Prognostic Factors for mrcc: Relevance in Clinical Practice

Prognostic Factors for mrcc: Relevance in Clinical Practice Daniel Heng MD MPH FRCPC Chair, GU Tumor Group Tom Baker Cancer Center University of Calgary

Prognostic Factors Patient Factors Performance Status Symptoms Tumor Burden Prior nephrectomy Sites of metastases Bone / Liver Metastases LDH Anemia Calcium Sodium Patient X Patient Y Proinflammatory Markers IL-6 ESR Neutrophilia Thrombocytosis C-reactive protein Treatment-related Patient Z Factors Prior therapy Prior radiotherapy Disease-free interval Diagnosis to treatment interval

MSKCC Prognostic Profiles Motzer et al JCO 2002

IKCWG Prognostic Criteria Manola et al Clin Cancer Res 2011

International mrcc Database Consortium Currently includes 3700 patients from 25 institutions

Int l mrcc Database Consortium Prognostic Factors KPS < 80% Dx to Tx Interval <1yr Anemia Hypercalcemia Neutrophilia Thrombocytosis Heng et al J Clin Oncol 2009

Prognostic Factors If patient has 0 factors: Favorable Prognosis If patient has 1-2 factors: Intermediate Prognosis If patient has 3-6 factors: Poor Prognosis

Prognostic Factors: Targeted Therapy Era Heng et al Lancet Oncology 2013 43 months 23 months 8 months

Benchmarks from IMDC Population (Data from IMDC) PFS (mon) (95% CI) 1 st line therapy (all pts) 7.2 (6.7-7.7) n=2659 1st line therapy in intermediate/poor risk patients & diagnosis to treatment interval < 1 year (similar to ADAPT 5.6 (5.3-6.1) (AGS003) pts) n=1174 OS (mon) (95%CI) 20.9 (19.6-22.5) n=2705 14.7 (13.3-16.5) n=1189 1st line therapy in patients with prior nephrectomy (similar to TIVO-1 (Tivozanib) pt) 2nd line therapy (similar to INTORSECT patients) 8.2 (7.8-8.6) n=2080 3.9 (3.6-4.3) n=1151 24.8 (23.1-27.3) n=2117 13.0 (12.2-14.7) n=1157 3rd line therapy (all pts) 4.0 (3.4-4.5) n=425 3rd line therapy in patients with 1 prior VEGF and 1 prior mtor inhibitor (similar to GOLD (dovitinib) pts) 4.4 (3.3-5.2) n=140 12.1 (10.7-13.9) n=455 18.0 (11.8-24.0) n=147 Ko et al BJC 2014

Harshman et al Lancet Oncol 2012 Conditional Survival Our prognostic criteria are used at the initiation of treatment How does survival change as you survive longer? How does survival change as you survive past the median in your risk group?

Harshman et al Lancet Oncol 2012 Survival of each risk group over time survived already

Conditional Survival in SEER Bianchi et al BJU 2013

The future of prognostication Reached the ceiling of clinical variables Need biologic markers to add to the accuracy of existing models IMDC model + X + Y to improve accuracy

Cancer Genome Atlas Research Network Nature 2013

Why are Prognostic Factors Important?

Prognostic Factors Important for patient counseling Will you live < 1 year or > 1 year? Important for clinical trial risk stratification and retrospective study adjustment methods

Iacovelli et al EJC 2013 Italian Database 281/2065 had 3 lines of targeted therapy VEGF VEGF mtor vs VEGF mtor VEGF HR 2.59 (1.59-4.22) after adjusting for prognostic criteria Assumes patients make it to three lines of therapy No axitinib in study

Prognostic Factors Important for planning therapy We use temsirolimus for poor risk patients Is active surveillance appropriate for small bulk, not growing, favorable risk, highly selected patients Is cytoreductive nephrectomy appropriate?

Cytoreductive Nephrectomy 3245 mrcc patients 676/1658 (41%) No nephrectomy 2569 (79%) patients with nephrectomy 982/1658 (59%) Cytoreductive Nephrectomy EXCLUDED 1587 (49%) w/ nephrectomy prior to metastases FINAL NUMBERS

Overall Survival Overall Survival Median OS 20.6 vs 9.5 months (p<0.0001) Adjusted HR 0.60 (95%CI 0.52-0.69, p<0.0001) Cytoreductive nephrectomy No Cytoreductive nephrectomy Months Since Initiation of Targeted Therapy

HR adjusted for IMDC criteria: 0.60 (95%CI 0.52-0.69, p<0.0001)

Incremental Benefit Overall Survival (Months) No CN OS (Months) < 24 7.1 n=456 <18 6.7 n=430 <12 5.5 n=366 <9 4.5 n=303 <6 3.2 n=230 <3 2.1 n=118 CN OS (Months) 12.3 n=480 10.0 n=395 7.3 n=290 5.5 n=218 4.0 n=151 2.2 n=71 P-value <0.0001 <0.0001 <0.0001 0.0027 0.0084 0.9429

Incremental Benefit Overall Survival (Months) No CN OS (Months) < 24 7.1 n=456 <18 6.7 n=430 <12 5.5 n=366 <9 4.5 n=303 <6 3.2 n=230 <3 2.1 n=118 CN OS (Months) 12.3 n=480 10.0 n=395 7.3 n=290 5.5 n=218 4.0 n=151 2.2 n=71 P-value Incremental Benefit (Months) <0.0001 +5.2 <0.0001 +3.3 <0.0001 +2.2 0.0027 +1.0 0.0084 +0.8 0.9429 +0.1

Incremental Benefit Overall Survival (Months) No CN OS (Months) < 24 7.1 n=456 <18 6.7 n=430 <12 5.5 n=366 <9 4.5 n=303 <6 3.2 n=230 <3 2.1 n=118 CN OS (Months) 12.3 n=480 10.0 n=395 7.3 n=290 5.5 n=218 4.0 n=151 2.2 n=71 P-value Incremental Benefit (Months) Hazard Ratio Adjusted for IMDC Criteria <0.0001 +5.2 0.72 (0.62-0.85) p<0.0001 <0.0001 +3.3 0.85 (0.72-1.00) p=0.0498 <0.0001 +2.2 0.97 (0.81-1.17) p=0.7614 0.0027 +1.0 0.98 (0.79-1.20) p=0.8108 0.0084 +0.8 1.02 (0.80-1.31) p=0.8561 0.9429 +0.1 1.03 (0.72-1.46) p=0.8782

Using IMDC Prognostic Factors # of IMDC Criteria Met No CN OS months (N) CN OS months (N) P value 0 92% (65/71) patients had CN, insufficient number to compare 1 22.5 (n=72) 30.4 (n=178) 0.0024 2 10.2 (n=143) 20.2 (n=253) <0.0001 3 10.0 (n=113) 15.9 (n=106) <0.0001 4 5.4 (n=103) 6.0 (n=67) 0.1664 5 3.6 (n=36) 2.8 (n=14) 0.5044 6 25% (3/12) patients had CN, insufficient number to compare

Cytoreductive Nephrectomy Perhaps not appropriate in patients with survival estimated to be < 1 year Perhaps not appropriate in patients with 4 or more adverse prognostic factors

Prognosis Is important for patient counseling, study design, and planning therapy Prognosis is dynamic Prognosis needs to be improved with biomarkers THANK YOU! daniel.heng@albertahealthservices.ca