Anti-angiogenic therapy and other solid tumours Alfredo Zurlo Roche, Basel, Switzerland.
-
Upload
ursula-mills -
Category
Documents
-
view
218 -
download
3
Transcript of 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)
Yang JC, et al. N Engl J Med 2003;349:427–34
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
Yang JC, et al. N Engl J Med 2003;349:427–34
2.5 4.8
Based on audited PD data where available
Phase II trial of Avastin in RCC: safety (any grade)
Yang JC, et al. N Engl J Med 2003;349:427–34
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
Spigel DR, et al. J Clin Oncol 2005;23(June 1 Suppl.):387s (Abstract 4540)
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)
Spigel DR, et al. J Clin Oncol 2005;23(June 1 Suppl.):387s (Abstract 4540)
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
Kindler HL, et al. J Clin Oncol 2005;23:8033–40
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)
Kindler HL, et al. J Clin Oncol 2005;23:8033–40
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
Kindler HL, et al. J Clin Oncol 2005;23:8033–40
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
*No cross over will be permitted
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
Zhu AX, et al. J Clin Oncol 2005;23 (June 1 Suppl.):337s (Abstract 4120)
Avastin plus GemOx in HCC:progression-free survival and overall
survival
1.00.80.60.40.20.0
Pro
babili
ty o
f bein
gpro
gre
ssio
n-f
ree
1.00.80.60.40.20.0
Pro
babili
ty o
f su
rviv
al
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)
Zhu AX, et al. J Clin Oncol 2005;23 (June 1 Suppl.):337s (Abstract 4120)
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*
*No cross over will be permitted
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