Bevacizumab in RenalCell Cancer RCC Kevin Kuzma, PharmD, BCOP Medical Science Liaison Genentech BioO

1
Bevacizumab inRenal-Cell Cancer (RCC)Kevin
Kuzma, PharmD, BCOPMedical Science
LiaisonGenentech BioOncology
2
Rationale for Targeting VEGF in RCC

• VHL gene is mutated in most hereditary RCC and
  sporadic RCC
• Consequence is VEGF overproduction
• VEGF stimulates endothelial cell growth and is a
  central factor in angiogenesis

3
Completed and Ongoing Trials in mRCC

• Completed
• Randomized, 3-arm, double-blind, phase II trial
  of bevacizumab monotherapy
• Multicenter, phase II combination bevacizumab and
  erlotinib
• Results Pending
• Randomized, phase III trial of bevacizumab plus
  IFN-?
• Randomized, double-blind, phase III of
  interferon-alpha 2b plus bevacizumab
• Randomized, double-blind, phase II trial of
  bevacizumab plus erlotinib

4
Completed Trials of Bevacizumab in Metastatic RCC
5
Phase II Trial of Bevacizumab Monotherapy in
Metastatic RCC
Low-Dose Bevacizumab (3 mg/kg, q2wk)
Placebo (n 40)
PD
Progressive Metastatic RCC (IL-2 failure or
ineligible) (N 116)
Low-Dose Bevacizumab (3 mg/kg, q2wk) (n 37)
PD
High-Dose Bevacizumab (10 mg/kg, q2wk) (n 39)
PD

• Primary end points TTP and RR
• Secondary end points survival and safety

IL-2 interleukin-2 PD progressive disease
TTP time to progression RR response rate Yang
J, et al. N Engl J Med. 2003349427-434
6
Phase II Trial of Bevacizumab in Metastatic RCC
Inclusion/Exclusion Criteria

• Inclusion criteria
• Measurable progressive metastatic clear-cell
  renal carcinoma
• ECOG performance status ?2
• Previous IL-2 therapy or not eligible for IL-2
• Exclusion criteria
• CNS disease
• Hemoptysis or history of tumor bleeding
• Therapy in the previous 4 weeks
• Ischemic vascular disease

Yang J, et al. N Engl J Med. 2003349427-434
7
Phase II Trial of Bevacizumab in Metastatic RCC
Efficacy
TTP time to progressionDetermined by Cox
proportional hazards model Duration 39, 15, 9,
6 months Yang J, et al. N Engl J Med.
2003349427-434
8
Phase II Trial of Bevacizumab in Metastatic RCC
Safety (Any Grade)
Yang J, et al. N Engl J Med. 2003349427-434
9
Phase II Trial of Bevacizumab in Metastatic RCC
Grade 3 Adverse Events

• No grade 4 adverse events were reported

Yang J, et al. N Engl J Med. 2003349427-434
10
Phase II Trial of Bevacizumab in Metastatic RCC
Conclusions

• High-dose bevacizumab (10 mg/kg, q2wk) delayed
  TTP in patients with RCC
• No significant difference in survival between
  groups
• May reflect small number of patients or trial not
  powered to detect a small/modest difference
• Predominant side effects included hypertension
  and asymptomatic proteinuria
• No thromboembolic complications seen as a single
  agent

TTP time to progression Yang J, et al. N Engl J
Med. 2003349427-434 Yang JC. Clin Cancer Res.
200410(Suppl)6367s-6370s
11
Phase II Trial of Bevacizumab in Metastatic RCC
Update

• 4 patients have received long-term bevacizumab
  therapy (3-5 years) without tumor progression
• 2/4 patients completed 2 years of high-dose
  therapy on protocol
• Bevacizumab restarted following relapse to
  baseline tumor burdens at study end
• Both patients re-attained tumor regression and
  remained stable for 3 to 3.5 years
• 2/4 patients remained stable on protocol, then
  subsequently received high-dose bevacizumab
  therapy at study end
• Both continued therapy for gt4 years and remained
  stable
• 3/4 patients have substantial proteinuria, but
  all retain normal renal function

Yang JC. Clin Cancer Res. 200410(Suppl)6367s-637
0s
12
Phase II Trial of Bevacizumab in Metastatic RCC
Conclusions From Update

• Long-term bevacizumab therapy may be feasible in
  this limited Phase II experience we find
• Some patients who relapse following
  discontinuation of bevacizumab may be to able to
  re-attain responses to therapy
• Tumor resistance to bevacizumab does not appear
  inevitable
• Toxic effects from long-term therapy in this
  study were consistent with that seen in other
  studies and consisted primarily of proteinuria

Yang JC. Clin Cancer Res. 200410(Suppl)6367s-637
0s
13
Bevacizumab/Erlotinib Phase II Combination Trial
in Metastatic RCC Rationale

• The biological heterogeneity of tumors requires a
  multifaceted approach to treatment
• The HER1/EGFR signaling cascade is thought to
  play a key role in the development of metastatic
  RCC1
• HER1/EGFR has also been shown to downregulate the
  expression of VEGF2
• Erlotinib is an orally available, small molecule
  HER1/EGFR tyrosine-kinase (TK) inhibitor

• Moch H, et al. Hum Pathol. 1997281255-1259
• Petit A, et al. Am J Pathol. 19971511523-1530

14
Bevacizumab/Erlotinib Phase II Combination Trial
in Metastatic RCC Study Schema
Continue Treatment For 12 months or until
Disease Progression
CR Week 1 2 3 4 5 6 7 8 9
PR SD
? ? ? ? ?
B B B B Re-evaluate
E
Progression
Doses B Bevacizumab 10 mg/kg, q2w, IV
infusion, E Erlotinib 150 mg PO daily
Off Treatment
CR Complete response PR partial response and
SD stable diseaseHainsworth J, et al. J Clin
Onc. 2005237889-7896.
15
Bevacizumab/Erlotinib Phase II Combination Trial
in Metastatic RCC Inclusion/Exclusion Criteria

• Inclusion criteria
• Clear cell RCC (or mixed tumors with gt75 clear
  cell component)
• Metastatic or unresectable locally recurrent
  cancer
• 0 or 1 previous chemotherapy/immunotherapy
  regimens
• ECOG performance status 0-1
• Measurable disease
• Previous nephrectomy (unless medically
  contraindicated due to advanced metastases)
• Exclusion criteria
• Previous angiogenesis inhibitors or HER1/EGFR
  inhibitors
• Active CNS metastases

Hainsworth J, et al. J Clin Onc.
2005237889-7896.
16
Bevacizumab/Erlotinib Phase II Combination Trial
in Metastatic RCC Efficacy

• 13 patients (22) had measurable decrease in
  tumor size
• Objective responses observed in lung, liver,
  bone, lymph node, and adrenal metastases
• No differences in response rate based on Motzer
  risk category or previous treatment

Hainsworth J, et al. J Clin Onc.
2005237889-7896.
17
Bevacizumab/Erlotinib Phase II Combination Trial
in Metastatic RCC Progression-Free Survival
Progression-Free Survival 12 months 44 18
months 26 Median Time to Progression 11 months

Hainsworth J, et al. J Clin Onc.
2005237889-7896.
18
Bevacizumab/Erlotinib Phase II Combination Trial
in Metastatic RCCOverall Survival
Overall Survival 12 months 78 18 months
60 Median Survival Not reached
Hainsworth J, et al. J Clin Onc.
2005237889-7896.
19
Bevacizumab/Erlotinib Phase II Combination Trial
in Metastatic RCC Safety
Hainsworth J, et al. J Clin Onc.
2005237889-7896.
20
Bevacizumab/Erlotinib Phase II Combination Trial
in Metastatic RCC Conclusions

• ORR 25 when combining bevacizumab with
  erlotinib.
• 61 of patients had stable disease 67 of these
  patients remained on treatment for gt 6 months.
• PFS (11.1 mo) and OS (NR gt 20 mo) compare
  favorably with other treatments for mRCC.
• Generally well tolerated mild-to-moderate rash,
  diarrhea, nausea, and vomiting were the most
  common side effects.
• Further studies are required to compare this
  regimen with standard regimens for mRCC.

NRNot reached Hainsworth J, et al. J Clin Onc.
2005237889-7896.
21
Ongoing Trials (Results Pending) of Bevacizumab
in Metastatic RCC
22
Bevacizumab/IFN Phase III Combination Trial in
Metastatic RCC (CALGB 90206) Rationale

• Various preclinical studies suggest that IFN is a
  weak antiangiogenic agent1
• Combining bevacizumab with IFN may result in
  synergistic antitumor activity

1. Slaton J, et al. Clin Cancer Res.
199952726-2734
23
Phase III Trial of Bevacizumab/IFN-?-2b
Combination Therapy in Metastatic RCC (CALGB
90206) Study Schema
Bevacizumab/IFN-?-2b
Previously Untreated Metastatic RCC (N 720)
IFN-?-2b alone/Placebo

• Primary endpoint survival

CALGB Cancer and Leukemia Group B
24
Phase III Trial of Bevacizumab/IFN-?-2a
Combination Therapy in Metastatic RCC (BO17705)
Study Schema
Bevacizumab/IFN-?-2a
Previously Untreated Metastatic Clear Cell RCC (N
638)
IFN-?-2a/Placebo

• Primary endpoint survival
• Secondary endpoints progression-free survival,
  time-to-progression, time to treatment failure,
  objective response rates, and safety

ROCHE TRIAL
25
Phase II Trial of Bevacizumab With or Without
Erlotinib in Metastatic RCC Study Schema (RACE)
Bevacizumab/Erlotinib
Previously Untreated Metastatic Clear Cell RCC (N
100)
Bevacizumab/Placebo

• Endpoints time-to-progression, response rate,
  duration of response, and survival

26
Bevacizumab Trials in RCC