Renal cell cancer: is immunotherapy dead

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Renal cell cancer is immunotherapy dead?

• Professor John Wagstaff
• South West Wales Cancer Institute
• Swansea
• UK

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Professor Pieter de Mulder
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Sponateous regressions

• First observed 60 years ago
• Prospective assessment
• 7 of patients
• Median duration of 2 years
• Initial watchful waiting is appropriate
• Asymptomatic patients
• Low volume disease
• Build this into clinical trial design

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Interleukin-2
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Interleukin-2Protocols used

• High dose bolus (Rosenberg)
• High dose continuous infusion (West)
• Low bolus
• Subcutaneous single agent
• SC combination (with IFN 5-FU) (Atzpodien)

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Metastatic Renal Cell Carcinoma High Dose Bolus
Interleukin-2Rosenberg NCI USA
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A meta-analysis of trials of Interleukin-2 in
metastatic renal cell cancerBaaten, Voogd
Wagstaff Eur J Cancer 2004 401127
Complete responses vs routeof administrationCIV
continuous infusionSCsubcutaneous
injectionBIVintermettent bolus injection
Duration of complete remissions
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Cytokine working partyJ. Clin. Oncol. 2003 Aug
15th

• HD IL-2 156 pts
• RR 21
• LD IL-2 150 pts
• RR 13 p0.04 vs HD
• SC IL-2
• RR 10 p0.033 vs HD

Survival of complete responders
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Carbonic Anhydrase IX Expression Predicts Outcome
ofInterleukin 2 Therapy for Renal CancerMichael
Atkins et al Clin Cancer Res 200511(10)May 15,
2005
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Allogeneic stem cell transplantation an old
beast in new clothes!
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Allogeneic stem cell transplantation an old
beast in new clothes!
Donor lymphocyte infusions in Chronic myeloid
leukaemia Dazzi et al Blood 2000 962712
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Allogeneic stem cell transplantation an old
beast in new clothes!
Allogeneic mini-stem cell transplantation
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Allogeneic stem cell transplantation an old
beast in new clothes!Childs et al, NEJM 2000
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Allogeneic stem cell transplantation in renal
cell cancerYang JC Childs R J Clin Oncol 2006
245576
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Vaccines Yang JC Childs R J Clin Oncol 2006
245576
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Interferon-a

• Introduced early 1980s
• Response rate 15-20
• Complete remissions are rare (1-2)
• Reduces risk of death at 1 year by one third

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Survival with interferonMSKCC scoring system

• Risk Factors are
• No prior nephrectomy
• KPS lt80
• Low Hb
• High corrected calcium
• High LDH

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Overview of cytokine based trials for metastatic
renal cell carcinoma
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Bevacizumab in metastatic renal cell cancer Yang
JC NEJM 2003 329427
Response rate4/39 10.3
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AVOREN TrialEscudier et al ASCO 2007 abs. nos. 3

• IFN IFN Placebo Bevacizumab
• Response Rate 13 31
• Duration of response 11 mos. 13 mos.
• Tumour shrinkage 39 70
• Progression free surv. 5.4 mos. 10.2 mos.
• Overall survival 19.8 mos. Not reached
• Grade 3/4 toxicity 45 60
• Discontinuation 12 28

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What we know what we dont!

• Majority of IFN patients got 2nd line sunitinib
• How many patients who received sunitinib got 2nd
  line cytokines what were the results?

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ASCO 2007 abs 15572 Kollmannsberger

• Retrospective analysis
• 36 IFN alone
• 23 IFN followed by SU
• 16 SU alone
• Median follow-up 6, 7.6 6.2 months
• 6 month OS 56, 72 100

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Conclusions

• Immunotherapy is not dead!!!
• Up front
• High dose IL-2
• Allogeneic stem cell transplant
• ? Interferon 1st in MSKCC risk group 0
• ? 1st line Interferon plus bevacizumab
• BUT

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What have we got?

• Interferon
• Interleukin-2
• Allogeneic stem cell transplant
• Sunitinib
• Sorafenib
• Bevacizumab
• Temsirolimus (RAD001)
• Axitinib

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Sunitinib after bevacizumab
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Sunitinib after bevacizumab
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Sunitinib after bevacizumab
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Sorafenib after bevacizumab
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Sorafenib after bevacizumab
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Possible sequencing

• 1st line
• High dose IL-2
• IFN bevacizumab
• Allogeneic stem cell transplant in partial
  responders
• Temsirolimus (MSKCC score 3)
• 2nd line
• Sunitinib
• Allogeneic stem cell transplant in partial
  responders
• 3rd line
• Sorafenib
• 4th line
• Axitinib

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