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Supplementary Data - Figure Legends

Percentage growth change of individual nsNSCLC metastases during bevacizumab treatment

Time from randomization to new brain lesions in AVAiL Trial

Patients with nonsquamous non–small cell lung cancer (nsNSCLC; largely lung adenocarcinoma) are at high risk of developing brain metastases. Preclinical data suggested that anti–VEGF-A therapy may prevent the formation of nsNSCLC brain metastases. Whether non-brain metastases are also prevented, and whether bevacizumab shows a brain metastases–preventive activity in cancer patients is unknown. Data of one nsNSCLC (stage IIIB/IV, AVAiL) and two breast cancer bevacizumab trials (HER2 negative, AVADO; HER2 positive, AVEREL) were retrospectively analyzed regarding the frequency of the brain versus other organs being the site of first relapse. For animal studies, the outgrowth of PC14-PE6 lung adenocarcinoma cells to brain macrometastases in mice was measured by intravital imaging: under control IgG (25 mg/kg) treatment, or varying doses of bevacizumab (25 mg/kg, 2.5 mg/kg, 0.25 mg/kg). Brain metastases as site of first relapse were significantly less frequent in the bevacizumab arm of the AVAiL trial (HR = 0.36, P < 0.001). In AVADO and AVEREL, no significant difference was seen. In mice, bevacizumab treatment led to secondary regressions of non-brain macrometastases, but did not reduce their total incidence, and did not improve survival. In a brain-seeking nsNSCLC metastasis model, treatment with bevacizumab inhibited brain metastases formation, which resulted in improved overall survival. In summary, bevacizumab has the potential to prevent brain metastases in nsNSCLC, but no preventive activity could be detected outside the brain. These data indicate that anti–VEGF-A agents might be particularly relevant for those stage III nsNSCLC patients who are at high risk to develop future brain metastases. Mol Cancer Ther; 15(4); 702–10. ©2016 AACR.

BACKGROUND: Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. METHODS: In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379. FINDINGS: Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (

726 Background: Primary tumor location is an important prognostic factor in mCRC. Efficacy differences with EGFR antibodies by tumor location show a predictive effect (Arnold et al. Ann Oncol 2017). Two first-line (1L) pivotal bev trials showed the prognostic value of sidedness (Loupakis et al. J Natl Cancer Inst 2015). In this exploratory study, further analysis of the predictive effect of bev is presented. Methods: Data from two randomized phase III studies (NO16966 [NCT00069095], AVF2107g [NCT00109070]) of bev+CT vs CT-alone as 1L treatment for mCRC were analyzed retrospectively. Patients (pts) with sidedness information available were included; pts from NO16966 (part 1) randomized to CT only were excluded. Sidedness was identified by case report forms. Results: Sidedness was determined in 1590 pts (27% Right and 73% Left) out of 2214 pts total (Table). In the pooled analysis, PFS improved with bev+CT compared to CT only in both right-sided (HR=0.75; 95% CI 0.61, 0.93) and left-sided (HR=0.76; 95% CI 0.67, 0.86) mCRC with similar magnitude of benefit in both sides. OS also improved with bev+CT in right-sided (HR=0.82; 95% CI 0.65, 1.03) and left-sided (HR=0.85; 95% CI 0.74, 0.98) pts. Conclusions: This exploratory subgroup analysis of two pivotal studies indicates that the effect of bev is independent of tumor location in mCRC patients. Survival outcomes. Clinical trial information: NCT00069095 and NCT00109070. [Table: see text]

Background Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting. Methods We did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients with HER2-negative measurable metastatic breast cancer; each received three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75–100 mg/m2) every 3 weeks. Progression-free patients were randomly assigned with an interactive voice-response system by block (size four) randomisation (1:1) to receive either bevacizumab and capecitabine or bevacizumab only (bevacizumab 15 mg/kg on day 1; capecitabine 1000 mg/m2 twice per day on days 1–14, every 3 weeks) until progression, stratified by oestrogen receptor status (positive vs negative), visceral metastases (present vs absent), response status (stable disease vs response vs non-measurable), and lactate dehydrogenase concentration (≤1·5 vs >1·5 × upper limit of normal). Neither patients nor investigators were masked to allocation. The primary endpoint was progression-free survival (from randomisation) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00929240. Findings Between July 16, 2009, and March 7, 2011 (when enrolment was prematurely terminated), 284 patients received initial bevacizumab and docetaxel; 185 (65%) were randomly assigned (91 to bevacizumab and capecitabine versus 94 to bevacizumab only). Progression-free survival was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (median 11·9 months [95% CI 9·8–15·4] vs 4·3 months [3·9–6·8]; stratified hazard ratio 0·38 [95% CI 0·27–0·55]; two-sided log-rank p

Purpose Rituximab has been shown to be active in follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. We conducted a randomized trial comparing mitoxantrone, chlorambucil, and prednisolone (MCP) chemotherapy plus rituximab with MCP alone. Patients and Methods Previously untreated patients with stage III or IV CD20+ indolent or mantle cell lymphoma were randomly assigned to either eight 28-day cycles of MCP plus rituximab (R-MCP; n = 181) or eight cycles of MCP alone (n = 177). All patients who achieved a complete or partial remission were treated with interferon maintenance until relapse. Herein, we report the results from the primary analysis population of patients with FL, who constituted the majority of patients (56%) recruited to the trial (n = 201; R-MCP, n = 105; MCP, n = 96). Results Rates of overall and complete response were significantly higher in the R-MCP arm than the MCP arm (overall response, 92% v 75%, respectively; P = .0009; complete response, 50% v 25%, respectively; P = .004). With a median follow-up time of 47 months, median event-free survival (EFS) and progression-free survival (PFS) times were significantly prolonged with R-MCP compared with MCP (EFS, not reached v 26 months, respectively; P < .0001; PFS, not reached v 28.8 months, respectively; P < .0001), and overall survival (OS) was significantly improved with R-MCP compared with MCP (4-year OS rate, 87% v 74%, respectively; P = .0096). Conclusion The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS, and OS in patients with previously untreated advanced FL, without a clinically significant increase in toxicity.

The aim of this study was to evaluate the safety, toxicity and therapeutic response of non-myeloablative radioimmunotherapy using 131I-rituximab in previously heavily treated patients with B-cell non-Hodgkin's lymphoma (B-NHL).Nine patients with relapsed, refractory or transformed B-NHL received ten radioimmunotherapies. Patients had a median of 5 (range 2-7) prior standard therapies. Four patients had received prior high-dose chemotherapy followed by autologous stem cell transplantation, and eight had received prior rituximab therapy. Histopathology consisted of four mantle cell, one follicular and four diffuse large B-cell lymphomas. Rituximab, a monoclonal chimeric anti-CD20 antibody (IDEC-C2B8), was labelled with 131I using the Iodogen method. The administered activity (2,200+/-600 MBq) was based on a dosimetrically calculated 45 cGy total-body radiation dose. All patients received an infusion of 2.5 mg/kg of rituximab prior to administration of the radiopharmaceutical.No acute adverse effects were observed after the administration of 131I-rituximab. Radioimmunotherapy was safe in our patient group and achieved one complete response ongoing at 14 months and two partial responses progressing at 12 and 13 months after treatment. One partial responder was re-treated with radioimmunotherapy and achieved an additional progression-free interval of 7 months. Four non-responders with bulky disease died 4.8+/-2.0 months after therapy. Three patients had an elevated serum lactate dehydrogenase (LDH) level prior to radioimmunotherapy and none of the patients responded. Of two patients who received radioimmunotherapy as an additional treatment after salvage chemotherapy, one continues to be disease-free at 9 months and one relapsed at 5 months' follow-up. Reversible grade 3 or 4 haematological toxicity occurred in seven of nine patients. Median nadirs were 35 days for platelets, 44 days for leucocytes and 57 days for erythrocytes.Radioimmunotherapy with 131I-rituximab in previously heavily treated B-NHL patients was safe and well tolerated, and four out of ten therapies induced responses. Radioimmunotherapy was less efficient in patients with bulky disease and elevated LDH. Severe haematological toxicity in seven patients did not cause significant clinical problems. Radioimmunotherapy seems to be an additional therapeutic option in carefully selected therapy-refractory B-NHL patients.

Background Evidence-based definitions of ‘poor-prognosis’ or ‘aggressive’ advanced breast cancer are lacking. Patients and methods We developed a prognostic factor index using data from 2203 patients treated with first-line chemotherapy plus bevacizumab for HER2-negative advanced breast cancer. Results The risk factors most closely associated with worse OS were: disease-free interval ≤24 months; liver metastases or ≥3 involved organ sites; prior anthracycline and/or taxane therapy; triple-negative breast cancer (TNBC); and performance status 2 or prior analgesic/corticosteroid treatment. Risk of death was increased threefold in patients with ≥3 versus ≤1 risk factors (hazard ratio 3.0 [95% CI 2.6–3.4; p Conclusions This prognostic index may enable identification of patients with a poorer prognosis in whom more intensive systemic regimens may be appropriate. The index may also be considered in designing new trials, although it requires validation in other datasets before extrapolation to non-bevacizumab-containing therapy. ClinicalTrials.gov identifier: NCT00448591 .

Objective Anti-CD20 chimeric monoclonal antibody rituximab (Mabthera; IDEC-C2B8) is currently tested in several clinical trials for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). In the present study, we investigated whether rituximab therapy may select for CD20 − subclones. Materials and Methods Leukemic B-CLL cells were isolated from patients with B-CLL and sensitivity to rituximab-induced cell death was examined. Levels of CD20 protein and mRNA were determined using flow cytometry and real-time PCR, respectively. Clonality analyses of leukemic cells throughout rituximab therapy were performed by GeneScan analysis of patient clone specific rearrangements of the complementarity determining region III of the heavy chain immunoglobulin. Results Cytotoxicity of rituximab in vitro did not depend on the protein levels of CD20. During therapy with rituximab CD20 + B-CLL cells were depleted and CD20 − leukemic cells emerged. After treatment, the initial CD20 + B-CLL cell clone reexpanded. CD20 − B-CLL cells retained their capacity to synthesize the CD20 molecule. Conclusions These data support the concept that in B-CLL rituximab treatment may not lead to the emergence of CD20 − leukemic variants. Our findings support clinical studies investigating the benefit of prolonged period of rituximab therapy in B-CLL disease.

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.

This study of first-line treatment in advanced-stage follicular lymphoma patients analysed the effects of MCP (mitoxantrone, chlorambucil and prednisolone) chemotherapy alone or in combination with rituximab (R-MCP) on circulating lymphoma cells (CLC) and assessed the prognostic value of a quantitative monitoring of CLC. CLC numbers were determined by quantitative polymerase chain reaction (PCR) for the t(14;18)-translocation or by allele-specific PCR for rearranged immunoglobulin heavy chain genes. We analysed blood samples from 43 patients treated in a randomized trial comparing eight cycles of MCP versus R-MCP. Clearance of CLC at the end of therapy was achieved in 21/25 patients (84%) treated with R-MCP compared with 0/18 after MCP alone (P0.0001). Aor = 2 log CLC reduction was associated with a favourable clinical response (P = 0.0004) and prolonged event-free survival (P = 0.02). In R-MCP patients, stable CLC numbers or consistently PCR-negative blood samples were associated with a continuing clinical remission whereas in two patients a relapse was preceded by aor = 2 log CLC increase. This study demonstrated that R-MCP led to a rapid and sustained eradication of CLC and aor = 2 log CLC reduction was associated with a superior quality and duration of the clinical response.

The feasibility and efficacy of flexible, response-adjusted rituximab maintenance therapy in B-cell chronic lymphocytic leukemia (B-CLL) was investigated in 12 patients with an at least minor response to four weekly cycles of 375 mg/m(2) of rituximab induction therapy. Rituximab maintenance therapy consisted of infusions of 100 mg rituximab every 4 weeks. If disease progression occurred, either the rituximab dose was increased or the time between infusions was shortened. Treatment-related side effects led to discontinuation of rituximab maintenance therapy in three cases. Maintenance therapy was successfully conducted for > or =6 months in seven cases; three of these individuals have been on maintenance therapy for >1 year to 3.5 years so far. Long-term toxicity, as determined based on hematological and immunological parameters, was mild.

Objective. Apoptosis mediated via CD95 (Fas/Apo-1) is a key regulator for the biology of normal and malignant lymphocytes. Although the function of CD95 on B-cell chronic lymphocytic leukemia cells (B-CLL cells) has been studied intensively, the clinical importance of CD95 expression on normal T cells in B-CLL has not been clarified. This study aimed to investigate whether expression of CD95 on peripheral blood T cells correlates with clinically relevant parameters of B-CLL disease. Materials and Methods. Expression of CD95 (Fas/Apo-1) on peripheral blood T lymphocytes of patients with B-CLL was determined using flow cytometry and was correlated with expression of activation markers, sensitivity to apoptosis by anti-CD95, and clinical data, such as blood count, Binet stage, therapy, progression-free probability, and survival probability. Results. Differential CD95 expression did not correlate with activation markers or with levels of apoptosis through anti-CD95. However, high levels of CD95 on T cells from B-CLL patients correlated significantly with low lymphocyte doubling time, increased Binet stages, and requirement for chemotherapeutic treatment. Furthermore, increased cell-surface CD95 on T cells was associated with reduced progression-free probability and poorer survival. Conclusions. CD95 levels on T cells correlate with the clinical course of B-CLL. Prospective studies appear warranted to investigate whether CD95 on T cells has a direct influence on B-CLL disease progression.

BACKGROUND: Analysis of data from 2203 patients (pts) with HER2-negative LR/mBC treated in the single-arm ATHENA study suggested that overall survival (OS) expectancy of a well-defined subset of pts with hormone receptor-positive LR/mBC was similar to that of pts with triple-negative breast cancer (TNBC). We used prognostic factors from ATHENA to analyze efficacy in the CAP cohort of the RIBBON-1 trial. PATIENTS AND METHODS: In the CAP cohort of RIBBON-1, pts with LR/mBC were randomized 2:1 to receive CAP with either BEV 15 mg/kg q3w (N=409) or placebo (PLA; N=206). The primary endpoint was investigator-assessed progression-free survival (PFS). Objective response rate (ORR) and 1-year OS rate were secondary endpoints. Exploratory efficacy analyses were done in three subgroups: TNBC; high-risk hormone receptor positive (>2 risk factors); and low-risk hormone receptor positive (≤2 risk factors) using the remaining risk factors identified in ATHENA (liver metastases/≥3 involved organs; disease-free interval [DFI] ≤24 months; prior anthracycline/taxane). The data cut-off was July 31, 2008. RESULTS: In all three subgroups, PFS and ORR numerically favored BEV-CAP, consistent with the significant PFS and ORR benefit in the intent-to-treat population. Median PFS, median OS, and 1-year OS rate with PLA-CAP suggested a similarly poor prognosis in pts with TNBC and pts with high-risk hormone receptor-positive LR/mBC. CONCLUSIONS: In these exploratory analyses, median OS in pts with high-risk hormone receptor-positive LR/mBC was short and similar to that in pts with TNBC, as seen in the ATHENA exploratory analysis. OutcomePLA-CAPBEV-CAPTNBCN=50N=87PFS events, n (%)42 (84)74 (85)PFS unstratified HR (95% CI)0.72 (0.49-1.06)Median PFS, months (95% CI)4.2 (3.5-5.9)6.1 (4.3-8.2)ORR, % (95% CI)10.6 (3.5-23.1)30.3 (20.2-41.9)1-year OS rate, % (95% CI)71 (55-81)70 (59-79)Deaths, n (%)26 (52)47 (54)Median OS, months (95% CI)20.5 (15.8-NR)19.7 (14.6-23.2)Hormone receptor-positive disease with additional risk factors*N=56N=92PFS events, n (%)42 (75)72 (78)PFS unstratified HR (95% CI)0.80 (0.54-1.17)Median PFS, months (95% CI)4.4 (3.1-6.2)7.1 (4.3-8.6)ORR, % (95% CI)22.4 (11.8-36.6)27.7 (18.4-38.6)1-year OS rate, % (95% CI)66 (52-77)80 (70-87)Deaths, n (%)32 (57)52 (57)Median OS, months (95% CI)19.6 (12.9-23.4)20.8 (17.5-25.7)Hormone receptor-positive disease with limited additional risk factors**N=90N=220PFS events, n (%)68 (76)139 (63)PFS unstratified HR (95% CI)0.67 (0.50-0.89)Median PFS, months (95% CI)7.7 (6.0-8.4)10.6 (9.1-12.0)ORR, % (95% CI)36.8 (24.4-50.7)41.5 (33.8-49.6)1-year OS rate, %86 (77-92)85 (80-89)Deaths, n (%)34 (38)83 (38)Median OS, months (95% CI)28.4 (23.4-NR)29.0 (25.8-NR)*ER and/or PgR positive with >2 risk factors (liver metastases/≥3 involved organs; DFI ≤24 months; prior anthracycline/taxane); **ER and/or PgR positive with ≤2 risk factors. Citation Format: Nicholas J. Robert, Veronique Dieras, Christian Jackisch, Stefanie Srock, Ulrich Freudensprung, Leonardo Faoro, Joyce O’Shaughnessy. Efficacy of first-line capecitabine (CAP) ± bevacizumab (BEV) according to risk factors in the RIBBON-1 randomized phase III trial in locally recurrent/metastatic breast cancer (LR/mBC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT322. doi:10.1158/1538-7445.AM2014-CT322

Aim: Combining BEV with 1st- or 2nd-line chemotherapy (CT) improves progression-free survival (PFS) in HER2-negative LR/mBC. The open-label randomised phase III TANIA trial evaluated further BEV in BEV-pretreated LR/mBC. Methods: Patients (pts) whose HER2-negative LR/mBC had progressed during/after ≥12 weeks of 1st-line BEV + CT were randomised 1:1 to 2nd-line single-agent CT either alone or with BEV (15 mg/kg q3w or 10 mg/kg q2w). Stratification factors were: hormone receptor status; time to 1st-line progression (PD; 1.5 × upper normal limit). 2nd-line therapy was continued until PD, unacceptable toxicity or consent withdrawal. At PD, pts in the CT arm received 3rd-line CT without BEV (no crossover); pts initially randomised to CT + BEV received 3rd-line CT + BEV. The primary endpoint was PFS from randomisation to 2nd PD/death. Additional endpoints included 2nd-line PFS in prespecified subgroups, 2nd- and 3rd-line PFS (randomisation to 3rd PD/death), 2nd-line objective response rate, overall survival (OS), safety, QoL and biomarkers. Sample size was calculated based on a log-rank test assuming median PFS of 7 → 9.3 mo and a HR of 0.75. PFS events were required in 384 of 488 pts for 80% power at 2-sided a = 0.05. Results: From Jan 2011 to Apr 2013, 494 pts were enrolled (247 CT; 247 CT + BEV). Baseline characteristics, CT vs CT + BEV: median age 54 vs 56 y; triple negative 23% vs 20%; disease-free interval ≤12 mo 10% vs 7%. The most frequently chosen 2nd-line CT was capecitabine (59% vs 61%). CT (N = 247) CT + BEV (N = 247) Median follow-up, mo 15.9 16.1 2nd-line PFS (primary endpoint) Events, n (%) 203 (82) 204 (83) Median 2nd-line PFS, mo 4.2 6.3 Stratified HR (95% CI) 0.75 (0.61–0.93) p = 0.0068a Best objective response rate, % (95% CI) 16.8 (11.7–22.9) 20.9 (15.2–27.5) Difference (95% CI) 4.1 (–4.2 to 12.4) p = 0.3457b 2nd-line grade ≥3 adverse events of special interest, %c (N = 238) (N = 245) Hypertension 7.1 13.5 Proteinuria 0.4 6.9 Venous thromboembolic event 2.1 3.3 Febrile neutropenia 1.7 3.3 Congestive heart failure 0.4 2.0 Bleeding 1.7 0.4 Arterial thromboembolic event 1.3 0 Wound-healing complication 0 0.8 Gastrointestinal perforation 0 0.4 Fistula/abscess 0 0 a2-sided stratified log-rank test. b2-sided chi-squared test with Schouten correction. cBEV basket terms, MedDRA v16.1. Data cut-off: 20 Dec 2013. Conclusions: The primary objective was met, showing statistically significantly improved PFS with BEV after PD on 1st-line BEV-containing therapy. 2nd-line safety results were as expected from previous BEV trials in LR/mBC. Final OS, 2nd and 3rd-line PFS and 3rd-line safety results are due in 2015. Disclosure: G. von Minckwitz: is a paid member on Roche's advisory boards, and has received speaker honoraria and conducted Roche-sponsored research; F. Puglisi: has received honoraria from Roche; J. Cortes: has received honoraria from Roche, Celgene, Novartis and Eisai and has acted as a consultant for Roche and Celgene; E. Vrdoljak: is a member of Roche advisory boards and has received corporate sponsored research; N. Marschner:is a member of Roche advisory boards and has received corporate sponsored research; C. Zielinski: has received speaker honoraria Roche, Eli Lilly and Pfizer; G. Romieu: is a member of a Roche Advisory Board; M. De Laurentiis: has received honoraria for talks, seminars and Advisory Board participation from Roche; C. Veyret: is an expert member of Roche Boards; S. De Ducla: is an employee of, and holds stock in Roche; U. Freudensprung: is an employee of F. Hoffmann-La Roche Ltd S. Srock: SS is an employee of, and holds stock in Roche; J. Gligorov: has acted as a Consultant/Advisor for, and has received honoraria and research funding from Roche. All other authors have declared no conflicts of interest.

Background: Until regulatory withdrawal of BEV–DOC in 2011, the combination was considered a valid first-line option for HER2-negative mBC based on results of a phase III trial [Miles, JCO 2010]. Progression-free survival (PFS) and response rate (RR) with first-line DOC (max 9 cycles) were significantly improved by adding BEV continued until disease progression (PD). The open-label randomised phase III IMELDA trial tested whether adding CAP to maintenance BEV continued until PD after initial BEV–DOC improves PFS. Methods: Patients (pts) with HER2-negative measurable mBC, ECOG PS Results: Between Jun 2009 and Mar 2011 (when enrolment was prematurely terminated) 284 pts were enrolled and treated; 185 (65%) were randomised. BEV (N = 94) BEV–CAP (N = 91) Median age, years (range) 54 (24–77) 49 (24–80) Triple-negative mBC, n (%) 21 (22) 25 (27) Visceral metastases, n (%)a 65 (69) 62 (68) ≥3 metastatic organs, n (%) 54 (57) 43 (47) Median duration of follow-up, months (range)b 30.4 (1.3–43.3) 31.6 (0.8–41.6) PFSb Events, n (%) 83 (88) 69 (76) HRc (95% CI) 0.38 (0.27–0.55) Log-rank p Median PFS, months 4.3 11.9 OSb Events, n (%) 53 (56) 33 (36) HRc (95% CI) 0.43 (0.26–0.69) Log-rank p Median OS, months 23.7 39.0 1-year OS rate, % (95% CI) 72 (61–80) 90 (82–95) Grade ≥3 AEsb, n (%) All 28 (30) 47 (52) Hand-foot syndrome 0 30 (33) Hypertension 3 (3) 8 (9) Proteinuria 4 (4) 4 (4) Gastroenteritis 3 (3) 0 aAt randomisation. bFrom randomisation. cStratified. Conclusions: Adding CAP to maintenance BEV provided statistically significant and clinically meaningful improvements in PFS (HR 0.38, p

555 Background: Chemotherapy is the standard of care for patients (pts) with HER2-negative endocrine-resistant MBC. The considerable variability in overall survival (OS) within this population relates essentially to prognostic factors (PF). Increasingly, large studies based on progression-free survival (PFS) as a primary endpoint are now being questioned. An accurate PF index may help in designing innovative trials with appropriate pts selection according to overall survival (OS) prognosis. Methods: The ATHENA trial assessed the safety of first-line bevacizumab combined with non-anthracycline-containing therapy in 2264 pts treated in 37 countries from 2006 to 2009. Pt characteristics, safety, and efficacy have been reported [Breast Cancer Res Treat 2011;130:133-43]. Sixty-one HER2-positive pts were excluded. A multivariate Cox regression model selected PF generating a simple PF index. Of note, skin, lymph node, ipsi-/contra- breast, or other soft tissue involvement was scored as a single organ. Results: After a median follow-up of 20.1 months and 1171 OS events (53% of pts), median OS for the entire sample and triple-negative (TNBC) and non-TNBC subgroups was 25.2 (95% CI 23.9–26.3), 18.3 (16.3–19.7) and 27.3 (26.3–29.3) months, respectively. PF most closely associated with poorer OS were: liver mets or >2 involved organs (HR 1.6; 95% CI 1.5–1.8); DFI ≤24 months (HR 1.7; 1.5–2.0); adjuvant anthracyline and/or taxane (HR 1.1; 1.2–1.4); and TNBC (HR 1.6; 1.4–1.8). A predictive model was designed stratifying by number of PF present (0/1 vs 2 vs 3/4). The model was consistent in both TNBC and non-TNBC populations (Table). Conclusions: A PF index may estimate figures and balance arms in future trials considering OS as primary objective. A well-defined group of non-TNBC accounting for 37% of patients has an OS estimate similar to the most aggressive TNBC. [Table: see text]

Rituximab proved to be effective in relapsed and refractory indolent NHL as a single agent and generated impressive results in phase II studies in combination with chemotherapy. In a prospective randomized trial we compared the efficacy and toxicity of rituximab (375 mg/m² d 1) plus MCP-chemotherapy ( mitoxantrone 8 mg/m² d 3 + 4, chlorambucile 3 x 3 mg/m² d 3 – 7, prednisolone 25 mg/m² d 3 – 7 ) given every 28 days for a total of 8 cycles versus MCP (d 1 – 5) x 8 cycles alone in advanced indolent NHL and MCL. Efficacy endpoints included overall and complete response rates, event free survival, progression free survival, overall survival and toxicity. For response assessment classical definitions have been used. Between 10/98 and 09/03 we randomized 358 patients (pts) with advanced stage follicular lymphoma (FL) (grade 1 + 2), lymphoplasmacytic lymphoma and MCL to either R-MCP or MCP. The study arms are well balanced for all demographic factors. 201/358 pts (56%) had FL. Both regimens were well tolerated with a low incidence of serious adverse events. The overall response rate (RR) and the complete response rate (CR) for all pts was 85,5% and 42% in the R-MCP arm versus 65,5% and 20% in the MCP arm (p