ESMO Guidelines 2014/2015

Annals of Oncology 25 (Supplement 3): iii1–iii9, 2014 doi:10.1093/annonc/mdu260 Published online 4 September 2014 Angiogenesis Tumoral

Reviewed in Tugues et al. Mol Aspects Med 2011;32(2):88-111. Angiogénesis Anti-angiogenics

Targeting Sustained Angiogenesis

“Mantained VEGF blocking achieves and prolongs tumor regression”

• Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials

Targeting Sustained Angiogenesis

“Mantained VEGF blocking achieves and prolongs tumor regression”

• Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials VEGF is an early and persistent promoter of tumour angiogenesis1–4

VEGF VEGF VEGF VEGF VEGF bFGF bFGF bFGF bFGF TGFβ-1 TGFβ-1 TGFβ-1 TGFβ-1 PLGF PLGF PLGF PD-ECGF PD-ECGF Pleiotrophin

Continued VEGF expression3

• Tumours continually require VEGF to recruit new vasculature5 • VEGF continues to be expressed throughout tumour progression, even as secondary pathways emerge2,3,6,7

1. Bergers, Benjamin. Nat Rev Cancer 2003; 2. Kim, et al. Nature 1993; 3. Folkman. In: DeVita, Hellman, Rosenberg, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins;2005; 4. Ferrara, et al. Nat Med 2003; 5. Inoue, et al. Cancer Cell 2002; 6. Mesiano, et al. Am J Pathol 1998; 8 7. Melnyk, et al. J Urol 1999 Prolonged angiogenesis inhibition with bevacizumab maintains tumour control over time

• First-line and continued VEGF inhibition are essential strategies in the treatment of patients with metastatic disease1–6

First-line use of bevacizumab: Continued use of bevacizumab: attaining tumour control maintaining tumour control

1. Mabuchi, et al. Clin Cancer Res 2008; 2. Bagri, et al. Clin Cancer Res 2010; 3. Grothey, et al. JCO 2008; 4. Galizia, et al. Clin Cancer Res 2004; 9 5. Mancuso, et al. J Clin Invest 2006; 6. Vosseler, et al. Cancer Res 2005 Preclinical evidence: prolonged angiogenesis inhibition with bevacizumab maintains tumour control over time1

• Human colorectal cancer (SW620) xenografts were implanted into mice1 • Anti-VEGF antibodies were given twice weekly for 3 weeks, or until the end of the study – anti-VEGF antibodies B20-4.1 and B20- 4.1.1. were used as murine surrogates of bevacizumab Data shown until <50% of mice remain on study. • Anti-VEGF treatment reduced tumour growth relative to control – tumour inhibition was more effective when treatment was continued for a longer period of time

EOS=end of study. * Continued for 3 weeks. † Continued until the end of the study.

Figure reprinted with permission from Bagri A, et al. Clin Cancer Res 2010;16:3887-900, Figures 2A and B

10 1. Bagri, et al. Clin Cancer Res 2010

Targeting Sustained Angiogenesis

“Mantained VEGF blocking achieves and prolongs tumor regression”

• Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials Early discontinuation of bevacizumab may compromise clinical effectiveness1,2

• In Study NO16966, a significant increase in median PFS was observed predominantly in the subset of patients who continued to receive bevacizumab until disease progression1,2

12 1. Saltz, et al. ASCO GI 2007 (Abstract); 2. Saltz, et al. JCO 2008

Targeting Sustained Angiogenesis

“Mantained VEGF blocking achieves and prolongs tumor regression”

• Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials MANTENIMIENTO

• Bevacizumab – MACRO, SAKK, AIO • Bevacizumab + FP – CAIRO, AIO • Bevacizumab + Erlotinib* – DREAM – Nordic-ACT

*Erlotinib no está aprobado en cáncer colorrectal14 MACRO: XELOX + Beva → XELOX + Beva o Beva monoterapia en mantenimiento

• Non-inferiority study • Objectives/endpoints – Primary endpoint: PFS – Secondary end points include: OS, ORR, time to response, duration of response, and safety

Patients XELOX-Beva x6 q3w with XELOX-Beva (n=239) Treat previously until untreated PD mCRC XELOX-Beva Single-agent (s/a) (N=480) x6 q3w (n=241) Beva

• XELOX-Beva (Xeloda 1000 mg/m2 bid days 1–14 q3w + oxaliplatin 130 mg/m2 + Avastin 7.5 mg/kg day 1 q3w) initially given for 6 cycles

Díaz-Rubio E. et al. The Oncologist 2011 MACRO: Supervivencia Libre de Progresión (ITT)

Treatment XELOX-Avastin s/a Avastin Follow-up median 21.1 (0–40) 20.4 (0–38) Progression-free probability months (range) 1.00

XELOX-Avastin s/a Avastin  0.75 No. of Patients 239 241 Event 161 (67%) 174 (72%) Censored 78 (33%) 67 (28%) 0.50 Median (95% CI) 10.4 (9.3–11.9) 9.7 (8.5–10.6) HR: 1.11 (0.89, 1.37)

0.25

0 0 3 6 9 12 15 18 21 24 27 30 33 36 Patients Time (months) at risk XELOX-A 239 204 158 108 71 49 27 13 7 4 2 1 0 s/a Avastin 241 199 160 102 58 40 27 17 11 8 6 4 1

16 Díaz-Rubio et al. Oncologist 2012 MACRO: Supervivencia Global (población ITT)

Treatment XELOX-Avastin s/a Avastin Follow-up median 21.1 (0–40) 20.4 (0–38) Survival probability months (range) 1.00

0.75

0.50

XELOX-Avastin s/a Avastin 

No. of patients 239 241 0.25 Event 131 (55%) 130 (54%) Censored 108 (45%) 111 (46%) Median (95% CI) 23.4 (20.0–26.0) 21.7 (18.3–25.1) HR: 1.04 (0.81–1.32)

0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Patients Time (months) at risk XELOX-A 239 227 208 191 170 146 120 85 60 40 23 13 6 2 s/a Avastin 241 226 210 193 159 132 101 77 54 39 26 19 8 0

17 Díaz-Rubio et al. Oncologist 2012 SAKK 41/06: non-inferiority trial of Beva continuation vs no continuation after 1L Beva + CT

Continued Beva PD (n=131)

Previously Beva + untreated mCRC chemotherapy R (n=262) (4–6 months)

No treatment PD (n=131)

• Phase III • Primary endpoint: non-inferiority in TTP (from randomisation) • Secondary endpoints: PFS, time to second-line treatment, OS, adverse events related to Beva, treatment costs

Koeberle, et al. ASCO 2013; Stein A et al. Clin Colorectal Cancer 2015 SAKK 41/06: TTP (from randomisation) was numerically increased with continued Beva vs no Bevacizumab

1.0

Continued Beva No Beva 0.8 No. of events 124 123

Median (95% CI) 4.1 (3.1–5.4) 2.9 (2.8–3.8)

0.60 HR 95% CI 0.74 (5.7–0.95) Non-inferiority p=0.47

0.40 TTP estimate TTP

0.20

2.9 4.1 0 0 6 12 18 24 30 36 42 48 Time (months) Patients at risk Avastin 131 40 14 8 6 5 3 2 1 No Avastin 131 22 10 7 5 1 1 1 0

Koeberle, et al. ASCO 2013. Koeberle, et al. ASCO 2013; Stein A et al. Clin Colorectal Cancer 2015

AIO 0207: Treatment algorithms

Hegewisch S et al. Lancet 2015 AIO 0207 TFS

Hegewisch S et al. Lancet 2015 AIO 0207 PFS

Hegewisch S et al. Lancet 2015

AIO 0207 OS

Hegewisch S et al. Lancet 2015

CAIRO3 study
study design

Presented By Cornelis Punt at 2015 ASCO Annual Meeting CAIRO3: Maintenance Cape-Beva DREAMS: Bevacizumab vs bevacizumab + erlotinib Johnsson A et al. Ann Oncol 2013

Clin Colorectal Cancer 2015 Slide 32

Presented By Dirk Arnold at 2016 ASCO Annual Meeting

Targeting Sustained Angiogenesis

“Mantained VEGF blocking achieves and prolongs tumor regression”

• Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials Continued bevacizumab may correlate with clinical benefits

• In the non-randomised, observational BRiTE study of bevacizumab plus chemotherapy in patients with mCRC, median OS was increased in patients receiving bevacizumab beyond progression vs those stopping bevacizumab at progression (31.8 vs 19.9 months, respectively, HR=0.48, p<0.001)1

PD=progressive disease.

• To be confirmed in ongoing prospective phase III trials

31 1. Grothey, et al. JCO 2008; 2. Grothey, et al. ASCO 2007 (Abstract and poster) Survival Outcomes of Beva Beyond Progression: USO and ARIES

Cartwrigh T et al. Clinical Colorectal Cancer 2012 Grothey A et al. Farmacoepidemiology and drugs safety 2014

Targeting Sustained Angiogenesis

“Mantained VEGF blocking achieves and prolongs tumor regression”

• Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials E3200: Añadir Bevacizumab a FOLFOX en 2ª línea incrementa la eficacia

FOLFOX/beva12.9 meses Folfox/beva:7.3 meses FOLOX: 10.8 meses P=0.0011 Folfox: 4.7 meses Beva; 10.2 meses Beva: 2.7 meses P< 0.0001

Giantonio et al. J Clin Oncol 2007; 25(12):1539-44 Bevacizumab: Ensayo ML18147 (TML)

Standard second-line CT (oxaliplatin BEV + standard first- or irinotecan-based) until PD line CT (either oxaliplatin or PD Randomise 1:1 irinotecan-based) BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin (n=820) CT switch: or irinotecan-based) until PD Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin

Primary endpoint • Overall survival (OS) from randomisation Secondary endpoints • Progression-free survival (PFS) included • Best overall response rate • Safety

Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based) • First-line PFS (≤9 months, >9 months) • Time from last BEV dose (≤42 days, >42 days) • ECOG PS at baseline (0/1, 2) Median: BEV + CT 11.2 months, CT 9.8 months

Median: BEV + CT 5.7 months, CT 4.1 months

Lancet Oncol 2013 Jan;14(1):29-37. TML Study Lancet Oncol 2013 Jan;14(1):29-37. PFS: KRAS population

Interaction test by KRAS status is negative (p=0.4436) OS: KRAS population

Interaction test by KRAS status is negative (p=0.1266) Conclusions

• Study confirms that continuing BEV beyond first progression while modifying CT is beneficial for patients with mCRC and leads to a significant improvement in OS and PFS

• This provides a new second-line treatment option for patients who have been treated with BEV + standard CT in first line while maintaining an acceptable safety profile BEBYP trial: Study Design

I-line CT * + BV R A. Second-line CT§ Stratification A ‐ Center N ‐ PS 0/1-2 D ‐ CT-free interval O (> vs ≤ 3 mos) M § ‐ II-line CT B. Second-line CT + BV

* • FOLFIRI § • FOLFIRI • FOLFOX • mFOLFOX-6 • FOLFOXIRI • Fluoropyrimidine mono-tx • Objetivo Principal: Progression Free Survival • Study conducted in 19 Italian centers • Supported by AIFA At a median follow-up of 45.3 months, 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%CI 0.52-0.95; stratified log-rank p=0.010)

Masi et al. Annals of Oncology 2015 Aflibercept

• Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgG Fc¹

• Blocks all human VEGF-A Aflibercept isoforms, VEGF-B and placental growth factor (PlGF)²

• High affinity—binds VEGF-A and PlGF more tightly than native receptors

• Contains human amino acid sequences¹

1. Adapted from Holash. Proc Natl Acad Sci. 2002;99:11393–11398. 2. Adapted from Tew. Clin Cancer Res. 2010;16:358–366.

43 Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA VELOUR*: Aflibercept fase III en segunda línea CCRm

612 pts Aflibercept 4 mg/kg IV Pacientes con cáncer + FOLFIRI q 2 semanas colorrectal metastásico después del fracaso de un 1:1 PROGRESIÓN DE LA MUERTE régimen basado en R 614 pts ENFERMEDAD oxaliplatino Placebo + FOLFIRI FACTORES DE q 2 semanas ESTRATIFICACIÓN: Prior Bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2)

Población de estudio: Objetivo primario: SG 1226 randomizados, 1216 tratados Objetivos secundarios: TR, SLP, seguridad, FC Análisis final de 863 OS eventos

*VELOUR acrónimo: VEGF Trap(aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen.

VELOUR es un estudio multinacional, aleatorizado, doble ciego, según elevados estándares de calidad, incluye revisión de los datos por un comité independiente

Van Cutsem et al. J Clin Oncol. 2012; 30 (28): 3499-3506 Ramucirumab binds specifically to VEGF receptor-2

Clarke JM and Hurwitz HI. Expert Opin Biol Ther 2013;13:1187–1196 ©2014 Eli Lilly and Company Nuevos fármacos antiangiogénicos: ramucirumab

Uso experimental – Fuera de indicación Ramuricurmab: RAISE OS (ITT)

Tabernero et al. Lancet Oncol 2015;16:499-508 Ramucirumab: RAISE PFS (ITT)

Tabernero et al. Lancet Oncol 2015;16:499-508 Ramucirumab: RAISE

Antiangiogénicos en 2º línea asociados a FOLFIRI CR-SEQUENCE Planned study design

FOLFOX + FOLFIRI + panitumumab bevacizumab Investigator choice: Unresectable 1st-line reintroduction mCRC R 1 or WT RAS Regorafenib 1:1 FOLFIRI + FOLFOX + or R panitumumab bevacizumab 2 other

N cycles until PD, toxicity or FOLFIRI + conversion surgery bevacizumab

N cycles until PD or toxicity 80405: Sidedness Predictive for Biologics
Biologic by 1° Side Interaction

Presented By Alan Venook at 2016 ASCO Annual Meeting Bevacizumab added survival benefit (OS) to the chemotherapy backbone, independent of tumour location

AVF2107g* NO16966‡

Chemotherapy 24,7 25 24,2 Chemotherapy 22,0 + bevacizumab 20,6 20 18,0 17,0

15,9 15 13,6

OS (months) OS 10

5

0 Right-sided Left-sided Right-sided Left-sided tumours tumours tumours tumours Tumour location *Phase III randomised study: 1L bevacizumab + IFL vs placebo + IFL ‡Phase III study: 1L bevacizumab + CAPOX/FOLFOX4 vs placebo + CAPOX/FOLFOX4 Loupakis, et al. J Natl Cancer Inst 2015 CRC Molecular Classification

CMS1 (MSI immune), hypermutated, MSU, and strong immune activation CMS2 (canonical), epithelial, marked WNT and MYC signaling activation CMS3 (metabolic ), epithelial and evident metabolic dysregulation CMS4 (mesenchymal), prominent TGF–btea activation, stromal invasion and angiogenesis Mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity

J. Guinney et al. Nature Medicine 2015 Anticuerpo dual con unión a Ang2 y VEGF-A : vanucizumab

Vanucizumab

Ang2 VEGF-A

McCAVE trial design

Induction Maintenance Anti-Ang2 Anti-VEGF-A (up to 8 cycles) (until PD) = LC06 = bevacizumab

CH1–CL cross over Bevacizumab + Bevacizumab + 5- Knobs into mFOLFOX6 FU/LV 1L mCRC holes R N=140 Vanucizumab + Vanucizumab + mFOLFOX6 5-FU/LV

Open-label safety run-in with n=6–18 patients Primary endpoint: estimated HR for PFS

NCT02141295, CT.gov Examples of anti-PDL1/PD1 therapies currently under investigation in CRC* Target Therapy Phase Trial design Trial ID

Atezolizumab I Solid tumours NCT01375842 (engineered IgG1, Ib Solid tumours (+ bevacizumab ± FOLFOX) NCT01633970 no ADCC) Anti-PDL1 II mCRC (+ bevacizumab + fluoropyrimidine) NCT02291289 MEDI4736 (modified IgG1, II mCRC NCT02227667 no ADCC) I/II MSI-high mCRC (± ipilimumab) (CheckMate 142) NCT02060188 Nivolumab I/II Solid tumours (+ INCB24360) NCT02327078 (IgG4) I/II Solid tumours (+ chemotherapy) NCT02423954 I/II Solid tumours (+ varlilumab) NCT02335918 I Solid tumours (+ aflibercept) NCT02298959 I/II GI cancers (+ mFOLFOX6) NCT02268825 Anti-PD1 KRAS, BRAF, NRAS WT mCRC (+ cetuximab or I/II NCT02318901 Pembrolizumab trastuzumab or trastuzumab emtansine) (IgG4, humanised) II mCRC (+ radiotherapy or ablation) NCT02437071 II mCRC (+ mFOLFOX6) NCT02375672 II mCRC (+ azacitidine) NCT02260440 II MSI-positive/-negative CRC NCT01876511

*Recruiting studies Clinicaltrials.gov ¡ Muchas Gracias! [email protected]