Neoadjuvant Systemic Therapy in Metastatic Renal Cell Carcinoma - - PDF document

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neoadjuvant systemic therapy in metastatic renal cell
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Neoadjuvant Systemic Therapy in Metastatic Renal Cell Carcinoma - - PDF document

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Winship Cancer Institute of Emory University Neoadjuvant Systemic Therapy in Metastatic Renal Cell Carcinoma Patients Bradley Carthon, MD, PhD Assistant Professor, Genitourinary Medical Oncology Disclosures No disclosures 1 Cytoreductive

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1 Winship Cancer Institute of Emory University

Neoadjuvant Systemic Therapy in Metastatic Renal Cell Carcinoma Patients

Bradley Carthon, MD, PhD Assistant Professor, Genitourinary Medical Oncology

Disclosures

  • No disclosures
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2

Choueiri , T. et al. The Journal of Urology, Volume 185, Issue 1, 2011, 60

  • 66

Cytoreductive Nephrectomy Effect on OS

Flanigan et al, N Engl J Med. 2001 Dec 6;345(23):1655-9.

Interferon Era VEGF Antagonist Era

Prior Perioperative Trials In RCC

Leiter, A., & Galsky, M. Targeting Vascular Endothelial Growth Factor Receptor Signaling in Renal Cancer: The Sooner the Better? European Urology. Available Online 7 Feb., 2014. DOI: 10.1016/j.eururo.2014.02.059

Adjuvant Neo‐Adjuvant

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The Hypothesis

Neoadjuvant therapy in metastatic RCC can:

  • Occur safely in context of surgery
  • Downsize tumors
  • Spare surgery in futile patients
  • Affect PFS and possibly OS

Neoadjuvant Bevacizumab and Primary Tumor Site Response

Jonasch E et al. JCO 2009;27:4076-4081

  • N=23 Bev + Erlotinib
  • N=27 Bev alone
  • 44/50 went to surgery (88%)
  • 6/50 progressed (poor risk)
  • Greater than 50% with some reduction
  • Delayed wound Healing in 20%
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4 Neoadjuvant Bevacizumab and Primary Tumor Site Response

Jonasch E et al. JCO 2009;27:4076-4081

Neoadjuvant Bevacizumab: Outcomes and Toxicities

Jonasch E et al. JCO 2009;27:4076-4081

  • 1 complete response
  • 10% partial response
  • 58% had stable disease.
  • PFS comparable at 11.0 mos
  • OS was at 25.4 mos
  • Safely Tolerated
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Surgical Data in Patients Receiving Neoadjuvant Sunitinib Therapy in mRCC

Powles T et al. Ann Oncol 2011;22:1041-1047 Powles T et al. Ann Oncol 2011;22:1041-1047

Patient Demographics: Neoadjuvant Sunitinib in mRCC

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6 Clinical Features in Patients Receiving Neoadjuvant Sunitinib in mRCC

Powles T et al. Ann Oncol 2011;22:1041-1047 Powles T et al. Ann Oncol 2011;22:1041-1047

Response with Neoadjuvant Sunitinib in mRCC

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Metastatic RCC: MSKCC Prognostic Model

Motzer RJ et al. J Clin Oncol. 2002;20:289‐96.

Proportion Surviving

Years Following Systemic Therapy 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Risk factors:

  • Diagnosis to treatment < 1 yr
  • KPS <80
  • Low Hgb
  • High corrected calcium
  • High LDH
  • Greater than 2 sites disease

0 risk factors 1 or 2 risk factors > 3 risk factors

Kaplan-Meier curve of overall survival from initiation of VEGF targeted therapy by cytoreductive nephrectomy, and KPS 80

  • r greater ( A ) or KPS less than 80 ( B ).

Choueiri , T. et al. The Journal of Urology, Volume 185, Issue 1, 2011, 60 - 66

CN Benefit by Performance Status in Targeted Therapy Era

KPS > 80 KPS < 80

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MSKCC Criteria in Patients on Neoadjuvant Sunitinib

Powles T et al. Ann Oncol 2011;22:1041-1047

Sunitinib in Non‐Resectable Patients‐Retrospective Data

  • 19 patients with advanced RCC unsuitable for nephrectomy
  • Received 50mg Sunitnib in 4/2 pattern
  • Partial responses in 3/19; 7/19 had stable disease; 9/19 had progression.
  • 4/19 (21%) of the patients later underwent nephrectomy
  • No unexpected complications and only 1 patient discontinued treatment

due to toxicity

  • 5 patients or 25% died of disease progression within 6 mos (T3 disease and

higher and peritoneal disease)

Thomas et al. Journal of Urology, Volume 181, Issue 2, 2009, 518 - 523

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Rini et al. The Journal of Urology, Volume 187, Issue 5, 2012, 1548 - 1554

Tumor Response with Sunitinib in Locally Advanced and Metastatic RCC

  • N = 30
  • Median 28% Decrease,
  • 45% able to subsequently undergo nephrectomy

Patients with Partial Response with Neoadjuvant Sunitinib in Locally Advanced and mRCC

Rini et al. The Journal of Urology, Volume 187, Issue 5, 2012, 1548 - 1554

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10 Neoadjuvant Axitinib Therapy in RCC

Karam et al. European Urology , 2014. Phase 2 Trial of Neoadjuvant Axitinib in Patients with Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma. http://dx.doi.org/10.1016/j.eururo.2014.01.035 Waterfall plot of tumor response in percentages at 12 wk of treatment. Orange indicates partial response, and blue indicates stable disease per RECIST.

Surgical Outcomes with Neoadjuvant Axitinib in RCC

  • 22 Patients did 12 week course
  • 28.3% median reduction of diameter
  • 11/24 had Partial response
  • 13/24 stable disease
  • No progression of disease while on

axitinib

  • No grade 4 or 5 complications noted
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11 Immediate Surgery or Surgery After Suninitinib in mRCC (SURTIME)

Projected N = 458

  • Resectable

Primary

  • Metastatic

Disease

  • No T3 or T4
  • No Poor Risk
  • No Prior

Therapy October 2014 est

R a n d

  • m

i z e Immediate Nephrectomy then Sunitinib Upfront Sunitinib then Nephrectomy + Post Op Sunitinib Efficacy End Points Primary:

  • Overall PFS

Secondary

  • OS
  • Morbitidy
  • Overall RR

Take Homes on Neoadjuvant Therapy in mRCC

  • Randomized Trials and Retrospective Data Demonstrating Safety
  • Downsizing Apparent in Many Cases, converting ‘unresectable’ patients
  • Spared Surgery in Futile Patients
  • Phase III Trial Ongoing

Given Safety, Downsizing, and Ability to Spare Futile Surgery, Data Support Neoadjuvant Systemic Therapy vs. Upfront Surgery in ‘unresectable’ and metastatic RCC patients