currently being studied in larger Phase II and III clinical trials, combined with hormone therapy or trastuzumab with or without cytotoxic chemotherapy. In this article, we discuss the mechanistic and preclinical data for everolimus, efficacy and safety results of clinical trials, and the landscape looking forward.

Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer

We assessed the efficacy and safety of capecitabine across treatment lines, and the impact of patient and disease characteristics on outcomes using data from phase II/III trials. Individual patient data were pooled from seven Roche/Genentech-led trials conducted from 1996 to 2008 where single-agent capecitabine was the test or control regimen for metastatic breast cancer (MBC). Data were analyzed from 805 patients: 268 in the first-line metastatic setting and 537 in the second-line or later setting. Baseline characteristics were balanced across treatment lines. Patients receiving second-line or later versus first-line capecitabine had lower objective response rates (ORR: 19.0 vs. 25.0 %, respectively, odds ratio 0.70; 95 % CI: 0.5-1.0) and significantly shorter progression-free survival (PFS: median 112.0 days [3.7 months] vs. 150.0 days [4.9 months]; p < 0.0001) and overall survival (OS: median 396.0 days [13.0 months] vs. 666.0 days [21.9 months]; p < 0.0001). In multivariate analysis by backward elimination, significantly improved ORR (p = 0.0036), PFS (p < 0.0001) and OS (p < 0.0001) with capecitabine were demonstrated in patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive versus both ER and PgR-negative tumors. Hand-foot syndrome (HFS) was the most common adverse event (AE) in 63 % of patients. Overall, 7 % of patients discontinued and two patients (<1 %) died from treatment-related AEs. Significantly improved survival was observed in patients developing capecitabine-related HFS (p < 0.0001 PFS/OS) or diarrhea (p = 0.004 OS; p = 0.0045 PFS) versus patients without these events. In this pooled analysis of individual patient data, first-line capecitabine was associated with improved ORR, PFS, and OS versus second or later lines. Multivariate analyses identified greater ORR, PFS, and OS with capecitabine in patients with ER and/or PgR-positive versus ER/PgR-negative tumors. Safety was in-line with previous phase III trials in MBC.

Phase III Trial of Lapatinib

A randomized, open-label, phase III study of taxane-based chemotherapy with lapatinib or trastuzumab as first-line therapy for women with human epidermal growth factor receptor (HER)-2/neu positive metastatic breast cancer. The COMPLETE (COMParison of Lapatinib Efficacy vs Trastuzumab, Each with a taxane, in first-line metastatic breast cancer) trial compared the efficacy and tolerability of lapatinib versus trastuzumab, each in combination with docetaxel or paclitaxel, as first-line therapy in patients with HER2-positive metastatic breast cancer. The primary endpoint was progression-free survival. The trial was discontinued following an interim analysis in April 2012 showing that trastuzumab recipients had significantly longer progression-free survival than lapatinib recipients.

A review of clinical endpoints and use of quality-of-life outcomes in phase III metastatic breast cancer clinical trials.

129 Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with most interventions intended to relieve disease symptoms, minimize treatment effects and prolong patient survival. The impact of disease and treatment on a patient's funcitonal abilities has led to an emphasis of incorporating quality of life (QoL) measures into clinical trials. The main objective of this study is to evaluate phase III clinical trials in MBC, and assess the inclusion of QOL as an endpoint, in addition to conventional efficacy endpoints. Methods: A structured PubMed search was conducted to identify phase III clinical trials published between Jan. 1990 and Aug. 2011, evaluating systemic treatment in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a particular focus on progression-based (PB), overall survival (OS), and QoL endpoints. Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. While the inclusion of QoL was not associated with the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as a clinical endpoint (p=0.016). When stratified by treatment arm, it was found that studies favouring standard therapy were more likely to include QoL (75%, p=0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management and treatment decisions, only one-third of identified phase III clinical trials included an assessment of QoL. About half of these trials showed no statistically significant differences in the QoL endpoint; of not, instruments of varying validity were utilized. There needs to be a greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints.

A review of clinical endpoints and use of quality of life outcomes in phase III metastatic breast cancer clinical trials.

e16547 Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with therapy used to relieve disease symptoms, minimize treatment effects and prolong survival. The impact of disease and treatment on patients has led to an emphasis of quality of life (QoL) measures in clinical trials. This study’s primary objective is to evaluate phase III clinical trials in MBC, and assess the inclusion of QoL as an endpoint. Methods: A PubMed search was conducted to identify phase III clinical trials published from Jan 1990 to Aug 2011, which evaluated systemic therapy in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a focus on progression-based (PB), overall survival (OS), and QoL endpoints. The instrument(s) used to evaluate QoL were also noted (if applicable). Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. 14 instruments were identified as QoL tools among the studies, with EORTC QLQ-C30 and FACT-B accounting for 54.7% of the instruments used. While the inclusion of QoL was not related to the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as an endpoint (p=0.016). Stratification by treatment arm found that studies favouring standard therapy were more likely to include QoL (75%, p=0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management, only one-third of identified phase III clinical trials included its assessment. Half of these trials showed no statistically significant differences in QoL endpoint; of note, instruments of varying validity were utilized. There needs to be greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints.

Tailored endpoints: A proposal for design of future clinical trials in metastatic breast cancer (MBC).

e13058 Background: Widespread access to active agents against MBC has produced significant improvements in survival, even though few phase III trials are powered to detect overall survival (OS) effects. However, regulatory agencies hold OS as gold standard for approval of new drugs. OS can be portioned into the sum of progression-free survival (PFS) and survival post-progression (SPP). Recent data suggest that OS is a reasonable primary endpoint only when median SPP is short. On the other hand, patients enrolled in first-line trials could have a long life-expectancy. Aim of this study was to evaluate PFS, OS and SPP in a consecutive series of patients with MBC in order to obtain information as a basis for design of future clinical trials. Methods: Four hundred patients with MBC diagnosed from January 2004 to February 2011 at University Hospital of Udine, Italy, were included in the study. We examined the role of potential of disease and patients’ characteristics in influencing the different measures of outcome. Results: Median OS was 33.71 months (mo), in line with the best literature. Median PFS at first-line (PFS1) was 9.33 mo, with linear decrease at second (5.06), third (3.58), and fourth (3.19) line, respectively. Median SPP after first-line (SPP1) was 18.69 mo. Interestingly, differences in outcome were noticed according to immunophenotype. The best prognosis was observed in luminal A disease (OS= 46.72 mo, PFS1= 15.61 mo, SPP1= 25.43 mo). In luminal B disease, median OS was 27.66 mo, PFS1 8.94 mo, and SPP1 13.21 mo, respectively. In patients with HER2-positive disease, mainly treated with anti-HER2 therapy, outcome approached that of luminal A disease (OS= 41.10 mo, PFS= 9.89 mo, SPP1 18.69 mo). Patients with triple negative disease (TNBC) experienced the worst prognosis (OS= 8.54 mo, PFS1= 4.04 mo, SPP1= 2.83 mo). Conclusions: The study demonstrated different results in the measures of outcome according to the line of treatment and specific disease characteristics. As a consequence, endpoints of clinical trials should be tailored taking into consideration prognostic/predictive factors as well as the line of treatment.