frank griesinger professor at the university of göttingen and chair of the department of medical...
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Frank GriesingerProfessor at the University of Göttingen and Chair of the Department
of Medical Oncology, Pius-Hospital, Oldenburg, Germany
Professor of Internal Medicine and Haematology and Medical Oncology at the University of Göttingen
Chair of the Department of Medical Oncology at the Pius-Hospital, Oldenburg, Germany
Member of the German Cancer Society and the steering committee of the German Lung Cancer Study Group
Co-author of more than 50 papers in international peer-reviewed journals
Pius-Hospital Oldenburg
Anti-vascular endothelial growth factor (VEGF) therapy: a
revolution in care for patients with renal cell cancer (RCC)
Frank Griesinger
Pius-Hospital OldenburgGermany
Historical approaches to RCC therapyStage of RCC
Therapeutic goals
Primary or first-line treatment options
Further or second-line therapy options
I–III Cure Radical ornephron-sparing nephrectomy
IL-2 or IFN immunotherapy at relapseBSC
IV Extend survivalStabilise diseasePalliation
Nephrectomy(if possible) IL-2 or IFN immunotherapyCytoreductive nephrectomy in appropriate patients prior to immunotherapy
BSC (including radiotherapy, metastasectomy or bisphosphonates for bone metastases)
IL-2 = interleukin-2; IFN = interferon alpha; BSC = best supportive care
Historical approaches to RCC therapy
Nephrectomy is curative in a proportion of patients diagnosed early
30% of patients present with metastatic disease (Stage IV)
RCC is insensitive to radiotherapy, chemotherapy and hormone therapy
Immunotherapy produces a response rate of up to 20% and median overall survival (OS) of 13 months
New therapeutic options are required
Rationale for anti-VEGF therapy in RCC
Adapted from Linehan WM, et al. J Urol 2003;170:2163–72
Tagged fordegradation
Normoxia Hypoxia
HIF
HIF accumulation
VEGF TGF, PDGF
Angiogenesis Autocrine growth stimulation
VHLprotein
VHLcomplex
X
HIFα degradation
Disruption of VHLprotein prohibits thepathway leading to HIFdegradation causing HIF accumulation
VHL = von Hippel-LindauHIF = hypoxia-inducible factor-TGF = transforming growth factor-PDGF = platelet-derived growth factor
Phase II trial of bevacizumab monotherapy in RCC (AVF0890g): study design
Primary endpoints: time to progression and response rate
Secondary endpoints: survival and safety
Initial trials of bevacizumab in RCC: AVF0890g
Progressive metastatic RCC (IL-2 failure or
ineligible)
Placebo (n=40)
Bevacizumab 10mg/kg every 2 weeks (n=39)
Bevacizumab 3mg/kg every 2 weeks (n=37)
Bevacizumab 3mg/kg every
2 weeksPD
PD
PD
Yang JC, et al. N Engl J Med 2003;349:427–34PD = progression of disease
Pat
ien
ts p
rog
ress
ion
-fre
e (%
)
Bevacizumab 10mg/kg every 2 weeks; p<0.001
Bevacizumab 3mg/kg every 2 weeks
Placebo
Months from date on-study0 6 12 18 24 30 36
100
80
60
40
20
0
Single-agent bevacizumab improves PFS in mRCC
PFS = progression-free survivalmRCC = metastatic renal cell cancer Yang JC, et al. N Engl J Med 2003;349:427–34
2.5 4.83.0
Safety profile of bevacizumab in mRCC
Adverse event (AE)
Bevacizumabsecond-line1
Bevacizumabfirst-line2
grade 3/4 grade 3/4
Proteinuria (%) 8 6Hypertension (%) 21 26Bleeding (%) 0 4Chest pain (%) 5 –Gastrointestinal perforation (%) – 0Neutropenia (%) – 0Diarrhoea (%) – 0Hand-foot syndrome (HFS) (%) – 0Nausea and vomiting (%) – 0Stomatitis (%) – 0
1Yang JC, et al. N Engl J Med 2003;349:427–342Bukowski RM, et al. J Clin Oncol 2007;25:4536–41
Bevacizumab/placebo 10mg/kg i.v. every 2 weeks until progression
IFN-2a 9MIU s.c. 3 times weekly (maximum of 52 weeks) (dose reduction allowed)
Multinational ex-US study: 101 study sites in 18 countries
Stratification factors: country and Motzer score
Bevacizumab + IFN-2a (n=327)
IFN-2a + placebo (n=322)
PD
PD
Escudier B, et al. Lancet 2007;370:2103–11
RCC patients(n=649)
i.v. = intravenous; IFN-2a = interferon-alpha2aMIU = million international unitss.c. = subcutaneous
1:1
Phase III trial of first-line bevacizumabin RCC (AVOREN)
Primary objective To evaluate the efficacy of the combination of
bevacizumab plus IFN-2a as compared with IFN-2a alone based on OS
Secondary objectives PFS, time to disease progression, time to treatment failure
and objective response rates of bevacizumab plus IFN-2a compared with IFN-2a alone
Safety profile of bevacizumab plus IFN-2a versus IFN-2a alone
Pharmacokinetics and pharmacodynamics of bevacizumab
Objectives
Escudier B, et al. Lancet 2007;370:2103–11
Inclusion criteria Confirmed metastatic RCC with >50% clear cell histology Nephrectomy KPS of 70% Measurable or non-measurable disease (according to RECIST)
Exclusion criteria Prior systemic treatment for metastatic RCC disease Evidence of current CNS metastases or spinal cord compression Evidence of bleeding diathesis or coagulopathy Full therapeutic doses of oral or parenteral anticoagulants
KPS = Karnofsky performance statusRECIST = Response Evaluation Criteria in Solid Tumors CNS = central nervous system
Key eligibility criteria
Escudier B, et al. Lancet 2007;370:2103–11
Statistical design and interim analysis Sample size calculation
– 80% power to detect an improvement in OS from 13 to 17 months with a HR of 0.76 at a significance level of 0.05
– required 445 events among 638 patients
– interim analysis prespecified at 250 events
A final PFS analysis to occur at the time of an interim OS analysis
– ≥90% power to detect an improvement in PFS with a HR of 0.71 at a significance level of 0.05
– the study would be unblinded after the final PFS analysis and continued on survival follow-up
HR = hazard ratio Escudier B, et al. Lancet 2007;370:2103–11
VariableIFN-2a
+ placebo (n=322)Bevacizumab
+ IFN-2a (n=327)
Female (%)Male (%)
2773
3268
Median age, years (range) 60 (18–81) 61 (30–82)
KPS (%) 100 90 80 70
393916 7
443218
6
Sites of metastases (%) Lung Lymph nodes Bone Liver
59362019
62341818
Motzer risk score (%) Favourable Intermediate Poor Not available
2956 8 7
275699
*Based on intent-to-treat (ITT) population
Patient characteristics*
Escudier B, et al. Lancet 2007;370:2103–11
Response
IFN-2a + placebo
(n=289)
Bevacizumab + IFN-2a
(n=306)
Overall response rate (RR) (%)*
Complete response (CR)
Partial response (PR)
13
2
11
31
1
30p=0.0001
Median duration of response(months)
Median duration of stable disease (SD) (months)
11
7
13
10*Patients with measurable disease only
Tumour response
Escudier B, et al. Lancet 2007;370:2103–11
HR=0.63, (95% CI: (0.52–0.75) p<0.0001Median PFS:
Bevacizumab + IFN = 10.2 months
Placebo + IFN = 5.4 months
Pro
bab
ility
of
bei
ng
p
rog
ress
ion
-fre
e
Number ofpatients at risk
Placebo + IFN 322 137 59 15 0
Bevacizumab+ IFN 327 196 107 18 0
Months0 6 12 18 24
1.0
0.8
0.6
0.4
0.2
05.4 10.2
Bevacizumab combined with IFN improves PFS over IFN alone
IFN = interferon; CI = confidence interval Escudier B, et al. Lancet 2007;370:2103–11
Baseline risk factor Total (n) HR
All patients 649 0.63
Sex Female Male
193456
0.600.64
Age (years) <40 40–64 65
26384239
0.650.540.77
Number of metastatic sites 2 >2
394252
0.670.54
Motzer score Favourable Intermediate Poor
18036354
0.600.550.81
0.2 0.5 1 2 5
HR
Subgroup analysis for PFS in AVOREN
Escudier B, et al. Lancet 2007;370:2103–11
*Stratified by Motzer score and region category; prespecified level of significance p=0.0056;
HR=0.75 (95% CI: 0.58–0.97), p<0.0267*Median OS:
Bevacizumab + IFN = not reached
Placebo + IFN = 19.8 months
Pro
bab
ility
of
surv
ival
Number ofpatients at risk
Placebo + IFN 322 262 176 53 1 0Bevacizumab+ IFN 327 275 197 60 2 0
Months0 6 12 18 24 30
1.0
0.8
0.6
0.4
0.2
019.8
Interim analysis of OS(251 of 450 scheduled events)
Escudier B, et al. Lancet 2007;370:2103–11
IFN-2a + placebo
(n=304)
Bevacizumab + IFN-2a
(n=337)
Median duration of treatment Bevacizumab/placebo (months) Dose intensity (%) IFN-2a (months) Dose intensity (%)
596 596
1092 891
Grade ≥3 AE (%)Serious AE
4516
6029
Discontinuation due to AE (%)Any study drugBevacizumab/placeboIFN-2a
12 612
281923
Death not due to PD (%) 2 2†
*Based on safety population†3/8 deaths were possibly related to bevacizumab
Overview of AEs*
Escudier B, et al. Lancet 2007;370:2103–11
Number of patients (%)
AE
IFN-2a+ placebo
(n=304)
Bevacizumab+ IFN-2a(n=337)
Any grade 3/4 AE 137 (45) 203 (60) Fatigue/asthenia/malaise 46 (15) 76 (23) Proteinuria 0 (0) 22 (6.5)
Neutropenia 7 (2) 15 (4) Hypertension 2 (0.7) 13 (3.9) Haemorrhage 1 (0.3) 11 (3.3) Diarrhoea 3 (<1) 7 (2) Venous thromboembolism 2 (0.7) 6 (1.8) Gastrointestinal perforation 0 (0) 5 (1.5) Arterial ischaemia 1 (0.3) 4 (1.2) HFS 0 (0) 0 (0) Stomatitis/mucosal inflammation 0 (0) 0 (0)
*Based on safety population
Selected grade 3/4 AEs*
Escudier B, et al. Lancet 2007;370:2103–11
Analysis of efficacy and safety of reduced-dose IFN in AVOREN
The standard dose of IFN-2a was 9MIU 3 times weekly s.c.
IFN-2a was withheld if grade 3 AE attributable to IFN-2a developed
IFN-2a was restarted with one dose level reduction (6MIU) if toxicity resolved to grade <1 within the first 28 days
If a subsequent grade 3 AE developed, IFN-2a dose was reduced to 3MIU (3 times weekly)
No re-escalation of the IFN-2a dose was allowed
Concurrent bevacizumab was maintained at the standard dose without reduction
Tumour response and clinical benefit in bevacizumab-treated patients in the total
and reduced-dose IFN populations
Total population Reduced-dose population
Placebo (n=289)
Bevacizumab (n=306)
Placebo (n=94)
Bevacizumab (n=124)
Response, n (%) OR CR PR
37 (13) 6 (2)
31 (11)
96 (31) 4 (1)
92 (30)
16 (17)4 (4)
12 (13)
39 (32) 2 (2)
37 (30)
SD, n (%) 144 (50) 141 (46) 58 (62) 71 (57)
Clinical benefit,* n (%) 181 (63) 237 (77) 74 (79) 110 (89)
PD, n (%) Not evaluable, n
95 (33) 13
61 (20) 8
18 (19) 2
13 (11) 1
Median duration of tumour response, months 11.1 13.5 9.1 13.6
*Clinical benefit = OR rate + SD rate; OR =overall response
Melichar B, et al. Eur J Cancer Suppl 2007;5:304 (Abstract 4518)
Number ofpatients at risk
Placebo + IFN 327 259 196 170 107 54 18 6 0Bevacizumab+ IFN 131 118 96 88 55 28 12 4 0
1.0
0.8
0.6
0.4
0.2
0
PF
S e
stim
ate
0 3 6 9 12 15 18 21 24
Months
Bevacizumab + reduced dose IFN-2aAll bevacizumab + IFN-2a patients
PFS for bevacizumab-treated patients in the total and reduced-dose populations
Grade 3 AEs 6 weeks before and 6 weeks after IFN dose reduction
0
10
20
30
40
Pat
ien
ts (
%)
BevacizumabPlacebo
6 weeks before reduction6 weeks after reduction
AVOREN trial – overall conclusions
Addition of bevacizumab to IFN statistically and clinically significantly improves PFS and tumour response, with a trend in favour of improved survival
Bevacizumab with IFN significantly improves PFS and RR in predefined patient subgroups
Treatment was well tolerated and no new toxicities emerged outside of those known with IFN and bevacizumab
IFN dose can be reduced to manage side effects while maintaining observed improvements in response rateand PFS
After AVOREN, where are we now in RCC?
Drug Target Description Clinical development stage in RCC
Bevacizumab VEGF Recombinant humanised monoclonal antibody
Bevacizumab + IFNα is approved in the EU for use in first-line therapy of advanced and/or metastatic RCC
Sunitinib VEGFR, PDGFR,c-KIT, Flt-3
Small-molecular TKI
Approved in the USA for advanced RCCApproved in the EU for advanced and/or metastatic RCC after failure of IFNα or IL-2 – now extended to include first-line usePhase III (adjuvant)
Sorafenib VEGFR-2,VEGFR-3, PDGFR, c-KIT, Flt-3, RET, RAF-1,
Dual-action multikinase inhibitor
Approved in the USA for advanced RCCApproved in the EU for advanced RCCfollowing failure or unsuitability for immunotherapyPhase III (adjuvant)
Temsirolimus mTOR Rapamycin ester inhibitor of mTOR
Approved in the USA for advanced RCCApproved in EU as first-line therapy for poor-risk advanced RCC
Adapted from Bellmunt J. Eur Urol 2007;(Suppl. 6):484–91
VEGFR = VEGF receptor; PDGFR = PDGF receptor; Flt-3 = fms-like tyrosine kinase-3;TKI = tyrosine-kinase inhibitor; mTOR = mammalian target of rapamycin
After AVOREN, where are we now in RCC? (cont’d)
Rapid expansion in available active therapies
– cytokines → bevacizumab, temsirolimus, sorafenib and sunitinib
Significant improvements in some outcomes: response rate and PFS but not (yet) OS or cure
Some questions still need to be addressed
– does immunotherapy have a long-term role?
– how can these agents be combined and/or sequenced, i.e. develop multiple lines of therapy?
– can therapy be sequenced to maximise survival?
– can patients most likely to respond be identified?
Combining novel agents with IFNα
Study Therapy ConclusionsEscudier1
Bevacizumab/IFN vs IFN
Bevacizumab plus IFN significantly improves PFS and RR compared with IFN alone; IFN side effects easily manageable whilst maintaining benefits
Hudes2 Temsirolimus vs IFN vs temsirolimus/IFN
Combining temsirolimus with IFN does not improve outcomes compared to temsirolimus alone
Bracarda3 Sorafenib/IFN (9MU) vs sorafenib/IFN (3MU)
Sorafenib does not add to the benefit of IFN first-line
Kondagunta4 Sunitinib/IFN (with dose interruptions and reductions)
Sunitinib and IFN tolerable only at reduced doses of both agents; efficacy no better than IFN alone
1Escudier B, et al. Lancet 2007;370:2103–11; 2Hudes G, et al. N Engl J Med 2007;356:2271–81; 3Bracarda S, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5100)
4Kondagunta GV, et al. J Clin Oncol 2007;25(Suppl. 1):260s (Abstract 5101)
What is the role of immunotherapy?
Immunotherapy produces durable CRs
– novel agents impact OR, SD and PFS
Combining bevacizumab with immunotherapy
– IFN (AVOREN)• improved PFS and RR, flexible dosing
– IL-2• well tolerated with promising antitumour activity
Immunotherapy still has a role as part of first-line therapy, but not as a single agent
Ernstoff MS, et al. J Clin Oncol 2007;25(Suppl. 1):651s (Abstract 15524)Garcia JA, et al. J Clin Oncol 2007;25(Suppl. 1):260s (Abstract 5103)
Trials of bevacizumab in combination with novel agents in RCC: efficacy
Combination n Efficacy
Bevacizumab + sunitinib1
20 Seven PRs and seven SDs (two with tumour reductions >30% but not confirmed due to withdrawal)
Bevacizumab + sorafenib2
24 Few patients with progressive disease ~40% partial response rate 15% of patients with near partial response
Bevacizumab + temsirolimus3
12 Eight PRs and three SDs
1Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099) 2Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031)
3Merchan JR, et al. J Clin Oncol 2007;25 (Suppl. 1):243s (Abstract 5034)
Trials of bevacizumab in combination with novel agents in RCC: safety
Combination n Safety findings
Bevacizumab + sunitinib1
20 Two DLTs (diffuse haemorrhage, epistaxis) Phase II dose will be bevacizumab 10mg/kg
plus either sunitinib 37.5mg or 50mg
Bevacizumab + sorafenib2
24 Sorafenib-associated DLTs (HFS and anorexia) prevented full-dose therapy
Optimal dosing to be defined
Bevacizumab + temsirolimus3
12 Full doses of both agents (bevacizumab
10mg/kg, temsirolimus 25mg) tolerated DLTs = grade 3 hypertriglyceridaemia,
mucositis AE profile additive
DLT = dose limiting toxicity
1Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099)2Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031)
3Merchan JR, et al. J Clin Oncol 2007;25(Suppl. 1):243s (Abstract 5034)
Data suggest bevacizumab is an excellent partner for combination therapy
Combining bevacizumab 10mg/kg with cytokines, sunitinib or temsirolimus is feasible1–3 (further studies needed for sorafenib)
No definitive data regarding combinations of sorafenib, sunitinib and temsirolimus in RCC available
VEGF increase with TKIs; therefore, rationale for addition of bevacizumab
1Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099)2Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031)
3Azad NS, et al. J Clin Oncol 2006;24(Suppl. 1):121s (Abstract 3004)
Rationale for sequencing therapy
Efficacy of different agents depends on when they are used
– cytokine use predominantly first line; no accepted role as second-line therapy
– bevacizumab more effective first line than later
OS likely to be maximised by use of all available active agents
Use of agents that inhibit different pathways may be expected to have further efficacy following progression
Summary of data for anti-VEGF(R) therapy following prior anti-VEGF(R) therapy
Trial n Comments
Sunitinib following bevacizumab1
61 14 PRs, 36 SDs; PFS 30 weeks No association between sensitivity to sunitinib
and prior response to bevacizumab
Sorafenib following bevacizumab2
197 PR 2.5%, SD 77.5%
Sequential sorafeniband sunitinib3
90 PR to sunitinib after sorafenib = 15% PR to sorafenib after sunitinib = 9% Six PDs, three PRs with both drugs
Sequential sorafeniband sunitinib4
37 PR to sunitinib after sorafenib = 17% PR to sorafenib after sunitinib = not reached Median duration of SD=32 and 8 weeks
1Hutson TE, et al. Eur J Cancer Suppl 2007;5:301 (Abstract 4510); 2Drabkin HA, et al. J Clin Oncol 2007;25(Suppl. 1):245s (Abstract 5041); 3Sablin MP, et al. J Clin Oncol 2007;25(Suppl. 1):244s
(Abstract 5038); 4Dham A, et al. J Clin Oncol 2007;25(Suppl. 1):261s (Abstract 5106)
What do data suggest about sequencing therapy for RCC?
Cytokines should be used first line
All novel agents are effective as second-line therapy after cytokines
– efficacy appears to differ, sunitinib1 and sorafenib1–3 having greater efficacy than bevacizumab
Sorafenib and sunitinib are active in second-line after bevacizumab4
and also each other
Sequencing available therapies should be investigated further to maximise use of all available therapies
– current data suggest that first-line bevacizumab-based combinations may be optimal, allowing patients to receive subsequent sunitinib/sorafenib-based therapy
1Tamaskar I, et al. J Clin Oncol 2006;24(Suppl. 1):240s (Abstract 4597)2Drabkin HA, J Clin Oncol 2007;25(Suppl. 1):245s (Abstract 5041)
3Rini BI, et al. J Clin Oncol 2006;24(Suppl. 1):222s (Abstract 4522) 4Dham A, Dudek AZ. J Clin Oncol 2007;25(Suppl. 1):261s (Abstract 5106)
Patient selection for novel agents
No evidence that VEGF status influences outcomes with VEGF-inhibiting therapy
– VEGF levels do not appear to predict for response to anti-VEGF(R) therapy
Motzer risk may affect outcomes and temsirolimus appears to be effective only in patients with poor Motzer risk
– Motzer risk designed to be used for immunotherapy
Currently, no basis on which to select patients for VEGF-inhibiting therapy
PD
Trials providing further insights: the BeST trial
Primary endpoints: PFS Secondary endpoints: safety, RR, OS, SD rate at 6 months
Metastatic RCC (stratification by prior therapy and MSKCC
risk category)
Bevacizumab 10mg/kg twice weekly (n=90)
Bevacizumab 10mg/kg twice weekly + sorafenib 200mg b.i.d. days 1–5 of 7 (n=90)
Bevacizumab 10mg/kg twice weekly + temsirolimus 25mg once weekly (n=90)
PD
PD
PD
Temsirolimus 25mg once weekly + sorafenib 200mg b.i.d. days 1–5 of 7 (n=90)
MSKCC = Memorial Sloan-Kettering Cancer Center; b.i.d. = twice daily
Global study: ~25 countries, ~200 sites
Stratification factors: nephrectomy and Motzer score
Bevacizumab + temsirolimus (n=411)
Bevacizumab + IFN-2a (n=411)
PD
RCC patients(n=822)
1:1
PD
Trials providing further insights: study 3311
Conclusions
A number of active agents now available
– complete sequence of treatment should be considered before starting first-line therapy
Data indicate that bevacizumab should be the partner of choice when considering trials of VEGF-inhibiting therapy
Bevacizumab plus IFN provides flexible treatment for patients with mRCC, allowing reduction of IFN dose to improve tolerability and manage toxicity without compromising efficacy
Trials of bevacizumab in mRCC should be performed first-line to ensure patients have further options for therapy in second- and third-line
Currently, no rationale to select patients for therapy
RCC treatment algorithm: 2007
Regimen Setting Therapy Options
Treatment-naïve patient
Motzer risk: good or intermediate
Bevacizumab IFNSunitinib
CytokinesSorafenib?
Motzer risk: poor TemsirolimusSunitinib
Sorafenib?
Treatment-refractory patient (second line)
Cytokine refractory
Sorafenib Sunitinib
Refractory to VEGF/VEGFR or mTOR inhibitors
Investigational? Sequential? TKIs or VEGF inhibitor
Modified from Bukowski RM, presented at ASCO 2007; adapted from Atkins, presented at ASCO 2006