Bevacizumab Arm Research Articles

Different Strategies for the Treatment of Age-Related Macular Degeneration in China: An Economic Evaluation.

Purpose. To assess the cost-effectiveness of bevacizumab compared to ranibizumab, verteporfin photodynamic therapy (PDT), and usual care for the treatment of age-related macular degeneration (AMD) in China. Methods. A Markov model was developed according to patient visual acuity (VA) in the better-seeing eye (Snellen scale). Four cohorts of patients were treated with one of the following therapies: bevacizumab, ranibizumab, PDT, or usual care. Clinical data related to treatments were obtained from published randomized clinical trials. Direct medical costs and resource utilization in the Chinese health care setting were taken into account. Health and economic outcomes were evaluated over a lifetime horizon. Sensitivity analyses were performed. Results. Treatment with ranibizumab provided the greatest gains in quality-adjusted life-years (QALYs). The cost per marginal QALY gained with bevacizumab over usual care was $1,258, $3,803, and $2,066 for the predominantly classic, minimally classic, and occult lesions, respectively. One-way sensitivity analysis showed considerably influential factors, such as utility values and effectiveness data. Probabilistic sensitivity analysis indicated that, compared to usual care, PDT and ranibizumab most cases would be cost-effective in the bevacizumab arm at a threshold of $7,480/QALY. Conclusion. Bevacizumab can be a cost-effective option for the treatment of AMD in the Chinese setting.

BMET-26PHASE 2 STUDY OF VB-111, AN ANTI-CANCER GENE THERAPY, AS MONOTHERAPY FOLLOWED BY COMBINATION OF VB-111 WITH BEVACIZUMAB, IN PATIENTS WITH RECURRENT GLIOBLASTOMA

BACKGROUND: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor-vasculature by expressing a fas-chimera transgene in angiogenic-endothelial cells. Safety and efficacy of VB-111 alone and in combination with bevacizumab (BEV) were evaluated in recurrent-Glioblastoma (rGBM) patients in this Phase 1-2 dose-escalation study. METHODS: VB-111 was administered at 3x1012 or 1x1013 bimonthly until progression, followed by BEV standard-of-care (SOC). The protocol was amended to add-on BEV 10mg/Kg biweekly combined with VB-111 bimonthly, until further progression. Assessments included safety, pharmacokinetics, overall survival (OS) (Kaplan Meyer) and tumor response (RANO). RESULTS: 46 patients at 4 sites (US and Israel) received up to 13 doses of VB-111. Upon further progression, 24 received VB-111 with BEV, 22 were treated with BEV SOC. VB-111 was safe and well-tolerated alone and in combination with BEV. There were 30 grade ≥3 AEs, of which 6 were considered possibly related to VB-111: thrombocytopenia, pyrexia, brain edema, depressed consciousness, general weakness, pulmonary embolism. Median OS was 16 months for patients receiving combination therapy versus 8 months for those receiving SOC (p= 0.05). OS of combination therapy was superior to the historical control BELOB BEV arm, 16 versus 8 months (p = 0.003). Of 46 patients who received VB-111, 25 patients spiked a fever post-VB-111 dosing at least once, while 21 didn't. Feverish patients demonstrated a median OS of 16 months, compared to non-feverish patients, with a median OS of 8.5 months (p = 0.03). CONCLUSIONS: VB-111 was safe and well-tolerated alone and in combination with BEV in rGBM patients. OS of patients who received VB-111 followed by combination therapy almost doubled compared to historical BEV data, and compared to patients who received VB-111 monotherapy. Toxicities were as expected in this population. A phase 3 randomized controlled trial is currently underway.

Efficacy and Safety of Bevacizumab Combined with Chemotherapy for Managing Metastatic Breast Cancer: A Meta-Analysis of Randomized Controlled Trials

Although the FDA revoked metastatic breast cancer (MBC) from bevacizumab (BEV) indication in 2011, BEV combined with paclitaxel has been written in the breast cancer NCCN guidelines. This systematic assessment was performed to evaluate the efficacy and safety of BEV + chemotherapy (CHE) for managing MBC. PubMed and EMBASE were searched for original articles written in English and published before July, 2015. Progression-free survival was significantly improved in the CHE + BEV arms compared to the CHE arms in overall group and in human epidermal growth factor receptor 2-negative group (HR 0.75, 95% CI: 0.68–0.84, P < 0.001; HR 0.75, 95% CI: 0.69–0.82, P < 0.001). There were no significant improvement in overall survival in the CHE + BEV arms compared to the CHE arms. Significantly more grade 3 febrile neutropenia, hypertension, proteinuria, and cardiac events were observed in the CHE + BEV arm, which are controllable and reversible. Severe bleeding occurred more in the BEV + taxane arms and in patients with brain metastases. Therefore, CHE + BEV significantly increases progression-free survival in patients with MBC, it should be considered as a treatment option for these patients under the premise of reasonable selection of target population and combined CHE drugs.

Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer.

Transmembrane receptors, such as the EGFR, are regulated by their turnover, which is dependent on the ubiquitin-proteasome system. We tested in two independent study cohorts whether SNPs in genes involved in EGFR turnover predict clinical outcome in cetuximab-treated metastatic colorectal cancer (mCRC) patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172), SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873), SGIP1 (rs604737; rs6570808; rs7526812), UBE2M (rs895364; rs895374), and UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. One hundred and fifty-three FOLFIRI plus cetuximab-treated patients served as validation set, and 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with progression-free survival (log-rank P = 0.005; HR, 0.60) within cetuximab-treated patients. No association with bevacizumab-treated patients (n = 168) could be established (P = 0.56; HR, 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC.

Randomized, phase II, placebo-controlled trial of onartuzumab and/or bevacizumab in combination with weekly paclitaxel in patients with metastatic triple-negative breast cancer

Increased hepatocyte growth factor/MET signaling is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer (TNBC). We evaluated the benefit of adding onartuzumab, a monoclonal anti-MET antibody, to paclitaxel with/without bevacizumab in patients with TNBC. Women with metastatic TNBC were randomized to receive onartuzumab plus placebo plus weekly paclitaxel (OP; n = 60) or onartuzumab plus bevacizumab plus paclitaxel (OBP; n = 63) or placebo plus bevacizumab plus paclitaxel (BP; n = 62). The primary end point was progression-free survival (PFS); additional end points included overall survival (OS), objective response rate (ORR), and safety. This trial was hypothesis generating and did not have power to detect minimum clinically meaningful differences between treatment arms. There was no improvement in PFS with the addition of onartuzumab to BP [hazard ratio (HR), 1.08; 95% confidence interval (CI) 0.69-1.70]; the risk of a PFS event was higher with OP than with BP (HR, 1.74; 95% CI 1.13-2.68). Most patients had MET-negative tumors (88%); PAM50 subtype analysis showed basal-like tumors in 68% of samples. ORR was higher in the bevacizumab arms (OBP: 42.2%; 95% CI 28.6-57.1; BP: 54.7%; 95% CI 41.0-68.4) compared with OP (27.5%; 95% CI 15.9-40.6). Median OS was shorter with OBP (HR, 1.36; 95% CI 0.75-2.46) and OP (HR, 1.92; 95% CI 1.03-3.59), than with BP. Peripheral edema was more frequent in the onartuzumab arms (OBP, 51.8%; OP, 58.6%) versus BP (17.7%). This study did not show a clinical benefit of the addition of onartuzumab to paclitaxel with/without bevacizumab in patients with predominantly MET-negative TNBC. NCT01186991.

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial.

The AVAglio (Avastin in Glioblastoma) and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy plus temozolomide. To establish whether certain patient subgroups derived an OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy was assessed for each patient subgroup. A total of 349 pretreatment specimens (bevacizumab arm, n = 171; placebo arm, n = 178) from AVAglio patients (total, N = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype. A multivariable analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the proneural subtype biomarker and treatment arm (P = .023). The group of patients with mesenchymal and proneural tumors derived a PFS benefit from bevacizumab compared with placebo; however, this translated to an OS benefit in the proneural subset only. Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type proneural glioblastoma may derive an OS benefit from first-line bevacizumab treatment. The predictive value of the proneural subtype observed in AVAglio should be validated in an independent data set.

5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study.

BackgroundSunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer.MethodsPatients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life.ResultsEnrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm.ConclusionWhile the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer.

Abstract P2-17-01: Overall survival (OS) in the IMELDA randomized phase III trial of maintenance bevacizumab (BEV) with or without capecitabine (CAP) for HER2-negative metastatic breast cancer (mBC)

Abstract BACKGROUND The open-label randomized phase III IMELDA trial demonstrated that adding CAP to maintenance BEV until disease progression (PD) after initial BEV–docetaxel (DOC) provides statistically significant and clinically meaningful improvements in both progression-free survival (PFS [primary endpoint]; hazard ratio [HR] 0.38 [95% CI 0.27–0.55]; log-rank p&amp;lt;0.001) and OS. We present OS in subgroups representing stratification factors and clinically important populations. METHODS Patients (pts) with HER2-negative measurable mBC, ECOG PS &amp;lt;2, and no prior chemotherapy for mBC were eligible. After 3–6 cycles of BEV–DOC, pts without PD were randomized to BEV alone or BEV–CAP (BEV 15 mg/kg q3w; CAP 1000 mg/m2 bid d1–14 q3w) until PD. Stratification factors were estrogen receptor (ER) status, visceral metastases, response status, and lactate dehydrogenase (LDH) concentration. OS from randomization was a secondary endpoint. The planned sample size of 360 enrolled pts (290 randomized) was calculated assuming a PFS HR of 0.70 (median PFS 5.8→8.3 months) with 80% power at 2-sided α=0.05 after 244 PFS events. Recruitment was stopped prematurely after regulatory withdrawal of the BEV–DOC combination but pts who had already been enrolled and randomized were followed as originally planned. RESULTS Between Jun 2009 and Mar 2011, 284 pts were enrolled and treated. Of these, 99 were not eligible for randomization (most commonly due to PD [41%] or AEs/toxicity [31%]) and 185 (65%) were randomized. At the time of the primary PFS analysis, representing study closure, median follow-up (from randomization) was 31.6 months. Median OS from randomization was 23.7 months in the BEV arm and 39.0 months in the BEV–CAP arm (events in 36% of pts). The HR for OS in the two randomized arms showed consistency between subgroups, favoring the BEV–CAP arm in all subgroups analyzed. SubgroupNo. of events/No. of pts (%)Unstratified HR (95% CI)1-y OS rate (%) BEVBEV–CAP BEVBEV–CAPAll53/94 (56)33/91 (36)0.43 (0.26-0.69)a7290&amp;lt;65 y46/81 (57)27/77 (35)0.51 (0.32-0.82)7293≥65 y7/13 (54)6/14 (43)0.50 (0.16-1.60)6879Triple negative16/21 (76)10/25 (40)0.44 (0.19-0.99)6290Hormone receptor positive37/73 (51)23/66 (35)0.53 (0.31-0.89)7591ER positiveb36/69 (52)23/64 (364)0.53 (0.32-0.90)7590ER negativeb17/25 (68)10/27 (37)0.44 (0.20-0.99)6491&amp;lt;3 metastatic organ sites17/40 (43)17/48 (35)0.75 (0.38-1.49)8193≥3 metastatic organ sites36/54 (67)16/43 (37)0.39 (0.22-0.71)6588Visceral metastasesb38/65 (58)23/62 (37)0.43 (0.26-0.73)7092No visceral metastasesb15/29 (52)10/29 (34)0.76 (0.34-1.70)7688Complete or partial responseb36/68 (53)24/68 (35)0.61 (0.37-1.03)7389Stable diseaseb14/22 (64)6/20 (30)0.22 (0.08-0.63)68100Non-measurableb3/4 (75)3/3 (100)0.30 (0.03-2.98)6767LDH ≤1.5×ULNb50/89 (56)30/85 (35)0.49 (0.31-0.76)7294LDH &amp;gt;1.5×ULNb3/5 (60)3/6 (50)1.01 (0.20-5.00)6044aStratified analysis. bStratification factor. CONCLUSIONS. Combining maintenance BEV with CAP until PD after initial BEV–DOC for mBC provides a statistically significant and clinically meaningful improvement in OS (secondary endpoint), seen consistently irrespective of baseline characteristics. Citation Format: Joseph Gligorov, Jose Bines, Emilio Alba, Giorgio Mustacchi, Saverio Cinieri, Vineet Gupta, Jean-Yves Pierga, Hakan Bozcuk, Rabab Gaafar, Sudeep Gupta, Guillermo Lopez Vivanco, Xiaojia Wang, Romulo Costa, Kadri Altundag, Ewa Chmielowska, Sabine de Ducla, Ulrich Freudensprung, Paulo Cortes, Dinesh Doval. Overall survival (OS) in the IMELDA randomized phase III trial of maintenance bevacizumab (BEV) with or without capecitabine (CAP) for HER2-negative metastatic breast cancer (mBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-17-01.

Abstract P3-11-01: Neoadjuvant chemotherapy with or without bevacizumab or everolimus: Survival analysis of The HER2-negative cohort of the GEPARQUINTO study (GBG 44)

Abstract BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates from 14.9% to 18.4% (P=0.04) overall; specifically in patients with TNBC (27.9% to 39.3% (P=0.003) (von Minckwitz et al, NEJM 2012). No difference in pCR rate was observed for adding everolimus to paclitaxel patients who had no early response to neoadjuvant chemotherapy (Huober et al, Eur J Cancer 2013). Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with 4xEC à 4x docetaxel with or without bevacizumab, 15 mg/Kg q3w before surgery. 408 patients not clinically responding to EC ± Bev were randomized to 12x weekly paclitaxel with or without everolimus 5mg/day. Patients with HR-positive tumors received endocrine treatment after surgery. 379 events are required to show a HR of 0.75 (α=0.05, ß=0.8) between the bevacizumab arms. 397 relapses and 234 deaths were observed after a median follow up of 3.8 years overall, of those 115 relapses and 75 deaths occurred in the non-responding cohort. RESULTS: Overall, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.780 for DFS and HR 0.974; P = 0.842 for OS) compared to patients receiving chemotherapy alone. Patients with TNBC showed no improvement in DFS (HR 0.991; P = 0.948) and OS (HR 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3, cT4a-c, cT4d; pCR or not, CR, PR, NC after first 4 cycles chemotherapy) showed a benefit from bevacizumab. No difference in DFS (HR 0.997; P=0.987) and OS (HR 1.11; P=0.658) was observed for patients who had no early response to neoadjuvant chemotherapy receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results finally do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for patients who had no early response to neoadjuvant chemotherapy. Citation Format: Bernd Gerber, Sibylle Loibl, Michael Untch, Holger Eidtmann, Mahdi Rezai, Peter A Fasching, Hans Tesch, Holm Eggemann, Iris Schrader, Kornelia Kittel, Claus Hanusch, Jens Huober, Christine Solbach, Christian Jackisch, Georg Kunz, Jens-Uwe Blohmer, Maik Hauschild, Tanja Fehm, Valentina Nekljudova, Gunter von Minckwitz. Neoadjuvant chemotherapy with or without bevacizumab or everolimus: Survival analysis of The HER2-negative cohort of the GEPARQUINTO study (GBG 44) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-01.

Abstract P3-11-16: S0800: Nab-paclitaxel, doxorubicin, cyclophosphamide, and pegfilgrastim with or without bevacizumab in treating women with inflammatory or locally advanced breast cancer (NCI CDR0000636131)

Abstract Background. Locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) remain difficult challenges despite progress in multimodality treatment. The SWOG trial S0800 (clinicaltrial.gov NCT00856492) compared bevacizumab in combination with weekly nab-paclitaxel followed by dose-dense AC to nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative IBC/LABC. The rationale was based on the proposed role of angiogenesis, potential role of improved flow and oxygenation in enhancing the delivery of chemotherapy agents, and the proapoptotic effect with certain chemotherapeutic agents, particularly taxanes. Methods. This was a randomized open-label Phase II trial with an accrual goal of 200 patients equally allocated to either bevacizumab (Arm 1) or no bevacizumab.Two patients were ineligible and five withdrew consent leaving 208 for analysis. The no bevacizumab group was further randomized to two sequences (Arm 2: nab-paclitaxel - AC+PEG-G versus Arm 3: AC+PEG-G- nab-paclitaxel) with 50 patients expected in each sequence. The primary endpoint of this study was pathologic complete response (pCR) defined as no evidence of invasive tumor at the primary site and axillary lymph nodes in the surgical specimen. The power for the primary comparison of bevacizumab (bev) versus no bevacizumab (no bev) ignoring sequence was 80% with a 1-sided α = 0.10. Randomization was stratified by hormone receptor status and type of disease (IBC or LABC). Results 215 patients were accrued May 2010 - September 2012. Most had LABC (88%) versus IBC (12%) and most tumors were hormone-receptor (HR) positive (67%). Fourteen (7%) patients had no definitive surgery (included as no pCR); 135 (65%) had residual disease (no pCR) and 59 (28%) had pCR. The bevacizumab pCR rate was higher (35/96; 38%) than that in the non-bevacizumab arms (24/112; 21%) (exact p=0.021; stratified p=0.015). In HR-positive disease there was slight improvement that was not statistically significant (bev 25% vs. non-bev 18%; p=0.41) while the difference was larger in HR-negative disease (bev 59% vs. non-bev 28%; p=0.014). In LABC the overall pCR rate was 29% with a higher rate in the bevacizumab patients (37% vs. 22%; p=0.035). For IBC there was improvement (30% vs. 14%), but not statistically significant (p=0.61) in a small sample. Overall, Grade 3 and 4 events were common in both (bev 67%; non-bev 65%), but did not differ by treatment. There were 21 deaths with 3-year overall survival (OS) of 87% and 83% for bevacizumab and non-bevacizumab, respectively (log-rank p=0.57). Conclusion Compared with combination anthracycline-taxane neoadjuvant chemotherapy, the Bev-Nab-paclitaxel-AC regimen significantly improved pCR rate overall, primarily for triple negative (TNBC) patients. This neoadjuvant regimen could be a good choice for TNBC/IBC . The observed pCR rate in ER negative disease (59%) suggests that the addition of bevacizumab to a standard chemotherapy backbone may improve outcome in this subset, and justifies further testing of such an approach. Correlative science studies to further delineate the biology of TNBC and the effects of bevacizumab are ongoing. Citation Format: Zeina A Nahleh, William E Barlow, Daniel F Hayes, Anne F Schott, Julie R Gralow, Edith A Perez, William M Sikov, Sudhathi Chennuru, Hamid Mirshahidi, Sarah Vidito, Danika L Lew, Lajos Pusztai, Robert B Livingston, Gabriel N Hortobagyi. S0800: Nab-paclitaxel, doxorubicin, cyclophosphamide, and pegfilgrastim with or without bevacizumab in treating women with inflammatory or locally advanced breast cancer (NCI CDR0000636131) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-16.

Abstract P5-19-10: Tolerability and anti-tumor activity of the oral PI3K inhibitor GDC-0941 in combination with paclitaxel, with and without bevacizumab or trastuzumab in patients with locally recurrent or metastatic breast cancer

Abstract Background: GDC-0941 is a potent and selective oral inhibitor of class I PI3K kinases that demonstrates broad activity in diverse xenograft cancer models and increases the anti-tumor activity of taxanes, associated with increased apoptotic cell death, in multiple BC xenografts. Methods: In the Phase Ib dose-escalation study, GDC4629g, GDC-0941 was administered in combination with paclitaxel dosed at 90 mg/m2 intravenous [IV] weekly for 3 out of 4 weeks, bevacizumab at 10 mg/kg IV biweekly, and trastuzumab 2−4 mg/kg IV weekly in 28-day cycles. The study was conducted in 2 parts: Part 1 evaluated oral doses of 60 and 100 mg GDC-0941 on a "21+7" (21 days on/7 days off) dosing schedule in combination with paclitaxel with and without bevacizumab. Part 2 evaluated GDC-0941 on a "5+2" schedule (5 days on/2 days off in a repeating pattern), at doses of 165 - 330 mg, in combination with paclitaxel (Arm A), paclitaxel plus bevacizumab (Arm B) or paclitaxel plus trastuzumab (Arm C). The primary objective was to evaluate safety, tolerability, and pharmacokinetics (PK), and to determine the maximum tolerated dose (MTD) for each combination. Anti-tumor activity was evaluated by RECIST v1.0 and available archival tumor samples were analyzed to assess PI3K related biomarkers. Results: 63 patients were enrolled: 20 in Part 1 and 43 in Part 2 (18 in Arm A, 16 in Arm B, and 9 in Arm C). The most frequent grade ≥3 drug-related adverse events (AEs) were: Part 1, neutropenia (45%), peripheral neuropathy and nail disorder (15% each); Part 2, Arm A, neutropenia (38%), pneumonia and rash (11% each); Arm B, neutropenia and rash (25% each); Arm C, rash and hypertension (11% each). The most common AEs assessed as being related to GDC-0941 were as follows: Most common AEs related to GDC-0941Adverse EventAll GradesGrade ≥ 3DIARRHEA45 (71.4%)2 (3.2%)NAUSEA33 (52.4%)0NEUTROPENIA29 (46.0%)17 (27.0%)RASH29 (46.0%)7 (11.1%)FATIGUE28 (44.4%)0STOMATITIS19 (30.2%)0DECREASED APPETITE15 (23.8%)1 (1.6%)VOMITING15 (23.8%)0 In Part 1, the MTD was not reached, the maximum administered dose (MAD) of GDC-0941 was 100 mg, a dose-limiting AE was subclavian vein thrombosis. In Part 2, Arm A, the MTD was 250 mg, Grade 3 febrile neutropenia, bacteremia, and rash were DLTs. In Arm B and Arm C, the MAD was 260 mg, Grade 3 rash was a DLT in both arms. No differences in the PK of either GDC 0941 or paclitaxel were observed when administered in combination compared to historical single-agent data. Best tumor response by RECIST was as follows: Part 1, 1 (5%) complete (CR) and 4 (21%) partial responses (PR); Arm A, 1 (6%) CR and 3 (17%) PR; Arm B, 7 (47%) PR; Arm C, 1 (11%) PR. Conclusions: GDC-0941 was generally well-tolerated in combination with paclitaxel with or without bevacizumab or trastuzumab at dose ranges of up to 330 mg at the "5+2" dosing schedule. Anti-tumor activity has been observed in combination with paclitaxel with and without bevacizumab or trastuzumab. Updated biomarker data and associations with clinical outcomes will be presented. Citation Format: Patrick Schöffski, Sara Cresta, Ingrid A Mayer, Hans Wildiers, Isabelle Rooney, Doris Apt, Steve Gendreau, Kari Morrissey, Mark Lackner, Jill Spoerke, Eric Winer. Tolerability and anti-tumor activity of the oral PI3K inhibitor GDC-0941 in combination with paclitaxel, with and without bevacizumab or trastuzumab in patients with locally recurrent or metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-10.

Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial

The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy. In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and β error of 0.05 and 0.20, respectively, 262 patients were required. In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data. This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.

SPIRITT: A Randomized, Multicenter, Phase II Study of Panitumumab with FOLFIRI and Bevacizumab with FOLFIRI as Second-Line Treatment in Patients with Unresectable Wild Type KRAS Metastatic Colorectal Cancer

BackgroundSecond-line treatment with chemotherapy and anti-epidermal growth factor receptor or anti-vascular endothelial growth factor antibodies improves outcomes in patients with wild type Kirsten rat sarcoma viral oncogene homolog (KRAS) metastatic colorectal cancer (mCRC). The choice of biological agent in second-line mCRC remains unclear. In this randomized, phase II estimation trial, we compared FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) in combination with panitumumab or bevacizumab in patients with disease progression during oxaliplatin-based chemotherapy and bevacizumab. Patients and MethodsOne hundred eighty-two patients were randomized to FOLFIRI with panitumumab or bevacizumab. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), and safety. ResultsPFS was similar between arms, with a hazard ratio (HR) of 1.01 (95% confidence interval [CI], 0.68-1.50; P = .97). Median PFS was 7.7 months (95% CI, 5.7-11.8) in the panitumumab arm and 9.2 months (95% CI, 7.8-10.6) in the bevacizumab arm. OS was also similar between arms, with an HR of 1.06 (95% CI, 0.75-1.49; P = .75). Median OS was 18.0 months (95% CI, 13.5-21.7) in the panitumumab arm and 21.4 months (95% CI, 16.5-24.6) in the bevacizumab arm. ORR was 32% (95% CI, 23%-43%) in the panitumumab arm and 19% (95% CI, 11%-29%) in the bevacizumab arm. Skin disorders, diarrhea, hypomagnesemia, hypokalemia, dehydration, and hypotension were more frequent in the panitumumab arm. Neutropenia was more frequent in the bevacizumab-containing arm. ConclusionPanitumumab or bevacizumab with FOLFIRI as second-line treatment had efficacy similar in patients whose disease progressed during oxaliplatin-based chemotherapy with bevacizumab, with expected toxicities. The development of more accurate biomarkers might help caregivers and patients to better choose between therapies for individual patients.

Gastrointestinal perforation in metastatic colorectal cancer patients with peritoneal metastases receiving bevacizumab.

To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease. We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts: (1) the AGITG MAX trial (Phase III randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine, bevacizumab and mitomycinC); (2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (any first-line regimen ± bevacizumab); and (3) two cancer centres in New South Wales, Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre (NSWCC) from January 2005 to Decenber 2012, (any first-line regimen ± bevacizumab). For the AGITG MAX trial capecitabine was compared to the other two arms (capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycinC). In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases. Secondary endpoints included progression-free survival, chemotherapy duration, and overall survival. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Eighty-four MAX, 179 TRACC and 69 NSWCC patients had peritoneal disease. There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts. Of the patients without peritoneal disease in the MAX trial, 4/300 (1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123 (0.8%) in the capecitabine alone arm. In the TRACC registry 3/126 (2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53 (1.9%) in the chemotherapy alone arm. In a further analysis of patients without peritoneal metastases in the TRACC registry, the rate of gastrointestinal perforations was 9/369 (2.4%) in the chemotherapy/bevacizumab group and 5/177 (2.8%) in the chemotherapy alone group. The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts: MAX 6.9 m vs 4.9 m, HR = 0.64 (95%CI: 0.42-1.02); P = 0.063; TRACC 9.1 m vs 5.5 m, HR = 0.61 (95%CI: 0.37-0.86); P = 0.009; NSWCC 8.7 m vs 6.8 m, HR = 0.75 (95%CI: 0.43-1.32); P = 0.32. Chemotherapy duration was similar across the groups. Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone.

NI-26 * COMPARATIVE ANALYSIS OF THE RANO AND MACDONAD'S CRITERIA IN RECURRENT GLIOBLASTOMA TREATED IN THE RANDOMIZED PHASE II TRIAL AVAREG WITH BEVACIZUMAB OR FOTEMUSTINE.

BACKGROUND: RANO criteria, which evaluate both contrast enhancement and T2/FLAIR alterations, have been recently defined, but no prospective validation exists. We examined the radiological data of patients with recurrent glioblastoma treated with bevacizumab (BEV) or fotemustine (FTM) in the randomized phase II AVAREG-ML25739 (EUDRACT 2011-001363-46) trial. METHODS: All MRIs of the pts have been evaluated (BEV/FTM: 59/32) accordingly with RANO and Macdonald's criteria, both locally and centrally. RESULTS: 223 MRIs were analyzed. Concordance between RANO and Macdonald criteria was found in 96.3% of cases at local evaluation and in 95.5% at central revision. Concordances between local and central assessments were 72.5% with RANO criteria and 71.1% with Macdonald's criteria. At local evaluation, pts treated with BEV had a disease control rate (DCR = CR/PR/SD) of 0.75 (95%CI: 0.62-0.85) with RANO criteria, and 0.76 (95%CI: 0.63-0.86) with Macdonald criteria, vs 0.59 (95%CI: 0.41-0.76) and 0.63 (95%CI: 0.44-0.79) with FTM. Central evaluation showed a DCR of 0.80 (95%CI: 0.68-0.90) both with RANO and Macdonald criteria for pts treated with BEV vs 0.50 (95%CI: 0.32-0.68)with FTM. In the BEV arm, only 6.8% of patients showed an increase of T2/FLAIR without T1 contrast enhancement. CONCLUSIONS: After 4 years from RANO proposal, we showed that there is a good concordance of disease evaluation in recurrent glioblastoma pts treated either with BEV or FTM in academic centers.

GE-10 * IDENTIFICATION OF PATIENTS WITH RECURRENT GBM THAT BENEFIT FROM BEVACIZUMAB

INTRODUCTION: To assess the effects of bevacizumab (BEV) in recurrent GBMs, a three-arm randomized phase II study was initiated (the BELOB trial) comparing BEV monotherapy, CCNU monotherapy and BEV + CCNU combinationtherapy. Primary endpoint was 9 months OS and was 38% [25,51], 43% [29,57] and 59% [43,72] in the BEV, lomustine and combination arms respectively. The BELOB trial results therefore provide evidence for clinical efficacy of BEV, at least in a recurrent GBM setting and when given in combination with lomustine. However, not all patients in this trial appeared to benefit equally from the combination treatment. In this study, we therefore aimed to identify patients that benefit from BEV. METHODS: RNA expression profiling was performed using DASL (Illumina, n = 118) and RNA sequencing (n = 78) of samples. RESULTS: The DASL and RNA-seq platform both show a high concordance between technical and biological replicates and with expression profiling on snap frozen tissue samples. Sample assignment to one of seven ‘intrinsic glioma subtypes’ (IGS; molecular subtypes of glioma based on similarities in gene-expression profiles [PMID: 19920198]) was also highly similar between the different platforms. Analysis of BELOB samples shows that most are assigned to poor prognostic subtypes (IGS-18 "EGFR-amplified, classical" n = 73 and IGS-23 "mesenchymal" n = 28). Nine patients were assigned to prognostically more favourable subtypes (IGS-9 and IGS-17), but these do not explain the more favourable outcome in the BEV + CCNU arm. Patients with tumors assigned to IGS-18 show benefit from combined treatment with bevacizumab + CCNU. In contrast, tumors assigned to IGS-23 may have worse performance in this arm, though patient numbers are small. CONCLUSIONS: DASL and RNA-seq perform well on RNA isolated from FFPE tissues stored (up to 20 years) in paraffin. Specific molecular subtypes of recurrent GBM show benefit from BEV + CCNU treatment.

O10.05 * FINAL ANALYSIS OF THE BELOB TRIAL (A RANDOMIZED PHASE II STUDY ON BEVACIZUMAB VERSUS BEVACIZUMAB PLUS LOMUSTINE VERSUS LOMUSTINE SINGLE AGENT IN RECURRENT GLIOBLASTOMA) AND FIRST RADIOLOGY REVIEW RESULTS

INTRODUCTION: Bevacizumab (BEV) is widely used in recurrent glioblastoma, alone or in combination with other agents. There is however no controlled trial to support this use. MATERIAL AND METHODS: In a Dutch multicenter randomized phase II study patients were assigned to BEV 10 mg/kg day 1, 15 and 29 iv, BEV 10 mg/kg day 1, 15 and 29 iv in combination with 110 mg/m2 lomustine orally on day 1, or lomustine 110 mg/m2 orally on day 1, in a 6- weekly schedule . Eligible were patients with histologically proven glioblastoma, first recurrence after chemo-irradiation with temozolomide, having concluded radiotherapy more than 3 months ago, with adequate bone marrow, renal and hepatic function, and WHO performance status (PS) 0-2. Primary endpoint was 9 months overall survival (OS). RESULTS: Between December 2009 and November 2011, 148 eligible patients were enrolled . Median age was 57 years (range, 24-77) and median WHO PS was 1. After a preplanned safety review after the first 8 patients the lomustine dose in the combination arm was reduced to 90 mg/m2, 44 patients were treated at this dose level. 130 patients were evaluable for response. Nine month OS [95% confidence interval] was 43% [29, 57] in the lomustine arm, 38% [25, 51] in the BEV arm, and 59% [43, 72] in the BEV/lomustine 90 arm. Objective response rate (complete or partial response) by local investigator was 5% in the lomustine arm, 38% in the BEV arm and 34% in the BEV/lomustine 90 arm. CONCLUSION: The combination bevacizumab/lomustine warrants further investigation, and is currently investigated in the randomized controlled phase III EORTC trial 26101. At the meeting the analysis based on IDH and MGMT status and the first results on the radiology review, pattern of progression and clinical impact of isolated T2/FLAIR progression will be presented.

560P - Impact of Pre-Treatment Lactate Dehydrogenase (Ldh) Levels on Prognosis and Bevacizumab Efficacy in Advanced Colorectal Cancer Patients

ABSTRACT Aim: As LDH and pro-angiogenesis factors are regulated by the same HIF1a-driven pathway, high lactate dehydrogenase (LDH) levels are associated with abnormal activation of the VEGF pathway. We assessed the impact of pretreatment LDH levels on the prognosis of advanced colorectal cancer (ACC) patients treated with first-line chemotherapy with or without the anti-VEGF monoclonal antibody, bevacizumab, in a phase 3 randomized trial (NCT01878422). Methods: The relationship between pre-treatment LDH and progression free (PFS) and overall survival (OS) was assessed in 376 patients randomized to receive FOLFOX4 or FOLFIRI with or without bevacizumab. PFS, OS and their 95% confidence intervals (95% CI) were calculated by the Kaplan-Meier method. Results: Information on pre-treatment LDH levels was available for 344 ACC patients; 119 had normal LDH values and 225 had an LDH above the upper limit of the normal range (abnormal LDH). At a median follow up of 36 months (range 1-65), abnormal LDH levels were predictive of a lower median PFS (8.3 months, 95% CI 7.1-8.9 versus 9.8 months, 95% CI 9.1-10.9, p= 0.003) and median OS (19.2 months, 95% CI 16.3-21.1 versus 28.0 months, 95% CI 21.4-36.6, p= 0.0003). In the bevacizumab arm, median PFS was 9.1 (95% CI 7.8-10.2) and 9.7 (95% CI 7.4-12.2) months in patients with abnormal LDH and normal LDH, respectively (p = 0.308), whereas in the chemotherapy-only arm median PFS was 7.2 (95% CI 6.5-8.5) and 9.8 (95% CI 8.9-11.5) months, respectively (p = 0.002). Median OS was significantly associated with LDH levels in both treatment arms. Chemotherapy + bevacizumab Chemotherapy Pre-treatment LDH No. of patients No. of events Median PFS (95% CI) No. of patients No. of events Median PFS (95% CI) p LDH 62 53 9.7 (7.4-12.2) 57 51 9.8 (8.9-11.5) 0.522 LDH ≥ ULN 101 98 9.1 (7.8-10.2) 124 118 7.2 (6.5-8.5) 0.108 p 0.308 0.002 Pre-treatment LDH No. of patients No. of events Median OS (95% CI) No. of patients No. of events Median OS (95% CI) p LDH 62 36 28.0 (17.8-37.6) 57 35 28.6 (21.3-38.7) 0.444 LDH ≥ ULN 101 85 15.8 (13.1-21.1) 124 101 20.2 (17.9-23.2) 0.282 p 0.015 0.007 ULN, upper limit of normal Conclusions: In our study abnormal LDH values were correlated with worse prognosis. Bevacizumab appeared to improve the PFS of this population, but not the OS. Disclosure: All authors have declared no conflicts of interest.

180P - Genome-Wide Association Study (Gwas) Identifies Candidate Neurotoxicity Markers in Platinum-Taxane Treated Ovarian Cancer Patients in Icon7

Aim: Neurotoxicity is known of both platinum and taxane agents. Factors associated with increased risk of peripheral neuropathy (PN) include cumulative dose and comorbidity. Individual genetic susceptibility may play a role. Applying GWAS methods to patients of ICON7 (NCT00483782), a phase 3 ovarian cancer trial of adding bevacizumab to carboplatin and paclitaxel, we evaluated the association of heritable genetic markers with PN. Methods: Germline DNA from 437 patients were genotyped using an Illumina Omni-Platform. In a cumulative-dose/m2-to-toxicity analysis, Cox proportional hazard models generated hazard ratios (HR) and 95% confidence intervals for the development of Grade 2 or higher PN. Baseline clinical multivariate models of toxicity, stratified by treatment arm, were compared with and without inclusion of individual genetic markers through likelihood ratio tests (LRT), assuming an additive genetic inheritance model. Results: After quality control steps, 396 predominantly genetic European patient samples and 727,683 markers were evaluable. 28% of patients developed Grade 2+ PN. Study country but not pre-existing diabetes was significantly associated with PN in clinical multivariate models; the bevacizumab arm was associated with a trend for increased PN (adjusted HR, aHR, 1.32 (1.0-1.7; P = 0.054). Although no single marker reached genome-wide significance level after adjustment for clinical factors, top identified multiple markers associated with PN were in the pyrin (PYR; P = 9.9x10−7) and RNA editing pathways (REP; P = 1.3x10−6 by LRT). In both, the presence of each additional at-risk allele was associated with a doubled odds of developing Grade 2+ PN: for PYR, the top variant had an a HR of 1.92 (95%CI: 1.5-2.5), while for REP, the top variant had an a HR of 2.12 (95%CI: 1.5-2.9). PYR pathway is associated with a caspase-activating platform, the inflammasone, and Schwann cell damage. The REP affects neuronal structure and physiology in several animal model systems. Conclusions: PYR and REP polymorphisms were the top markers associated with PN in carboplatin-paclitaxel treated ovarian cancer patients. Validation in other trials is warranted.

354PD - Cost Effectiveness Analysis of Everolimus Plus Exemestane Vs. Bevacizumab Plus Paclitaxel and Bevacizumab Plus Capecitabine for the Management of Postmenopausal Women with Er+ Breast Cancer

ABSTRACT Aim: Background: Estrogen receptor positive (ER+) metastatic breast cancer patients progressing on nonsteroidal aromatase inhibitors are candidates for treatment with everolimus (EVE) plus exemestane (EXE) or with chemotherapy. The aim of the study was to conduct a cost-effectiveness analysis (CEA) of EVE plus EXE versus bevacizumab (BEV) plus paclitaxel (PACL) and BEV plus capecitabine (CAPE) for the management of postmenopausal women with ER+ breast cancer from the perspective of the Greek National Health System. Methods: A Markov model, consisting of three health states, was used to describe disease progression and evaluate the CE of comparators. The model evaluated the comparators over a lifetime horizon in the course of a 1-month cycle from a third-party payer perspective. Efficacy, safety and utility data considered in the model were extracted from randomized Phase III clinical trials. Direct medical costs used reflecting the year 2013. Probabilistic sensitivity analysis was also conducted. Primary outcomes were quality-adjusted life years (QALYs) and total lifetime costs. Results: Discounted survival and quality adjusted survival of EVE plus EXE treated patients was higher compared to BEV plus PACL by 0.28 life-years and 0.19 QALYs, respectively, and by 0.21 life-years and 0.16 QALYs when compared to BEV plus CAPE. EVE plus EXE was the less costly treatment in terms of drug acquisition, administration and concomitant medications. The total lifetime cost per patient for EVE plus EXE was estimated at e46,251, for BEV plus PACL at e53,422 and for BEV plus CAPE at 50,619 e. The higher drug acquisition and administration cost of BEV plus PACL (EVE plus EXE: 16,956 e vs. BEV plus PACL: 22,379 e) partially explained the higher total lifetime cost over EVE plus EXE. Moreover, the higher pre-progressed costs of the BEV plus CAPE arm accounted for the largest part of the difference in the total lifetime cost between BEV plus CAPE and EVE plus EXE. Probabilistic analysis confirmed the results. Conclusions: Results suggest that EVE plus EXE may be a dominant (more effective and less costly) alternative relative to BEV plus PACL and BEV plus CAPE in the treatment of ER+ mBC patients failing initial therapy with NSAIs. Disclosure: G. Kourlaba: received funding from Novartis Hellas SA in order to perform the current cost-effectiveness analysis; M. Chatzikou: is employee of Novartis Hellas SA. All other authors have declared no conflicts of interest.