anti-angiogenic therapy and other solid tumours alfredo zurlo roche, basel, switzerland

Anti-angiogenic therapy andother solid tumours

Alfredo ZurloRoche, Basel, Switzerland

Requirement for improved cancer therapies

Despite recent improvements in cancer therapy, there remains a great need for the development of more effective therapies

• The increase in cancer incidence associated with the ageing population adds to this need

A combination of systemic chemotherapies and radiotherapy has provided improvements in clinical outcomes, but often at the expense of increased toxicity

Novel agents offer potentially increased efficacy and limited toxicity compared with conventional chemotherapies

Most human tumour types express VEGF: rationale for Avastin therapy

ICC = immunocytochemistry; ISH = in-situ hybridisation; ELISA = enzyme-linked immunosorbent assay; RI = radioimmunoassay; Haem. = haematological; SCLC = small cell lung cancer; CRC = colorectal cancer; CML = chronic myeloid leukaemia; GI = gastrointestinal; VEGF = vascular endothelial growth factor

Study Cancer n Tumours (%) Test

Gasparini, 1997 Breast 260 95 ELISA

Toi, 1995 152 55 ICC

Imoto, 1998 Lung NSCLC 91 53 IHC

O’Byrne, 2000 NSCLC 223 47 IHC

Volm, 1997 SCLC 109 59 IHC

Maeda, 2000 GI CRC 100 37 IHC

Amaya, 1997 CRC 136 43 IHC

Ishigami, 1998 CRC 60 100 ISH

Ogata, 2003 Oesophagus 92 24 IHC

Shih, 2000 Oesophagus 117 31 IHC

Paley, 1997 Ovarian 68 43 ISH

Yamamoto, 1997 70 97 ELISA

Jacobsen, 2004 Renal 229 100 IHC

Aguayo, 2002 Haem. AML 58 100 ELISA

Verstovsek, 2002 Haem. CML 184 100 RI

Ongoing/planned phase III trials ofAvastin in other indications

Trial Phase n Cancer Treatment Primary endpoint

AVOREN (BO17705)

III 638 Advanced renal cell cancer

IFN-2a ± Avastin Duration of survival

AVITA (BO17706)

III 600 First-line metastatic pancreatic cancer

Gemcitabine + Tarceva® ± Avastin

Duration of survival

MAGIC2 (ST03)

III 1,100 (Neo)adjuvant gastric cancer

Epirubicin + cisplatin + Xeloda® ± Avastin

Duration of survival

ICON-7(BO17707)

III 1,512 FIGO stage I–IV epithelial ovarian cancer

Paclitaxel + carboplatin ± Avastin

Progression-free survival

Hepatocellular carcinoma

Several phase II trials are planned

Renal cell cancer (RCC)

Phase II trial of Avastin monotherapy in RCC: study design

Primary endpoints: time to progression and response

rate

Secondary endpoints: survival and safety

Progressive metastatic RCC (IL-2 failure or

ineligible)

Placebo (n=40)

Avastin 10mg/kg every2 weeks (n=39)

Avastin 3mg/kg every2 weeks (n=37)

Avastin 3mg/kg every 2 weeks

IL-2 = interleukin-2; PD = progression of disease

PD

PD

PD

Yang JC, et al. N Engl J Med 2003;349:427–34

*Determined by Cox-proportional hazard model†Duration: 39+, 15, 9 and 6 monthsHR = hazard ratio

Phase II trial of Avastin in RCC: efficacy (planned analysis)


Treatment arm Complete response

Partial response

Median time to

progression (months)

HR* (vs placebo)

Placebo (n=40) 0 0 2.5 –

Avastin 3mg/kg (n=37)

0 0 3.0 1.26 (p=0.053)

Avastin 10mg/kg (n=39)

0 4† (10%) 4.8 2.55 (p<0.001)

Pati

ents

pro

gre

ssio

n-f

ree (

%)

Two-sided unadjusted analysis (log-rank test): p<0.001

Avastin 10mg/kg (median time to progression = 4.8 months)

Placebo (median time to progression = 2.5 months)

Phase II trial of Avastin in RCC: time to tumour progression (planned

analysis)

Months from start of treatment0 6 12 18 24 30 36

100

80

60

40

20

0


2.5 4.8

Based on audited PD data where available

Phase II trial of Avastin in RCC: safety (any grade)


Adverse event

Placebo (n=40) n (%)

Avastin 3mg/kg (n=37) n (%)

Avastin 10mg/kg (n=39) n (%)

Hypertension 2 (5) 1 (3) 14 (36)

Proteinuria Grade 1/2

15 (38)

13 (37)

22 (56)

Malaise 6 (15) 6 (16) 13 (33)

Epistaxis 1 (3) 5 (14) 8 (21)

Chest pain 0 0 2 (5)

Fever 0 1 (3) 4 (10)

Haemoptysis 2 (5) 1 (3) 1 (3)

Pulmonary embolism 1 (3) 0 0

Long-term Avastin use in a phase II trial in RCC

Four patients in the original study have been on Avastin for 3–5 years

• two patients completed the protocol-defined 2 years of therapy (one partial response, one minor response) and relapsed off-therapy— both patients had further tumour regression after Avastin was

reinstated and have remained stable on treatment for a further3–3.5 years

• two patients with stable disease at 2 years subsequently received Avastin 10mg/kg and were stable for >4 years

Yang JC. Clin Cancer Res 2004;10:6367s–70s

Change in RCC tumour burden during

Avastin therapy

Yang JC. Clin Cancer Res 2004;10:6367s–70s

200

180

160

140

120

100

80

60

40

20

0

Tum

ou

r b

urd

en c

om

pare

d t

o b

ase

line (

%)

0 20 40 60

Placebo Avastin 3mg/kg

0 20 4060

200

180

160

140

120

100

80

60

40

20

00 20 40 60 80

200

180

160

140

120

100

80

60

40

20

0

Avastin 10mg/kg

Weeks of treatment

Phase II trial of Avastin plus Tarceva® in RCC: study design

Objectives: assess the efficacy and safety of Avastin plus Tarceva in patients with advanced RCC

Avastin 10mg/kg i.v. given every 2 weeks

Tarceva 150mg orally, given every day

Treatment to continue for 12 months or until disease progression

Avastin 10mg/kg every 2 weeks +

Tarceva

Metastatic RCC patients (n=63) PD

Spigel DR, et al. J Clin Oncol 2005;23(June 1 Suppl.):387s (Abstract 4540)

i.v. = intravenous

Phase II trial of Avastin plus Tarceva in RCC: efficacy


Number of patients (%) (n=59)

Median overall survival (months) 22.8

1-year overall survival 76

Median time to progression (months) 11.1

1-year progression-free survival 45

Response Complete response 2 (3)

Partial response 13 (22)

Minor response 13 (22)

Stable disease 23 (39)

Phase II trial of Avastin plus Tarceva in RCC: safety

Number of patients (%)

Grade 1/2 Grade 3/4

Rash 58 (93) 8 (13)

Diarrhoea 51 (82) 8 (13)

Nausea/vomiting 29 (47) 6 (10)

Hypertension 22 (35) 6 (10)

Bleeding 34 (55) 5 (8)

Proteinuria 38 (61) 5 (8)

Pruritus 25 (40) 2 (3)

Neuropathy 7 (11) 2 (3)

Oedema 8 (13) 1 (2)


Avastin plus Tarceva in RCC:a phase II trial update

Avastin 10mg/kg every 2 weeks + Tarceva 150mg

daily

Avastin 10mg/kg every 2 weeks +

placebo

Primary endpoints were progression-free survival and response

Study closed to accrual

First-line metastaticRCC patients

(n=104)

PD

PD

Multicentre, phase II trial

Addition of Tarceva to Avastin resulted in progression-free survival and response rates similar to those achieved with

Avastin alone

Phase III trial of Avastin in RCC (AVOREN)

IFN-2a + Avastin 10mg/kg every 2

weeks

IFN-2a + placebo

Primary endpoint is survival

Treatment administration• Avastin 10mg/kg every 2 weeks until progression

• IFN-2a 9MIU three times/week (maximum of 52 weeks)

Multinational ex-US study

Recruitment is complete

RCC patients(n=638)

*No cross over will be permitted

PD*

PD

Phase III trial of Avastin in RCC (CALGB 90206)

IFN-2b + Avastin

10mg/kg every2 weeks

IFN-2b alone

CALGB = Cancer and Leukemia Group B

RCC patients(n=700)

Primary endpoint is survival

Recruitment is complete

Avastin in RCC: summary

Avastin monotherapy has demonstrated long-term antitumour activity

Avastin alone is well tolerated:

• no life-threatening adverse events or deaths related to Avastin therapy have been reported

• hypertension and proteinuria are the most common Avastin-related events

Two ongoing phase III trials (AVOREN and CALGB 90206, respectively) including approximately 700 patients in each are evaluating the efficacy and safety of IFN-2a ± Avastin 10mg/kg every 2 weeks

Pancreatic cancer

Avastin plus gemcitabine in patients with advanced pancreatic cancer: phase II study

design

Single-arm, phase II multicentre trial (NCI sponsored) at seven sites

Treatment• gemcitabine 1,000mg/m2 i.v. on days 1, 8 and 15 of a 4-week

cycle• Avastin 10mg/kg i.v. every 2 weeks• treatment was limited to six cycles of bevacizumab/gemcitabine

— patients without disease progression after six cycles could receive single-agent Avastin until progression

CT scans obtained every two cycles

Primary endpoint: objective tumour response

Kindler HL, et al. J Clin Oncol 2005;23:8033–40

NCI = National Cancer InstituteCT = computed tomography

Avastin plus gemcitabine in patients with advanced pancreatic cancer:

efficacy results

ResponsePatients (n=52)

n (%)

Complete response 0

Partial response 11 (21)

Stable disease 24 (46)

Tumour progression 13 (25)

Median duration of response was 10 months

Median duration of stable disease was 6.3 months

Criteria for concluding Avastin plus gemcitabine is an active regimen (≥9 responses in 50 patients) met


Avastin plus gemcitabine in patients with advanced pancreatic cancer: efficacy results

(cont’d)

Response Outcome

Median progression-free survival (months)

5.4 (95% CI: 3.7–6.2)

Median overall survival (months) 8.8 (95% CI: 7.4–9.7)

6-month survival (%) 77 (95% CI: 63–86)

1-year survival (%) 29 (95% CI: 17–42)

n=52

CI = confidence interval Kindler HL, et al. J Clin Oncol 2005;23:8033–40

Avastin plus gemcitabine in patients with advanced pancreatic cancer: grade 3/4 non-haematological

safety profile

AST = aspartate aminotransferase ALT = alanine aminotransferase AP = alkaline phosphatase

Adverse event

Patients (n=52) n (%)

Anorexia 2 (4)

Fatigue 9 (17)

Hyperglycaemia 7 (13)

Infection 2 (4)

Nausea 3 (6)

AST 4 (8)

ALT 5 (10)

AP 4 (8)

Bilirubin 3 (6)


Avastin plus gemcitabine in patients with advanced pancreatic cancer: Avastin-related non-

haematological safety profile

Grade

Adverse event (n=52) 1 2 3 4

Bleeding 16* 0 0 1†

Headache 11 2 1 0

Hypertension 6 7 10 0

DVT/PE 0 3 3 4

Proteinuria 10 8 1 0

Visceral perforation 0 0 0 4‡

*Includes epistaxis (12); gum bleeding (2)†Fatal GI bleed‡Three bowel perforations (one fatal); one oesophageal tear

GI = gastrointestinal


Locally advanced (stage III) and

metastatic (stage IV) first-line pancreatic

cancer (n=530)

Gemcitabine + placebo

Gemcitabine + Avastin (10mg/kg)

every 2 weeks

PD

PD

Phase III trial of first-line Avastin with gemcitabine

in pancreatic cancer (CALGB 80303)

Primary endpoint: overall survival (90% power to detect a 35% increase in survival from 6 to 8.1 months)

Treatment administration• gemcitabine 1,000mg/m2 weekly for 3 weeks of each 4-week cycle• Avastin 10mg/kg every 2 weeks

CALGB = Cancer and Leukemia Group B

Primary endpoint: overall survival (increase from 6.9 to 9.0 months)Secondary endpoints include progression-free survival and response rateAvastin 5mg/kg every 2 weeks until disease progression

Previously untreated metastatic

pancreatic cancer (n=600)

Gemcitabine + Tarceva + placebo

Gemcitabine + Tarceva + Avastin

5mg/kg every2 weeks

PD*

PD


Phase III trial of first-line gemcitabine plus Tarceva with or without Avastin in pancreatic

cancer (AVITA)

Avastin in pancreatic cancer: summary

Avastin plus gemcitabine improved response rate, time to progression and overall survival compared with that expected with gemcitabine alone in patients with advanced pancreatic cancer

Avastin plus gemcitabine is well tolerated. Rates of thrombosis and significant bleeding are not higher than expected in this patient population

Two ongoing phase III trials (AVITA and CALGB 80303, respectively) are evaluating gemcitabine/Tarceva ± Avastin (n=600) and gemcitabine ± Avastin (n=530) as first-line treatments for metastatic pancreatic cancer

Hepatocellular carcinoma (HCC)

Avastin in patients with HCC

A phase II study is investigating the safety of Avastin 5mg/kg or 10mg/kg every 2 weeks in patients with unresectable HCC

28 patients have been treated for at least 8 weeks

• two patients had serious oesophageal bleeding

• two patients discontinued therapy (one grade 3 transient ischemic attack and one grade 3 hypertension)

25 patients evaluable for efficacy

• two patients had a partial response

• 18 patients had stable disease

Preliminary assessment indicates that Avastin therapy is feasible and potentially effective in this indication

Schwartz JD, et al. Presented at: 2006 Gastrointestinal Cancers Symposium; 26–28 January 2006; San Francisco, Ca. Abstract

210

Avastin plus GemOx in HCC: study design

A phase II study is examining Avastin (10mg/kg) with GemOx (gemcitabine 100mg/m2 and oxaliplatin 85mg/m2) in patients (n=30) with HCC

Treatment

• first cycle (2 weeks): Avastin monotherapy (10mg/kg, on day 1)

• subsequent cycles (4 weeks):

Zhu AX, et al. J Clin Oncol 2005;23 (June 1 Suppl.):337s (Abstract 4120)

Agent Dose Days of treatment

Gemcitabine 100mg/m2 2 and 16

Oxaliplatin 85mg/m2 2 and 16

Avastin 10mg/kg 1 and 15

Avastin plus GemOx in HCC: efficacy

Evaluable patients (n=30*)

Partial response, n (%) 5 (17)

Stable disease, n (%) 16 (53)

Progressive disease, n (%) 6 (20)

>50 decrease in AFP, n (%) 11 (37)

3-month progression-free survival, n (%) 4 (8)

6-month progression-free survival, n (%) 3 (6)

Median time to progression (months) 4.6

Median overall survival (months) 10.7 *10 patients remain on study


Avastin plus GemOx in HCC:progression-free survival and overall

survival

1.00.80.60.40.20.0

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0 1 2 3 4 5 6 7 8 9 10 11 12

0 1 2 3 4 5 6 7 8 9 10 11 12Time (months)

Time (months)


Avastin with transarterial chemoembolisation in HCC

Pilot study examining Avastin given with TACE in HCC

Preliminary data in five patients suggest Avastin with TACE is well tolerated and shows prolonged disease control

• None of the Avastin-treated patients demonstrated significant neovascularisation

• Avastin-treated patients had smaller increases in VEGF levels following TACE than controls

• Main side effects were hypertension, proteinuria and bleeding

TACE = transarterial chemoembolisation VEGF = vascular endothelial growth factor

Britten CD, et al. J Clin Oncol 2005;23 (June 1 Suppl.):342s (Abstract 4138)

Other indications

FIGO stage I–IV epithelial

ovarian cancer(n=1,512)

Paclitaxel + carboplatin

Paclitaxel + carboplatin +

Avastin (7.5mg/kg every 3 weeks)

Phase III trial of first-line Avastin with paclitaxel and carboplatin in ovarian cancer

(ICON-7)

Primary endpoint: progression-free survival

Treatment administration (3-week cycle)• paclitaxel 175mg/m2 (3 hours) on day 1 until disease progression or for a maximum of

6 cycles• carboplatin AUC=6 i.v. on day 1 until disease progression or for a maximum of 6 cycles

Duration of treatment phases: 18 weeks 36 weeks

Avastin alone(7.5mg/kg

every 3 weeks)

Observation*


Phase III trial of Avastin in (neo)adjuvant gastric cancer (MAGIC2)

Resectable adenocarcinoma of the stomach

and gastro-oesophageal

junction(n=1,100)

ECX + Avastin

7.5mg/kgevery 3 weeks

(x3 cycles)

ECX(x3 cycles)

Primary endpoint: duration of survival

ECX regimen (3-week cycle): epirubicin 50mg/m2 i.v. day 1; cisplatin 60mg/m2 i.v. day 1; Xeloda 1,250mg/m2 orally in two divided doses days 1 to 21

Treatment breaks

1: 5-week interval between last Xeloda and surgery (8 weeks between last Avastin and surgery)

2: 8 to 10-week interval between surgery and post-operative adjuvant therapy

Avastin 10mg/kg every 4 weeks

(x6 cycles)

Treatment break: 1 2

Surgery

ECX + Avastin

7.5mg/kgevery 3 weeks

(x3 cycles)

ECX(x3 cycles)

Neoadjuvant Adjuvant Maintenance

Follow

up

Summary

Avastin adds consistent benefit when combined with standard first-line chemotherapies for different cancer types

• trials to date have demonstrated that Avastin combined with chemotherapy improves efficacy, including response rate, time to progression and survival, compared with chemotherapy alone

Avastin (10mg/kg) monotherapy is an active agent in patients with RCC

• treatment significantly increased time to progression

Avastin has a favourable safety profile and does not exacerbate the toxicity of the therapeutic regimen with which it is combined

Phase III trials of Avastin in different cancers, including renal, pancreatic, hepatocellular and ovarian cancers are ongoing/planned

anti-angiogenic therapy and other solid tumours alfredo zurlo roche, basel, switzerland

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