Antiangiogenic Therapy for Colorectal Cancer Thanks to the investigators for providing p g their slides. Al B. Benson III, MD, FACP Professor of Medicine Feinberg School of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University Combination Bevacizumab Plus IFL: Overall Survival Impact of Targeted Agents: Adding Bevacizumab to Cytotoxics 100 n=411 Previously untreated mCRC (n=923) (n 923) IFL + Bevacizumab* n=402 402 PD* PD* Overall su urvival (%) IFL + Placebo Primary Endpoint: Survival 5-FU/LV + Bevacizumab* PD* n=110 15.6 80 20.3 60 IFL + Bevacizumab 40 20 IFL + placebo 0 0 * 5.0 mg/kg q2w † Patients receiving bevacizumab could continue therapy past disease progression in combination with second line therapy Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 10 No. at Risk IFL + bevacizumab IFL + placebo 402 411 362 363 20 Months 320 292 30 178 139 73 51 20 12 1 0 0 0 Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. Period 2: Overall Survival Data thru Mar 1, 2006 (ITT) BICC-C Trial: Addition of Bevacizumab FOLFIRI Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1) 5-FU: 400 mg/m2 (bolus) (D1) 5-FU: 2400 mg/m2 (46(46-h infusion) (D1) q2wks + 5 mg/kg bevacizumab q 2wks mIFL Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8) LV: 20 mg/m2 (D1, 8) q3wks + 7.5 mg/kg bevacizumab q 3wks Median OS (Months) 1 Year FOLFIRI+ BEV NR 87% -- -- mIFL + BEV 18.7 61% 2.5 (1.3,5.0) 0.01 Regimen R A N D O M I Z A T I O N Celecoxib 400 mg bid Placebo CapeIRI mg/m2 Irinotecan: 250 (D1) Capecitabine: 1000 mg/m2 bid (D1(D1-14) q3wks Stratification: Age, PS, Low dose aspirin use Proportion of Patients Who Survive ed R A N D 1st1st-line O mCRC M N = 117 I 5/04– 5/04–12/04 12/04 Z A T I O N 40 1 HR (95% CI) P Value 0.8 0.6 0.4 FOLFIRI + bevacizumab 0.2 mIFL + bevacizumab 0 0 5 10 15 20 25 30 Months 1 E3200: FOLFOX + Bevacizumab in Second-Line mCRC FOLFOX-4 FOLFOXFOLFOX-4 + FOLFOX-4 Bevacizumab bevacizumab FOLFOX- PD FOLFOX-4 + bevacizumab g g q2wk q 10 mg/kg Previously treated mCRC (n=880) (n 880) E3200: FOLFOX + Bevacizumab in Second-Line mCRC Results PD Bevacizumab monotherapy* 10 mg/kg q2wk Primary Endpoint: Response Rate (%) 22%* 9% 3% Survival S i l Median PFS (mos.) 7.2* 4.8 2.7 Median OS (mos.) 12.9* 10.8 10.2 PD *Statistically significant compared with FOLFOX or bevacizumab alone. • Bevacizumab monotherapy arm discontinued at planned interim Giantonio BJ, et al. Proc Am Soc Clin Oncol. 2005;23:248s. Abs #2. Giantonio BJ, et al. Proc Am Soc Clin Oncol. 2005;23:248s. Abs #2. Randomized Phase II: Final TREE 1 and 2 Trial Results NO16966 study design Oxaliplatin+ 5-FU (TREE(TREE-1) Confirmed ITT ORR Median TTP (mo) mFOLFOX n=45 41% bFOL n=44 20% CapeOx n=39 27% 87 8.7 69 6.9 59 5.9 (TREE(TREE-1) + Bevacizumab FOLFOXFOLFOX-B n=71 52% bFOLbFOL-B n=70 39% CapeOxCapeOx-B n=72 46% 9.9 8.3 10.3 Confirmed ITT ORR Median TTP (mo) Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 XELOX N=317 XELOX + placebo N=350 XELOX + bevacizumab N 350 N=350 FOLFOX4 N=317 FOLFOX4 + placebo N=351 FOLFOX4 + bevacizumab N=350 Protocol amended to 2x2 placebocontrolled design after bevacizumab phase III data1 became available (N=1401) Initial 2-arm open-label study (N=634) Hochster HS, et al. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. 2006; 24 (suppl. 18S):3510. 1Hurwitz PFS XELOX non-inferiority: primary objective met based on ITT PFS chemotherapy + bevacizumab superiority: primary objective met 1.0 1.0 HR = 1.04 [97.5% CI 0.93–1.16] 0.8 0.6 0.4 0.2 8.0 8.5 5 10 0.6 0.4 0.2 8.0 0 0 0 HR = 0.83 [97.5% CI 0.72–0.95] (ITT) P = .0023 0.8 Upper limit ≤ 1.23 (non-inferiority margin) PFS estiimate PFS estimate H, et al. Proc ASCO 2003;22 (Abstract 3646) 15 Months 20 FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab XELOX/XELOX+placebo/XELOX+bevacizumab 25 30 N=1017; 826 events N=1017; 813 events 0 5 9.4 10 15 20 25 Months FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events 2 Figure 3. Separation after ~6 months in bevacizumab-containing arms between ‘general’ and ‘on treatment’ PFS XELOX / FOLFOX-4 + bevacizumab XELOX / FOLFOX-4 + placebo PFS estima ate 1.0 0.8 ON TREATMENT: HR HR=0.63 0.63 (97.5% CI 0.52–0.75, p<0.0001) 0.6 GENERAL: HR=0.83 (97.5% CI 0.72–0.95, p=0.0023) 0.4 0.2 0 0 Figure 4. Overall survival (ITT population) XELOX / FOLFOX-4 + bevacizumab XELOX / FOLFOX-4 + placebo n=699 (420 events) Survival estim mate 15 • Duration of treatment was similar in bevacizumab- and placebocontaining arms. • Median treatment duration: n=701 (455 events) – Bevacizumab + XELOX HR=0.89 (97.5% CI 0.76–1.03) p=0.0769 0.6 0.4 • 0.2 19.9 10 Months 20 Treatment exposure 1.0 0.8 5 6.1 months (range 0–15.3) – Placebo + XELOX 5 4 months (range 0–15.7) 5.4 0 15 7) – Bevacizumab + FOLFOX-4 6.3 months (0–14.9) – Placebo + FOLFOX-4 6.0 months (range 0–15.6). Only 29% of bevacizumab recipients and 44–50% of placebo recipients were treated until disease progression.a 21.3 0 0 6 12 18 24 30 Months Safety • A higher proportion of patients discontinued therapy because of AEs in the bevacizumab-containing arms vs. the placebo-containing arms (31% vs. 21%). • Most treatment discontinuations were due to chemotherapy-rather than bevacizumab-related events. • Most common reasons for treatment discontinuation were neurotoxicity, GI events, general disorders and hematological events. • Predefined grade 3/4 AEs of interest to bevacizumab and chemotherapy are presented in Table 3. 36 aIncludes non-progressive patients stopping treatment at week 48 (end of primary treatment phase) Conclusions • The addition of bevacizumab to front-line oxaliplatin-based chemotherapy significantly improves PFS. • The overall safety profile is in line with previous trial experience in colorectal cancer. • Analysis of ‘on treatment’ PFS vs. ‘general’ PFS suggests that continuation of bevacizumab until disease progression may be necessary to optimize the effect of bevacizumab on PFS. • The observed overall survival difference did not reach statistical significance (p=0.077). 3 BRiTE Registry: Study Schema Evaluable patients (n=1953) BRiTE: •932 deaths (1/21/07 cut-off) •Median followup 19.6 mo 1st Progression ( 1445) (n=1445) Physician decision - no randomization Axel Grothey, M.D. Mary Sugrue, M.D. Ph.D. for the BRiTE Investigators No Post-PD Treatment (n=253) *BBP=bevacizumab beyond first progression 19 19 BRiTE ASCO Presentations To Date* No BBP* (n=531) BBP* (n=642) Grothey, ASCO 2007, abstract #4036 1st Line Chemotherapy Use in BRiTE HTN management Preliminary Safety/Effectiveness Overall safety Study Start 2004 Preliminary Safety/Effectiveness Overall survival Elderly(>75): Safety and Effectiveness Elderly (>65): Safety and Effectiveness GI perforation ATE Bleeding Overall effectiveness BBP Wound healing complications 2007 2008 2005 2006 Confirmed FOLFOX as most common 1st line CT in combination with Bevacizumab for mCRC in US. Kozloff et al. 2007 Gastrointestinal Cancers Symposium, Orlando, Jan. 19-21, 2007. * Novel presentations; does not include encore presentations 22 BRiTE Safety: Overview Figure 1. Schematic of Disease Progression and Interim Disposition of Patients in BRiTE All Patients (N=1953) New or worsened HTN (requiring medication), % ATE, % Bleeding events (grade 3/4), % 19.4 1.8 2.4 GI Perforation, % 1.8 Figure 1. Schematic of Disease Progression; OS=overall survival; TTP=time-to-progression *Nineteen patients received post-progression treatment with BV only and have been excluded from the BBP analysis. The remaining 508 patients have not yet had PD noted by investigator assessment. Incidence of Bevacizumab-related safety events in BRiTE is similar to incidence of events reported in pivotal trials Grothey et al. ASCO, Chicago, June 1-5, 2007. Figure 2. Interim Disposition of Patients in BRiTE (N=1953 with 1445 1st PD and 932 Deaths Reported as of the January 21, 2007 Data Cutoff) Grothey ASCO 2007 23 4 Figure 3. A) Graphical Representation of BV Use in BBP Patients and B) Frequency Distribution of Time from 1st PD to Start of BV Post 1st PD for Patients in the BBP Subgroup RESULTS (continued) • The proportion of patients with ECOG PS 0 was higher in the BBP than in the No BBP subgroup (50.2% versus 39.9%) (Table 3). • The BBP and No BBP subgroups were balanced on: – – – – Figure 3A. Graphical Representation of BV Use in BBP Patients Figure 3B. Frequency Distribution of Time from 1st PD to Start of BV Post 1st PD for Orange lines represent the time course of treatment with BV in Patients in the BBP Subgroup days for each patient who has progressed (n=642) with overlay of time of 1st PD (blue asterisks] • The pattern of BV use for patients who used BBP is shown in Figure 3. – 312 of 642 (49%), received BV continuously from 1st-line to beyond 1st PD (Figure 3A). – The majority of patients in the BBP subgroup (n=571, 89%) either used BV continuously into 2nd-line, or restarted BV within the 1st 4 months post-1st PD (Figure 3B). – 132 of the 642 BBP patients (20%) discontinued BV prior to 1st PD and restarted BV within 28 days of 1st PD. – 198 of the 642 BBP patients (31%) discontinued BV either prior to or at 1st PD and restarted BV >28 days after 1st PD. Grothey ASCO 2007 Figures 4, 5. Kaplan-Meier Estimates of A) Survival Beyond 1st PD and B) OS • Figure 4 displays the Kaplan-Meier curve for survival beyond 1st PD by subgroups based on treatment beyond 1st PD (1st PD occurred at 0 months). • Figure 5 displays the Kaplan-Meier curve for OS by subgroups based on treatment beyond 1st PD. Use of 1st-line CT Proportion of patients exposed to all 3 active CT agents TTP 1st-line exposure to BV • Total duration of BV use was longer in the BBP subgroup, as expected. • Of the 1445 patients with PD, 542 (37.5%) used an EGFR inhibitor post 1st PD (including BBP and No BBP); 489 of these (90%) used cetuximab. Grothey ASCO 2007 Preliminary efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI and fluoropyrimidines for mCRC: First BEAT S. Berry, D. Cunningham, M. Michael, A. Kretzschmar, F. Rivera, M. DiBartolomeo, M. Mazier, E. Van Cutsem, on behalf of the First BEAT investigators Abstract #350 Figure 4. Kaplan-Meier Estimates of Survival Beyond Figure 5. Kaplan-Meier Estimates of OS by Subgroups 1st PD by Subgroups Based on Post-PD Therapy Based on Post-Progression Therapy Grothey ASCO 2007 Serious Bevacizumab-Related Adverse Events First BEAT: Study Schema First-line metastatic CRC (1,965) Bevacizumab + standard chemotherapy PD • Bevacizumab: 5mg/kg Q2W or 7.5mg/kg Q3W • Endpoints: safety and efficacy • Median follow-up 22.9 months Berry 2008 ASCO GI abstract #350 Event (%) Any AE or SAE (n=1,914) CTC grade 3–5 or SAE* (n=1,914) Hypertension 29.9 Proteinuria 10.4 5.3 1.1 Bl di Bleeding 31 0 31.0 34 3.4 Wound-healing complications 4.0 1.1 Arterial thromboembolic events 1.5 1.5 GI perforation 1.9 1.8 Berry 2008 ASCO GI abstract #350 5 The Angiogenic Switch Angiogenesis • Physiologic Angiogenic 1-2 mm Switch Small tumor • Nonvascular • “Dormant” Larger tumor • Vascular • Metastatic potential • Pathologic – Longitudinal bone growth – Tumor growth – Wound healing – Rheumatoid arthritis – Secondary sexual development – Psoriasis • Corpus luteum formation – Retinopathies – Age-related macular degeneration Targeted Therapy: Bevacizumab Indications Angiogenesis: A Balanced Process Activators VEGF and receptors • In combination with chemotherapy: – Advanced colorectal cancer – Advanced breast cancer – Advanced lung cancer Inhibitors TSP-1 bFGF and receptors Angiostatin TGFβ and receptors Endostatin Others Interferons-α, -β, and -γ • Monotherapy: Interleukins-4, 12, 18 • Indications pending: – Early stage colon cancer – Glioblastoma – Renal cell cancer uPAR Others TSP-1 = thrombospondin-1; uPAR = urokinase plasminogen activator receptor. The Angiogenic Switch In Hepatic Micrometastasis 180 uM 290 uM 520 uM 2 mm We can hypothesize that Bev prevented the “angiogenic switch” and kept tumors beneath the threshold of detection by imaging. Avascular Within the limits of O2 diffusion Portal Perfusion Mixed Portal and Arterial Perfusion Arterial Perfusion Liu, Matsui. Radiology 2007 6 The Mechanism of Action of Bev in the Adjuvant Setting is Likely to be Different Than in the Advanced Stage Setting There Are No Known Predictive Biomarkers for Anti-VEGF Therapy IFL +/- Bev Trial Mechanism Advanced Disease* Adjuvant Anti-angiogenic (block new blood vessel growth) Possible, (no direct evidence) Probable, based on C08 findings (no direct evidence) Induction of EC Apoptosis Possible Not likely, cooption likely to provide nutrients in small volume disease Vasoconstriction Possible Unlikely, changes in tumor blood flow not relevant when tumor is microscopic Normalization Maybe Probably not relevant for microscopic tumors Direct Effect on Tumor Cells Maybe ✔ Maybe *Ellis, Hicklin. Nat Rev Ca 2008 Proposed Biomarker Outcome Plasma VEGF Not Predictive Primary Tissue VEGF (ISH, IHC) Not Predictive Upstream Mediators of VEGF (ras, raf, P53) Not Predictive Other Angiogenic Mediators (TSP-2) Not Predictive Jubb et al. J Clin Oncol 24:217-227, 2006 Ince et al. J Natl Cancer Inst. 97(13):981-9, 2005 Holden et al. ASCO. Abstract: 3555, 2005 Specific imaging of VEGF-A expression with radiolabeled anti-VEGF monoclonal antibody Thamar H. Stollman, Marian G.W. scheer, William P.J. Leenders, Kiek C.N. Verrijp, Annemieke C. Soede, Wim J.G. Oyen, Theo J.M. Ruers, and Otto C. Boerman Kaplan-Meier estimates for progression-free survival (PFS) of patients with low and high baseline volume transfer constant of contrast agent (Ktrans) and blood plasma volume fraction (Vp) Hahn, O. M. et al. J Clin Oncol; 2008 Figure 3. Biodistribution of In-111 bevacizumab in athymic male mice with s.c. LS174T tumors at 1, 3 and 7 days post injection (5 mice/group). Figure 4. Scintigraphic images of athymic male mice with s.c. LS174T tumors immediately after injection and at 1, 3 and 7 days post injection of In-111-bevacizumab (25 Ci/mouse, 3g/mouse). 7 Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100 Bryan P. Schneider, Molin Wang, Milan Radovich, George W. Sledge, Sunil Badve, Ann Thor, David A. Flockhart, Bradley Hancock, Nancy Davidson, Julie Gralow, Maura Dickler, Edith A. Perez, Melody Cobleigh, Tamara Shenkier, Susan Edgerton, Kathy D. Miller Schneider, et al. JCO 2008, 26(28), 4672-4678 Fig 1. Kaplan-Meier curve for overall survival (OS) in experimental arm by genotype; (A) vascular endothelial growth factor (VEGF)-2578 C/A; (B) VEGF-1154 G/A Candidate Single Nucleotide Polymorphisms Gene and Single Nucleotide Polymorphism White: Frequency of Rare Allele African American: Frequency of Rare Allele -2578 C/A Promoter A = 49% A = 24% -1498 C/T Promoter C = 49% C = 33% -1154 G/A Promoter A = 33% A = 10% -634 G/C 5’ Untranslated region C = 32% C = 35% 936 C/T 3’ Untranslated region T = 15% T = 13% 889 G/A (V297I) Exon 7 A = 9% A = 20% 1416 A/T (Q472H) Exon 11 T = 25% T = 10% VEGFR-2 Schneider, B. P. et al. J Clin Oncol; 26:4672-4678 2008 Fig 2. Kaplan-Meier curve for overall survival (OS) in the experimental arm (by vascular endothelial growth factor genotype) compared with the control and combination arms (not subdivided by genotype) Schneider, B. P. et al. J Clin Oncol; 26:4672-4678 2008 Copyright © American Society of Clinical Oncology Location VEGF Schneider, B. P. et al. J Clin Oncol; 26:4672-4678 2008 Copyright © American Society of Clinical Oncology Hypertension and Overall Survival: Axitinib Rini, BI et al. Proc. ASCO 2008, Abstract 3543 Relationship Between HTN and the Efficacy of Anti-VEGF Rx Reference N Scartozzi et al. 39;25;1 1 Malignancy Treatment Colorectal cancer 5-FU, irinotecan + bevacizumab Main Findings 20% grade 2-3 HT; response in patients with grade 2-3 HT: 75% (n = 8) versus 32% (n = 31), P = 0.04 Rixie et al. 40; 32 mRCC Sunitinib 22.5% grade 3 HT; response in patients with grade 3 HT: OR 5.69 (95% CI 2.51-12), P = 0.03 Rini et al. 52 Cytokineresistant mRCC Axitinib Overall survival in patients with DBP ≥90 mmHg: not reached (n = 32) versus 12.9 months (n = 20) Rini et al. 62 Sorafenibresistant mRCC Axitinib Overall survival in patients with DBP ≥90 mmHg: not reached (n = 39) versus 8.4 months (n = 23) Spano et al. 69 Pancreatic carcinoma Gemcitabine + Axitinib 6% grade 3 HT, 22% all-grade HT; overall survival in patients with DBP ≥90 mmHG: 13.0 months (95% CI 8.5-16.6) versus 5.6 months (95% CI 4.8-7.2) Friberg et al. 52 Pancreatic carcinoma Gemcitabine + bevacizumab 19% grade 3 HT; overall survival in patients with early HT (<56 days of treatment): 13.7 months versus 8.7 months (P = 0.007) Rini et al. 32 Melanoma Axitinib Overall survival in patients with DBP ≥90 mmHg: 13 months (n = 19) versus 6.4 months (n = 13) Rini et al. 32 NSCLC Axitinib Overall survival in patients with DBP ≥90 mmHg: 15 months (n = 19) versus 11.6 months (n = 13) Rini et al. 60 Thyroid cancer Axitinib Overall survival in patients with DBP ≥90 mmHg: not reached (n = 39) versus 21.6 months (n = 21) Schneider et al. 345 Breast cancer Paclitaxel + bevacizumab Overall survival in patients with grade 3-4 HT (n = 52): 38.7 months versus 25.3 months (n = 293), P = 0.02 Mir et al. Ann Onc 2009 8 Angiogenic Cytokines Are Increased Prior to Disease Progression In Metastatic Colorectal Cancer Patients Treated With Bevacizumab Proposed Mechanisms of Bevacizumab Resistance Scott Kopetz, Paulo M. Hoff, Cathy Eng, Michael Overman, Overman Katrina Y Y. Glover Glover, David Z Z. Chang Chang, Robert A. Wolff, James L. Abbruzzese, Lee M. Ellis, John V. Heymach The University of Texas, M.D. Anderson Cancer Center, Houston, Texas Centro de Oncologia, Hospital Sírio Libanês, Sao Paulo, Brazil Ellis, Hicklin, Clin Cancer Res, 2008 Study Purpose and Methods Cycle 2 Day 15 Bevacizumab Bevacizumab FOLFIRI FOLFIRI placental growth factor [PlGF] matrix metalloprotease 9 [MMP-9] b i fibroblast basic fib bl t growth th factor f t [bFGF] I t l ki 8 [IL-8] Interleukin [IL 8] hepatocyte growth factor [HGF] Eotaxin / CCL11 platelet derived growth factor-BB [PDGF] stromal derived factor 1a/CXCL12 [SDF-1] stem cell factor/KIT ligand [SCF] monocyte chemotactic protein 3 [MCP-3] Interleukin 1-beta [IL-1β] macrophage colony stimulating factor [M-CSF] † † 0.5 * – p<0.05 for a priori primary cytokines, multiple comparison adjusted for exploratory cytokines. † † † 0.25 Pl • Comparisons by nonparametric Wilcoxon paired test † 1 G granulocyte colony stimulating factor [G-CSF] 2 After Bevacizumab After FOLFIRI + Bev * IL -8 E-Selectin * P9 Exploratory Cytokines 4 M M Primary Cytokines Every 2 weeks Cytokine Modulation after Single-agent Bevacizumab, and after FOLFIRI + Bevacizumab n • Multiplex bead assay, ELISA for panel of 38 cytokines, 6 identified for a priori evaluation: After FOLFIRI + Bev • Subsequent samples were obtained every two weeks • n=40 with evaluable samples at the selected time points F Study Methods After Bevacizumab Eo ta xi Kopetz, et al. ASCO ’07 Abs 4089 Baseline Median ffold change from baseline 43 previously untreated patients First cycle consisted of single agent bevacizumab Response rate of 60% Progression-free survival of 12.8 months Overall survival of 30.7 mos. Cycle 4+ Day 43 Bevacizumab • Trial: Phase II of FOLFIRI + Bevacizumab – – – – – Cycle 3 Day 29 le ct in 2) just prior to progressive disease on a bevacizumabcontaining regimen • Sample Collection Study Aim 1: Cycle 1 Day 1 ESe 1) after treatment with bevacizumab bF G F • Purpose: To evaluate circulating levels of cytokines: Study Methods There were no significant changes in the other cytokines •p<0.05; † p<0.05 after multiple comparison correction •Error bars represent a nonparametric estimate of SD 9 PlGF and bFGF are Increased Prior to Progression p=0.04 40 p<0.01 30 p<0.01 bFGF F (ng/mL) 30 20 ULN 20 10 ULN as e B as el in ev e ac A iz fte um rF ab O Pr LF io IR rt I+ o B Pr og re ss io n B fte rB A B lin ev e ac A iz fte um rF ab O Pr LF io IR rt I+ o B Pr og re ss io n 0 0 • PlGF, bFGF, and HGF were increased prior to progression on a bevacizumab-containing regimen – PlGF increased after single-agent bevacizumab an peaked prior to progression bevacizumab, • There is considerable variation in the magnitude of these changes between patients • Myeloid lineage activators and chemotactic cytokines are increased prior to progression A fte r PlGF ((pg/mL) p<0.01 Conclusions ULN = upper limits of normal for healthy controls Implication of Findings • Markers for early detection of resistance • Provides therapeutic targets to reverse resistance to antiangiogenic therapy • Individualize continued anti-angiogenic therapy after progression i • PlGF signaling may be inhibited by VEGF tyrosine kinase inhibitors • bFGF receptor tyrosine kinase inhibitors are in clinical development • Absence of alternate angiogenic signaling at progression may represent opportunity for continued benefit from bevacizumab 10
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