Chemotherapy For Advanced Disease Research Articles

393P - Efficacy of Eribulin in a Second-Line or Later Setting in Patients (Pts) with Metastatic Breast Cancer (Mbc): a Pooled Analysis

ABSTRACT Aim: Eribulin (E) is under review by the European Medicines Agency for use as a second-line and later therapy for pts with locally advanced/MBC who have advanced after prior chemotherapy. To assess the efficacy of E in this setting, we conducted pooled analyses of data from 2 phase 3 open-label studies in pts with locally advanced/MBC. Methods: In study 1, pts who had received 0–2 chemotherapies for advanced disease were randomized 1:1 to E mesilate (1.4 mg/m2 iv on days 1 and 8 every 21 days) or capecitabine (1.25 g/m2 orally bid on days 1–14 every 21 days). In study 2, pts had received 2–5 chemotherapies, and were randomized 2:1 to E (as above) or treatment of physician's choice. For this analysis, overall survival (OS) was assessed by Cox regression and stratified log-rank tests for the overall intent-to-treat population and by HER2, HR and triple negative (TNBC) status. Results: In all, 1644 pts (median age 55.0 yrs) were included, most in the 2nd (35.8%) or 3rd (37.0%) -line settings for advanced disease. E significantly improved OS vs control in the overall, HER2 - , HR+ and TNBC groups (Table). Similar OS data were seen in the HR- and non-TNBC groups (data not shown). E significantly improved progression-free survival (PFS) overall (3.9 vs 3.2 months; HR: 0.88; 95%CI: 0.78, 0.98; p = 0.020), and for HER2- (3.7 vs 2.9 months; HR: 0.84; 95% CI: 0.73, 0.96; p = 0.009), HR+ (4.1 vs 3.5 months; HR: 0.85; 95% CI: 0.73, 0.98; p = 0.028) and TNBC (2.8 vs 2.5 months; HR: 0.76; 95% CI: 0.60, 0.97; p = 0.026) but not HER2+ pts (3.8 vs 4.2 months; HR: 1.0; 95%CI: 0.75, 1.35; p = 0.970). Overall HER2 - HER2 + HR + TNBC E Con E Con E Con E Con E Con n 946 698 663 497 150 104 574 432 199 153 Median OS,amonths 15.1 12.5 15.1 12.0 13.5 11.7 15.7 13.5 12.4 8.1 HR (95% CI)b 0.84 (0.76, 0.94) 0.84 (0.74, 0.96) 0.75 (0.57, 1.00 0.85 (0.74, 0.99) 0.70 (0.55, 0.86) pb 0.003 0.011 0.054 0.038 0.003 aBased on survival curves adjusted by study; bstratified by region, prior capecitabine use and study (and HER2 status for the overall group). E, eribulin; Con, control; HR, hazard ratio; OS, overall survival. Conclusions: In this pooled analysis, E significantly improved OS in a second-line or later setting vs available therapies in the overall, HER2 - , HR + , HR - , TNBC and non-TNBC groups. Treatment differences were not significant in HER2+ pts, but there were fewer pts. Eribulin was thus superior to available therapies in a second-line or later setting in pts with locally advanced/MBC who have advanced after ≥ 1 chemotherapy for advanced disease. Disclosure: C. Twelves: has disclosed a consultant or advisory role with Eisai for which he has been compensated. He has also received honoraria and other remuneration from Eisai; J. Cortes: has disclosed a consultant or advisory relationship with Novartis, Celgene and Roche for which he has been compensated. He has also received honoraria from Novartis, Celgene, Roche and Eisai; M. Olivo: Martin Olivo is an employee of Eisai Inc.; Y. He: Yi He is an employee of Eisai Inc. All other authors have declared no conflicts of interest.

Pazopanib versus paclitaxel in relapsed urothelial tumors: A randomized phase II study investigating pazopanib versus weekly paclitaxel in relapsed or progressive transitional cell carcinoma of the urothelium (PLUTO).

TPS4589 Background: Urothelial cancer (UC) is a chemosensitive disease. There is a clear role for first line, platinum-based chemotherapy in advanced disease, response rates being around 40-50%. Ho...

NSC-631570 alkaloid mixture modulates the human equlibrative transporter nucleoside 1 and deoxycytidine kinase gene expressions in pancreatic ductal adenocarcinoma cell cultures

Pancreatic ductal adenocarcinoma (PDAC) is treated by palliative chemotherapy for advanced disease. Gemcitabine is the standard drug in both adjuvant and palliative treatment, but yields a marginal impact on disease outcome. Several attempts to improve the efficacy of gemcitabine by addition of a second cytotoxic or targeted agent have not shown a significant survival advantage. NSC-631570, showed greater median survival in combination with gemcitabine compared to gemcitabine alone in the palliative treatment of unresectable PDAC. However, the authors did not study the interactions between alkaloids and molecular determinant expressions involved in the metabolism of gemcitabine. Therefore, the aim of present study was to evaluate the modulation of the expression of two pivotal genes (hENT1 and dCK) involved in gemcitabine activity. In vitro studies on cell lines and primary cell Cultures from PDAC patients were treated with NSC-631570 at IC50 concentration for 48h. the quantitation of gene expression was performed using the standard curve method and the ΔΔCT calculation. Alkaloids mixture positively modulates the expression of hENT1 mRNA in all PDAC cell cultures. The 2 (-ΔΔCt) analyses revealed a mean increase of 2.8 fold with respect to untreated control cells. In two cell lines cells alkaloids positively affects mRNA expression of dCK gene as well. Based on the previous clinical data the Alkaloids-gemcitabine combination appears a promising regimen and the results of the present study provide the experimental basis for the further clinical testing of the NSC-631570-gemcitabine schedule in PDAC patients.

Bi-weekly liposomal doxorubicin for advanced breast cancer in elderly women (≥70years)

We conducted a multicenter prospective trial to assess tolerability and activity of pegylated liposomal doxorubicin (PLD) in women ≥ 70 years with locally-advanced or metastatic breast cancer. All patients underwent Multidimensional Geriatric Assessment (MGA). Frail patients were excluded. Normal cardiac function was required for inclusion. A bi-weekly schedule of PLD at 20mg/mq was adopted. Thirty-two patients were enrolled with a median age of 78 years, 78.1% with visceral involvement, and 37.6% previously treated with chemotherapy for advanced disease. A mean of 7.8 cycles were delivered (range 1 to 20), with a median cumulative dose intensity of 8.9 mg/m(2)/week. Grade 3-4 toxicities were anemia (6.3%), palmar-plantar erythrodysesthesia (6.3%), mucositis (6.3%), infection (3.1%), and pulmonary embolism (3.1%). No cardiac events were registered. Causes of treatment interruption were maximal response (15.6%), progression (40.6%), refusal/loss to follow-up (28.1%), toxicities (9.4%), or other (6.3%). Response was obtained in 33.3% of 27 evaluable patients; median time to progression (TTP) was 10.3 months. MGA status (vulnerable vs. fit) did not have an impact on response, progression, and toxicity. Bi-weekly PLD is well tolerated in both fit and vulnerable patients, with an apparently fairly good response rate and TTP (possibly biased by subsequent endocrine therapy and loss to follow-up). Close observation of patients is recommended in order to avoid early refusal/loss to follow-up.

Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathy

Peripheral neuropathy is a common toxicity associated with tubulin-targeted chemotherapeutic agents. This Phase II study compares the incidence and severity of neuropathy associated with eribulin mesylate or ixabepilone in metastatic breast cancer (MBC). The primary objective was to assess the incidence of neuropathy; the study was designed to detect a difference in neuropathy rate of 35 % for eribulin versus 63 % for ixabepilone (odds ratio 0.316, 80 % power, 0.05 two-sided significance level). Eligibility criteria included: MBC; prior taxane therapy; at least one chemotherapy for advanced disease; no or minimal pre-existing neuropathy (Grade 0 or 1). The intent-to-treat population comprised 104 patients randomized (1:1) to eribulin mesylate (1.4 mg/m2, 2–5 min intravenous on days 1 and 8) or ixabepilone (40 mg/m2, 3 h intravenous on day 1) on a 21-day cycle. 101 patients in the safety population received a median of 5.0 eribulin and 3.5 ixabepilone cycles. Incidence of neuropathy (any grade) was 33.3 and 48.0 %, and peripheral neuropathy was 31.4 and 44.0 % for eribulin and ixabepilone, respectively. After controlling for pre-existing neuropathy and number of prior chemotherapies, these differences were not significant. Compared with ixabepilone, fewer patients receiving eribulin discontinued treatment due to neuropathy (3.9 vs. 18.0 %) or adverse events (AEs) in general (11.8 vs. 32.0 %). Time to onset of neuropathy was 35.9 weeks for eribulin and 11.6 weeks for ixabepilone, and time to resolution was 48 versus 10 weeks, respectively; other AEs were comparable. Objective responses were 15.4 versus 5.8 % and clinical benefit rates were 26.9 versus 19.2 %. In conclusion, after controlling for pre-existing neuropathy and number of prior chemotherapies, the differences in the incidence of neuropathy with eribulin and ixabepilone were not statistically significant. Onset of neuropathy tended to occur later with eribulin and resolve later.

A randomized, double-blind, placebo (Pbo)-controlled phase III study of ombrabulin plus cisplatin in patients (pts) with advanced-stage soft-tissue sarcoma after failure of anthracycline and ifosfamide chemotherapies.

10506 Background: Ombrabulin (AVE8062) is a vascular disrupting agent that damages established tumor vasculature and has demonstrated synergistic antitumor activity with cisplatin in vivo. In a phase I study, ombrabulin 25 mg/m² plus cisplatin 75 mg/m² was identified as the recommended dose in pts with solid tumors (AACR 2008; Abs 08-AB-4925). This phase III study evaluated the efficacy and safety of ombrabulin plus cisplatin in pts with advanced soft-tissue sarcoma (NCT00699517). Methods: Pts (aged ≥18 yrs, ECOG PS ≤2) with metastatic soft-tissue sarcoma who had received prior anthracycline and ifosfamide, with ≤2 prior chemotherapies for advanced disease, were randomized (1:1) to receive either ombrabulin 25 mg/m² or Pbo plus cisplatin 75 mg/m² every 3 weeks. The primary objective was to compare progression-free survival (PFS) between arms; secondary objectives included overall survival (OS) and safety. Results: Overall, 355 pts (median age 52 yrs; 51.5% male) were randomized (176 ombrabulin, 179 Pbo) in 44 centers worldwide. Median duration of follow-up was 27.9 and 30.5 months in Pbo and ombrabulin arms, respectively. PFS analysis showed a statistically significant improvement with ombrabulin (median 1.54 vs 1.41 months Pbo; HR=0.76, 95% CI 0.59–0.98; p=0.0302), with 3- and 6-month rates in favor of ombrabulin vs Pbo: 35.4% vs 24.9% and 19.3% vs 10.6%, respectively. A trend for an improvement with ombrabulin was observed in 3 of the 4 prespecified histology strata: liposarcoma, leiomyosarcoma, and “other”, but not for pleomorphic. Analysis of OS did not show statistically significant improvement with ombrabulin (median 11.43 vs 9.33 months Pbo, HR=0.85, 95% CI 0.67–1.09). OS rates at 1 year were in favor of ombrabulin (48.6% vs 42.4% Pbo). Grade 3/4 TEAEs more frequently seen with ombrabulin included neutropenia (19.2% vs 7.9% Pbo) and thrombocytopenia (8.5% vs 3.4% Pbo). Conclusions: Although this trial met its primary efficacy endpoint, the combination of ombrabulin and cisplatin did not demonstrate sufficient clinical benefit in pts with advanced soft-tissue sarcoma to warrant further study. Clinical trial information: NCT00699517.

INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced esophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG).

TPS4157 Background: Advanced Oesophago-Gastric Carcinoma (AOGC) has a poor prognosis, and there is no established standard treatment following failure of first or second line chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor which targets kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT), and has shown activity in other solid tumours. Following promising results in colon cancer and GIST, this study will determine if regorafenib has sufficient activity and safety to warrant further evaluation in a phase III trial as a second or third line therapy for AOGC. Methods: International (Australia & New Zealand (ANZ); Canada (NCIC CTG), Korea) randomised phase II, double-blind, placebo-controlled trial with 2:1 (REG:placebo) randomisation and stratification by: (1) Lines of prior chemotherapy for advanced disease (1 vs. 2). (2) Geographic region. Eligible patients with histological confirmation of OGC, with measurable metastatic or locally advanced disease that is refractory to, or relapsed following, first or second line CT, will receive best supportive care plus 160mg REG or matching placebo orally on days 1-21 of each 28 day treatment cycle until disease progression or prohibitive adverse events. Primary endpoint is progression free survival (PFS). Secondary endpoints: PFS by baseline VEGF, response rate, overall survival, safety, quality of life and exploratory plasma angiogenesis and tissue growth factor biomarkers. 150 patients will be randomized in a 2:1 (REG:PBO) ratio. This will provide 90% power to detect a PFS rate at 2 months in the REG arm ≥ 66% versus < 50%. If 16 of 33 (evaluable) REG participants have progressed by 2 months, then the study will be reassessed or stopped. Results: As of January 2013, 19 of 29 planned ANZ sites are open, with 10 patients enrolled. Regulatory approval has been received for 16 sites in Canada and 7 sites in Korea. 4 Korean sites have received ethics approval with recruitment expected to commence in early April 2013. Clinical trial information: ACTRN12612000239864.

Ph III randomized studies of the oral pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer (BC) after aromatase inhibitor (AI; BELLE-2) or AI and mTOR inhibitor (BELLE-3) treatment.

TPS650^ Background: The PI3K/Akt/mTOR pathway is commonly dysregulated in BC and linked to resistance to endocrine therapy, including AIs. Buparlisib is an oral inhibitor of class I PI3K isoforms (α, β, γ, δ), showing near complete tumor regression in an in vivo model of ER+ BC in combination with fulvestrant. Preliminary clinical activity in BC pts has been observed with buparlisib as a single agent and in combination with letrozole (Mayer et al. ASCO 2012). Methods: BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060) are 2 Ph III randomized, double-blind, placebo-controlled trials of oral buparlisib (100 mg/d) in combination with fulvestrant (500 mg) given on D1 and 15 of Cycle 1 and D1 of each 28-day cycle thereafter in postmenopausal women with HR+/HER2– locally advanced/metastatic BC. Additional eligibility criteria: disease progression on/after AI treatment for BELLE-2; prior treatment with AI and progression on mTOR inhibitor in combination with endocrine therapy (as last therapy prior to study entry) for BELLE-3; ≤1 previous line of chemotherapy for advanced disease; available archival tumor tissue for PI3K-related biomarker analysis. Randomization to either arm (1:1 for BELLE-2 and 2:1 for BELLE-3) is stratified according to PI3K pathway activation status (activated vs non-activated vs unknown) and visceral disease status (present vsabsent). Study treatment is given until disease progression or discontinuation for any reason. Co-primary endpoints in both trials: PFS in full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints: overall survival (OS) in full and PI3K pathway-activated populations; other secondary endpoints: PFS and OS in PI3K non-activated/unknown population, overall response rate, clinical benefit rate, safety (CTCAE 4.03), PK, and patient-reported outcomes (EORTC QLQ-C30 and QLQ-BR23). Estimated enrollment is 842 pts for BELLE-2 and 615 for BELLE-3. As of January 2013, 96 pts were randomized to BELLE-2 and 1 pt to BELLE-3. Recruitment is ongoing globally. Clinical trial information: NCT01610284 and NCT01633060.

A phase II trial of weekly docetaxel for second-line treatment of urothelial carcinoma.

e15613 Background: Despite high response rates (RRs) with first-line platinum-based chemotherapy in advanced urothelial carcinoma (UCC), treatment after first-line failure remains unclear. The present multi-center phase II trial evaluated the tolerability and efficacy of weekly docetaxel as second-line chemotherapy for UCC. Methods: Between Aug 2010 and Sep 2012, 31 patients with measurable UCC, progressive after one prior platinum-based chemotherapy for advanced disease, were treated with docetaxel 30 mg/m2 on days 1 and 8. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The primary endpoints were the RR, progression-free survival (PFS), and safety. To detect a 20% difference in RR (6% vs. 26%), 28 eligible patients were required. Results: All 31 patients were previously treated with gemcitabine/platinum and had Bellmunt risk of one or more. The patients’ median age was 64 years (range, 40 to 79) and 31 (100%) patients had an ECOG performance status of 1. A total of 106 (median, 2; range, 1 to 16) chemotherapy cycles were delivered. Although fatigue (13%) and anorexia (6%) were the most frequently observed grade 3 or 4 toxicities, safety profiles were generally mild and manageable. One patient developed prolonged thrombocytopenia which led to treatment discontinuation but was resolved thereafter. In an intent-to-treat analysis, two (6%) patients achieved objective response, which maintained for 3.0 to 7.8 months. Eight patients experienced disease stabilization, resulting in a disease control rate of 32%. The median PFS and overall survival were 1.4 (95% CI, 1.3 to 1.6) and 9.6 (95% CI, 7.8 to 11.4) months, respectively. Conclusions: Second-line chemotherapy with weekly docetaxel was well tolerated but demonstrated modest antitumor activity in patient with advanced UCC who had progression after first-line platinum-containing regimen and poor prognostic factors. Clinical trial information: NCT01711112.

Cetuximab in Advanced Bladder Cancer

TO THE EDITOR: Second-line treatment for patients with advanced bladder cancer who experience progression after first-line platinum-based regimens remains an unmet medical need. In recent years, vinflunine was the first agent to be approved by a regulatory agency (European Medicine Agency) in this setting. Wong et al 1 should be congratulated for having conducted a randomizedphaseIItrialofcetuximabwithorwithoutpaclitaxelin39 patients with previously treated urothelial cancer. The authors concluded that cetuximab has limited activity as a single agent, whereas the combination of cetuximab and paclitaxel warrants additional study. However, a few points concerning the design of this study could have altered the conclusions. Selection of Patients Wong et al 1 included patients experiencing failure during firstline chemotherapy for advanced disease or perioperative (neoadjuvant or adjuvant) therapy without any restriction on the time from previous treatment. Progression of disease within 6 months in the

Abstract OT3-3-05: Neurotoxicity characterization phase II randomized study of nab-paclitaxel versus conventional paclitaxel as first-line therapy of metastatic HER2-negative breast cancer. An ONSOCUR Study Group.

Abstract Background: Nab-paclitaxel (Nab-P) is a nanoparticle albumin-bound form of paclitaxel that is thought to exploit natural albumin pathways to enhance the selective uptake and accumulation of paclitaxel at the site of the tumour, thus reducing its diffusion to normal tissues. Nab-P has been approved for the treatment of metastatic breast cancer patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. Toxicity profile of Nab-P is well characterized with significantly less haematological toxicities compared with conventional paclitaxel (P). Nab-P derived grade III neuropathy is short-lasting and more reversible than conventional P-derived neuropathy, probably due to absence of Cremophor solvent, or due to P itself. However there is still a lack of clinical and physiological characterisation of Nab-P induced neuropathy. The Current used tools for early detection and continuous evaluation of neurotoxicity are not optimal. Most used toxicity scales are limited, as they do not provide a detailed information of the severity of the neuropathy, its impact on quality of life, or physiopathology mechanisms. In addition, an inter-individual variability exists in terms of neurotoxicity predisposition when taxanes are used; it seems to be related to polymorphic differences in genes implicated in transport and metabolism of these drugs. Specific aims: Primary objective is to characterize neurotoxicity according to Total Neuropathy Score (TNS) and electromyographic changes. Secondary endpoints are determine the rate of neuropathy chemo-induced, the predictive value of some genetic variants (SNPs) for the development of neuropathy, clinical activity, toxicity profile and safety of treatments and quality of life (EORTC QLQ-C30 and CIPN20). Trial design: Phase II open-label randomised clinical trial with four parallel arms: a) conventional paclitaxel 80 mg/m2 on days 1, 8 and 15; b) Nab-P 100 mg/m2 on days 1, 8 and 15; c) Nab-P 150 mg/m2 on days 1, 8 and 15; d) Nab-P 150 mg/m2 on days 1 and 15. Study treatments will be administered in a 28-day cycle until progression disease, intolerable toxicity or investigator's decision. Eligibility criteria: Women >18 years, with cytological or histological confirmation of HER2-negative breast cancer, metastatic disease, not prior chemotherapy for advanced disease, no prior grade > 1 neuropathy from any cause, measurable or evaluable disease, ECOG >2 and adequate bone marrow, renal and hepatic functions. No Relevant comorbidities. Statistical methods: This is an exploratory safety study to better characterize neurotoxicity in patients treated with Nab-P compared toP. Therefore no formal sample size or power calculations will be performed. We expect to recruit 60 patients, 15 in each treatment arm, in 18 months. Recruitment will start on October 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-05.

Abstract P1-12-04: Carboplatin, nab-paclitaxel and bevacizumab as first-line treatment for metastatic breast cancer.

Abstract Background: Bevacizumab added to weekly paclitaxel resulted in improved progression free survival (PFS) and objective response rates (ORR) compared to weekly paclitaxel alone. Nab-paclitaxel and the platins are active in MBC. We conducted an efficacy and safety study of carboplatin, nab-paclitaxel and bevacizumab. Methods: A phase II open label prospective multi-site study enrolled patients (pts) who had measurable MBC according to RECIST 1.1 criteria and no prior chemotherapy for advanced disease. The primary endpoint was PFS with secondary endpoints of overall survival (OS), ORR, and safety. Pts initially received carboplatin AUC 6 day 1, 22,43, plus weekly nab-paclitaxel 100mg/m2 and bevacizumab 15mg/m2 day 1,22,43 of a 56 day cycle. This was later changed to carboplatin AUC 6 day 1, nab-paclitaxel 100mg/m2 day 1,8,15, and bevacizumab 10mg/m2 day 1,15 of a 28 day cycle. Thirty-two pts were required to detect an increase in median PFS from 6.7 to 10.5 mo with 80% power based on a one-sided p = 0.05. Kaplan–Meier analyses estimated PFS and OS. The log rank test was used for the comparison of survival curves between pts with triple negative MBC (TNBC) and pts with non-TNBC. Results: Thirty-two pts were enrolled between 2/2008 and 11/2011 by 1 academic and 5 community oncology practices. Two pts were ineligible due to non-measurable disease and not included in the response analyses. The median age was 58 years (range 35–81), 22 pts (69%) had an ECOG PS 0, 9 (28%) had a PS 1, 1 (3%) PS 2. Twenty-four (75%) pts had ER+ disease, 7 (22%) had TNBC, 1 (3%) had ER-HER2+ disease not eligible for trastuzumab-based therapy. Metastatic sites were bone (26%), liver (18%), loco-regional (16%), and lung (12%). One pt (3%) had bone and loco-regional disease only, 19 (59%) had visceral dominant disease. The median number of weeks on treatment was 28.9 (range 5–131). The median PFS in all pts was 13.6 months (mo) (95% CI 11.2–21.9), with a median OS of 26.8 mo (95% CI 13.3–41.2). The ORR (2 CR and 18 PR) was 66.7% (CI 47.2–82.7). There also were 6 (20%) unconfirmed PR and 3 (10%) stable disease, resulting in a clinical benefit rate of 96.7% (CI 82.78–99.92). There was no significant difference in PFS (median 13.6 vs 16.1mo, p = 0.37) or OS (median 13.6 vs 26.8mo, p = 0.32) in pts with TNBC versus non-TNBC disease. The most common toxicities of any grade (gr) include neutropenia and thrombocytopenia in 24 pts (75%) each, leukopenia and fatigue in 17 pts (53%) each, anemia in 15 (47%), and neuropathy in 10 (31%). Gr 4 neutropenia was seen in 7 pts (22%) without febrile neutropenia, and gr 4 thrombocytopenia occurred in 6 (19%). There were no pts with gr 4 sensory neuropathy. All pts required chemotherapy dose delays, 15 (47%) had chemotherapy dose reductions. Conclusions: The carboplatin, nab-paclitaxel and bevacizumab combination is highly effective with good tolerance in first line MBC. As the role of anti-angiogenic therapy in first line metastatic breast cancer is being clarified, this would be an attractive regimen to test in the (neo)adjuvant setting and together with novel molecular targeted agents. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-04.

Comparison of the incidence of peripheral neuropathy (PN) with eribulin versus ixabepilone (IXA) in metastatic breast cancer (MBC) patients: A randomized phase II study.

121 Background: Eribulin mesylate is approved for patients (pts) with MBC who have previously received ≥2 chemotherapeutic regimens for metastatic disease including an anthracycline and taxane in either the adjuvant or metastatic setting. This study compared incidence and severity of neuropathy adverse events (AEs) in pts receiving eribulin or IXA. Methods: Pts (locally recurrent/MBC; prior taxane therapy; ≥1 prior chemotherapy for advanced disease; pre-existing neuropathy Grade 0 [n=51] or 1 [n=53]) were randomized to receive 1.4 mg/m2 eribulin mesylate (2–5-min intravenous (IV), Days 1 and 8 of a 21-day cycle) or 40 mg/m2IXA (3 h IV, Day 1 of a 21-day cycle). The primary objective was to compare incidence of neuropathy AEs by CTCAE grade. Secondary objectives: severity of neuropathy AEs by CTCAE grade, patient neurotoxicity questionnaire (PNQ), and vibration sensitivity using Vibration Perception Threshold (VPT); time to onset of treatment-emergent neuropathy (TEN); efficacy; safety and tolerability. Results: Incidences ofPN and TEN (all grades) with eribulin (n=51) versus (vs) IXA (n=50) were 31.3% vs 44.0%, p=0.1632 and 33.3% vs 48.0%, p=0.1284, respectively. Severity (grade ≥3) was numerically lower with eribulin than IXA (PN: 9.8% vs 20.0%; TEN: 9.8% vs 22.0%). No significant differences were seen in baseline to worst PNQ scores. Median worst post-baseline VPT scores were lower with eribulin than IXA (index finger: 2.3 vs 2.4 vibration units [vu]; great toe: 7.75 vs 8.6 vu). Median time to onset of TEN was earlier with IXA (11.6 weeks [wks]) than eribulin (35.9 wks). TEAEs were comparable. Median treatment duration was 15.0 wks (eribulin) and 10.5 wks (IXA). Reasons for discontinuation (eribulin vs IXA): TEN (3.9% vs 18.0%); any TEAE (11.8% vs 32.0%); progressive disease (68.6% vs 48.0%). Objective response and clinical benefit rates were 15.4% vs 5.8% and 26.9% vs 19.2% for eribulin and IXA, respectively. Conclusions: Although not statistically significant, neuropathy AEs were less common with eribulin than IXA. Eribulin was associated with longer time to onset of TEN and fewer discontinuations due to neuropathy and other toxicities.

Expression of thymidylate synthase and orotate phosphoribosyltransferase in thymic carcinoma

Thymic carcinoma is a rare thymic epithelial tumor in which chemotherapy for advanced disease has not yet been established. Thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) protein expression levels in thymic carcinoma were evaluated as possible indicators of the anticancer activity of 5-fluorouracil (5-FU) drugs using immunohistochemistry (IHC). A total of 24 samples of thymic carcinoma were used in the present study. The tumor sections were immunohistochemically stained for TS and OPRT. As a comparison with thymic carcinoma, we also assessed the TS and OPRT protein expression levels in 55 lung cancer samples. The TS expression was positive in 12 of 24 thymic carcinoma samples (50%) and OPRT expression was positive in 10 (42%). The association between TS and OPRT expression and Masaoka stages of thymic carcinoma was analyzed. The TS and OPRT expressions in stage IV were significantly higher compared to that in stages I, II or III. We also compared the TS and OPRT expression levels between thymic carcinoma and lung cancer (33 adenocarcinomas and 22 squamous cell carcinomas). TS expression in thymic carcinoma was significantly lower compared with lung squamous cell carcinoma. OPRT expression in thymic carcinoma was significantly higher compared to lung adenocarcinoma. The combination of a relatively low expression of TS and high expression of OPRT suggests an improved antitumor effect of 5-FU drugs in thymic carcinoma compared to in lung carcinoma.

Diagnostik und Therapie des malignen Pleuramesothelioms - von der Palliationzur kurativen Intention

Malignant pleural mesothelioma continues to be a clinical challenge and its incidence will continue to increase worldwide. Once diagnosed with pleural mesothelioma, patients nearly invariably die of the disease. While the benefit of chemotherapy for advanced disease has been established, many other aspects of treatment continue to be controversial, in particular in regard to surgery and radiotherapy. However, the best survival data is reported from groups using multimodality treatment including surgery for patients qualifying from a tumor stage - and functional perspective. Therefore, efforts should focus on improving staging systems. Translational studies should be included with the final aim of finding reliable markers for response to therapy. Despite both, the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development, the number of new treatments that have been approved for patients has not increased. As mesothelioma is a rare disease, the number of patients is limiting and more innovative trial designs (such as multi-arm multi-stage trials [1]) using cooperative platforms to eliminate less effective treatments may be the best way forward.

Phase Ib study of CNTO 888 (anti-CCL 2) in combination with chemotherapies for treatment of patients with solid tumors.

3059 Background: CC-chemokine ligand 2 (CCL2) is expressed in various malignancies, implicated in angiogenesis, proliferation and metastasis. CNTO888 is a hIgG1κ mAb with selective high CCL2 binding affinity and showed preclinical antitumor activity. Methods: Primary objectives were safety and a recommended dose of CNTO 888 in combination with chemotherapy: Arm 1 - 15 mg/kg CNTO 888 + docetaxel 75 mg/m2 Q3W; Arm 2 - 15 mg/kg CNTO 888 + gemcitabine 1000 mg/m2 on D1 and 8 Q3W; Arm 3 - 15 mg/kg CNTO 888 + paclitaxel 175 mg/m2 and carboplatin AUC6 Q3W; Arm 4 - 10 mg/kg CNTO 888 Q2W + pegylated doxorubicin 50 mg/m2 Q4W. Two (Arms 1, 2, 3) or 4 (Arm 4) prior chemotherapies for advanced disease were allowed. Pharmacokinetic (PK) profile of CNTO 888 and chemotherapies, free and total CCL2, CTC/CEC count, and uNTX were evaluated. Adverse events (AE) and dose limiting toxicities (DLT) were evaluated after 6 subjects completed 1 cycle. Results: 53 subjects (22F/31M) were treated: Arm 1 n=15, Arm 2 n=12, Arm 3 n=12, Arm 4 n=14. Two DLTs occurred: a grade 4 febrile neutropenia (Arm 1) and a grade 3 neutropenia (Arm 2). All 4 combinations were found to be safe and tolerable and continued enrolment to a minimum of 12 subjects evaluable for safety and PK. Best overall response were partial response (PR) (1) and stable disease (18; 2 ≥ 4 months). One subject with pancreatic adenocarcinoma achieved PR, allowing for surgical resection. Most frequently reported (≥ 20%) related serious AEs are: Arm 1: Neutropenia, Stomatitis, Fatigue, Febrile neutropenia, Alopecia. Arm 2: Anemia. Arm 3: Thrombocytopenia, Alopecia, Neutropenia, Asthenia, Fatigue, Anemia, Arthralgia, Nausea, Vomiting. Arm 4: Stomatitis, Rash, Fatigue, Nausea, Anemia, Neutropenia. CNTO 888 did not affect the chemotherapy PK profile; similarly, chemotherapy did not affect the CNTO 888 PK profile. No subjects (n=38) tested positive for antibodies to CNTO 888. Free CCL2 declined 2 hrs post treatment and returned to baseline levels by 48 hrs and continued to increase with further administrations in all treatment arms. There were no consistent changes with other biomarkers. Conclusions: CNTO 888 in combination with standard chemotherapy was well tolerated but few objective responses were seen.

Vejez y cáncer de mama, el desafío del siglo 21

Due to the increase in life expectancy in Chile, more than 10% of the population is 60 years or older. Since the incidence of most cancers increases with age, one of every two men and one in three women will develop a malignancy during their lifetime. In Chile breast cancer is the first leading cause of death from cancer among women. Its detection in postmenopausal women has steadily increased since the eighties, due to the expanded use of mammography. Less than 10% of patients participating in randomized controlled trials for the treatment of breast cancer, are older than 60 years, despite the fact that biological characteristics of breast cancer in older women are different and that most patients with breast cancer are of that age. Due to the high incidence of estrogen receptor positive tumors in this age group, most patients are candidates for hormone therapy. However, in those who need chemotherapy, therapeutic decisions are based on the existence of concomitant diseases and the tolerance to cytotoxic therapy. We review the relationship between age and cancer, the particular characteristics of breast cancer in older women and the alternatives of treatment with chemotherapy in advanced disease.

The impact of chemotherapy and fertility-sparing surgery on recurrence of serous borderline ovarian tumors: A multi-institutional study of 491 patients

Objective: The benefit of chemotherapy in advanced disease and risk of fertility-sparing surgery (FSS) in younger women with borderline ovarian cancer remains controversial. We proposed to examine the role of chemotherapy and FSS in this multi-institutional study.

S3-7: Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial.

Abstract Background: The mTOR pathway is constitutively activated in hormone-resistant advanced breast cancer (ABC). In phase II trials, everolimus (EVE) showed promising efficacy both as monotherapy and in combination with endocrine therapy in patients with estrogen receptor-positive (ER+) ABC. This double-blind, placebo-controlled, phase III study evaluated EVE plus exemestane (EXE) in patients with ER+ ABC refractory to letrozole or anastrozole. Patients and Methods: Eligible patients were randomized (2:1) to EXE (25 mg/day) with EVE (10 mg/day) or with matching placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, quality of life (QoL), and safety. Results: 724 patients were randomized (485: EVE+EXE; 239: EXE). Baseline characteristics were well balanced; median age was 62 years, 56% had visceral involvement, and 84% had documented benefit from previous endocrine therapy, which included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy for advanced disease (25%). This analysis is based on 457 events and median follow-up of 12.5 months. PFS by investigator assessment showed a hazard ratio (HR) of 0.44 (95% CI: 0.36−0.53) and a median duration of 7.4 (EVE+EXE) vs 3.2 months (EXE) (P<1 × 10−16) and 12-month estimate of 31% vs 10%. PFS by central assessment showed an HR of 0.36 (95% CI: 0.28−0.45) and a median duration of 11.0 (EVE+EXE) vs 4.1 months (EXE) (P<1 × 10−16) and 12-month estimate of 48% vs 18%. Response rates and clinical benefit rate were also higher for EVE+EXE (12.0% vs 1.3% and 50.5% vs 25.5%). A total of 138 patients died; 17.3% in the EVE+EXE arm and 22.6% in the EXE arm. The most common grade 3/4 adverse events were stomatitis (8% vs 1%), anemia (7% vs 1%), hyperglycemia (5% vs < 1%), dyspnea (4% vs 1%), and fatigue (4% vs 1%) for the EVE+EXE and EXE groups, respectively. Grade 3 pneumonitis was observed in patients receiving EVE (3% vs 0%). No difference in time to deterioration of QoL was observed. EVE increased EXE steady-state Cmin and Cmax levels by 45% and 64%, respectively, with no difference in estradiol levels. Serum markers of bone resorption and bone formation increased in the EXE arm and generally decreased in the EVE+EXE arm. Conclusion: The addition of EVE to EXE is associated with significant and sustained prolongation of PFS. Adverse events were higher in the combination arm but manageable by dose interruption and/or reduction and did not affect QoL. EVE in combination with an aromatase inhibitor is a promising therapeutic option for women with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-7.

S4-8: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) + docetaxel (DOC) as first-line therapy for HER2−positive locally recurrent/metastatic breast cancer (LR/mBC)

Abstract Background: H + taxane is an established and effective first-line treatment for HER2−positive LR/mBC. Preclinical data provide the rationale for combining BEV and H in HER2−positive LR/mBC but clinical data in this setting are limited to single-arm phase II studies. AVEREL is the first randomized trial of BEV in HER2−positive LR/mBC. Methods: Eligible patients had measurable or evaluable HER2−positive LR/mBC (centrally confirmed IHC 3+ or FISH/CISH +), ECOG performance status 0/1, and had received no prior chemotherapy for advanced disease. Prior adjuvant H/taxanes were permitted unless disease had recurred <6/<12 months after the last dose, respectively. Patients with CNS metastases were excluded. Patients were stratified according to adjuvant H, prior (neo)adjuvant taxane (further stratified by time to relapse since last dose of [neo] adjuvant chemotherapy/no chemotherapy), hormone receptor status, and measurable disease, and were randomized to receive either H (8 mg/kg → 6 mg/kg q3w) + DOC (100 mg/m2 q3w) or H + DOC + BEV (15 mg/kg q3w). H and BEV were given until disease progression; DOC was given for a planned minimum of 6 cycles unless progression or unacceptable toxicity mandated earlier discontinuation. The primary endpoint was progression-free survival (PFS). Additional endpoints included overall survival (OS), overall response rate (ORR; assessed by RECIST 1.0), duration of response, time to treatment failure, safety (NCI CTCAE v3.0 adverse events [AEs] and AEs of special interest for BEV), quality of life (FACT-B), and translational research. The primary analysis of PFS was prespecified after 310 investigator-assessed PFS events. The statistical design provided 90% power to detect a PFS hazard ratio (HR) of 0.69 (median PFS 11→16 months) with α=0.05. Results: Between Sep 2006 and Feb 2010, 424 patients were enrolled from 60 centers; 421 received treatment. Baseline characteristics were generally well balanced in the H + DOC and H + DOC + BEV arms: median age 55 and 53 years, respectively; visceral metastases 71% and 77%; prior adjuvant H 12% and 13%; disease-free interval <12 months 43% in both arms; measurable disease 85% in both arms. Median follow-up was 26 months in both arms. Efficacy results are summarized in the table. No new safety signals were observed. The following grade ≥3 AEs were more common in the BEV-containing arm than the H + DOC arm: congestive heart failure (5.1% vs 2.9%, respectively); febrile neutropenia (11.6% vs 8.7%); hypertension (11.6% vs 0.5%). Grade 5 AEs occurred in 1.4% of the H + DOC + BEV arm vs 1.9% of the H + DOC arm. Conclusions: The addition of BEV to H + DOC improved PFS without reaching statistical significance according to investigator assessment (unstratified HR 0.82; 95% CI 0.65−1.02). The improvement as assessed by Independent Review Committee was statistically significant. Evaluation of biomarkers is ongoing to try to identify those patients who may benefit from first-line BEV-containing therapy for HER2−positive LR/mBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-8.