Winship Cancer Institute of Emory University Neoadjuvant Systemic Therapy in Metastatic Renal Cell Carcinoma Patients Bradley Carthon, MD, PhD Assistant Professor, Genitourinary Medical Oncology Winship Cancer Institute, Emory University Atlanta, GA 30322
Objectives Review Data On Neoadjuvant Therapy In Metastatic RCC With Regards To: Safety Tumor Reduction Outcomes in Intermediate vs. Poor Risk Patients
Cytoreductive Nephrectomy Effect on OS Interferon Era VEGF Antagonist Era Flanigan et al, N Engl J Med. 2001 Dec 6;345(23):1655-9. Choueiri, T. et al. The Journal of Urology, Volume 185, Issue 1, 2011, 60-66
Prior Perioperative Trials In RCC Adjuvant Neo-Adjuvant 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
The Hypothesis Neoadjuvant therapy in metastatic RCC can: Occur safely in context of surgery Downsize tumors Spare surgery in futile and poor risk patients Maintain or Improve the PFS Benefit of CN
Metastatic RCC: MSKCC Prognostic Model Proportion Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 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 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years Following Systemic Therapy Motzer RJ et al. J Clin Oncol. 2002;20:289-96.
Neoadjuvant Bevacizumab and Primary Tumor Site Response N=23 Bev + Erlotinib N=27 Bev alone 6/50 progressed (poor risk) 44/50 went to surgery (88%) Delayed wound Healing in 20% Greater than 50% with some reduction Jonasch E et al. JCO 2009;27:4076-4081
Neoadjuvant Bevacizumab and Primary Tumor Site Response Jonasch E et al. JCO 2009;27:4076-4081
Neoadjuvant Bevacizumab: Outcomes and Toxicities 1 complete response 10% partial response 58% had stable disease PFS at 11.0 mos OS at 25.4 mos Safely Tolerated Jonasch E et al. JCO 2009;27:4076-4081
Patient Demographics: Neoadjuvant Sunitinib in mrcc Powles T et al. Ann Oncol 2011;22:1041-1047
Surgical Data in Patients Receiving Neoadjuvant Sunitinib Therapy in mrcc /52 Powles T et al. Ann Oncol 2011;22:1041-1047
Response with Neoadjuvant Sunitinib in mrcc Powles T et al. Ann Oncol 2011;22:1041-1047
CN Benefit by Performance Status in Targeted Therapy Era KPS > 80 KPS < 80 Kaplan-Meier curve of overall survival from initiation of VEGF targeted therapy by cytoreductive nephrectomy, and KPS 80 or greater ( A ) or KPS less than 80 ( B ). Choueiri, T. et al. The Journal of Urology, Volume 185, Issue 1, 2011, 60-66
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
Tumor Response with Sunitinib in Locally Advanced and Metastatic RCC N = 30 Median 28% Decrease, 45% able to subsequently undergo nephrectomy Rini et al. The Journal of Urology, Volume 187, Issue 5, 2012, 1548-1554
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
Neoadjuvant Axitinib Therapy in RCC Waterfall plot of tumor response in percentages at 12 wk of treatment. Orange indicates partial response, and blue indicates stable disease per RECIST. 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
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
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 o m i z e Immediate Nephrectomy then Sunitinib Upfront Sunitinib then Nephrectomy + Post Op Sunitinib Efficacy End Points Primary: Overall PFS Secondary OS Morbidity Overall RR
Take Homes on Neoadjuvant Therapy in mrcc Randomized Trials and Retrospective Data Demonstrate Safety Downsizing Apparent in Many Cases, converting Unresectable patients Spared Surgery in Futile, Poor Risk Patients Phase III Trial Ongoing Given Safety, Downsizing, and Ability to Spare Futile Surgery, Data Supports Neoadjuvant Systemic Therapy vs. Upfront Surgery in Unresectable and Metastatic RCC patients