Prognostic Factors for mRCC:Relevance in Clinical Practice

Daniel Heng MD MPH FRCPCChair, GU Tumor Group

Tom Baker Cancer CenterUniversity of Calgary

Prognostic FactorsPatient Factors

Performance StatusSymptoms

ProinflammatoryMarkers

IL-6ESR

NeutrophiliaThrombocytosis

C-reactive proteinTumor Burden

Prior nephrectomySites of metastasesBone / Liver MetastasesLDHAnemiaCalciumSodium

Treatment-relatedFactors

Prior therapyPrior radiotherapy

Disease-free intervalDiagnosis to treatment interval

Patient X

Patient Y

Patient Z

MSKCC Prognostic Profiles

Motzer et al JCO 2002

IKCWG Prognostic Criteria

Manola et al Clin Cancer Res 2011

International mRCC Database ConsortiumCurrently includes 3700 patients from 25 institutions

Int’l mRCC Database Consortium Prognostic Factors

AnemiaHypercalcemia

NeutrophiliaThrombocytosis

KPS < 80%Dx to Tx Interval <1yr

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

Heng et al Lancet Oncology 2013

Prognostic Factors: Targeted Therapy Era

43 months

8 months

23 months

Benchmarks from IMDCPopulation (Data from IMDC) PFS (mon)

(95% CI)OS (mon) (95%CI)

1st line therapy (all pts) 7.2 (6.7-7.7)n=2659

20.9 (19.6-22.5)n=2705

1st line therapy in intermediate/poor risk patients & diagnosis to treatment interval < 1 year (similar to ADAPT (AGS003) pts)

5.6 (5.3-6.1)n=1174

14.7 (13.3-16.5)n=1189

1st line therapy in patients with prior nephrectomy (similar to TIVO-1 (Tivozanib) pt)

8.2 (7.8-8.6)n=2080

24.8 (23.1-27.3)n=2117

2nd line therapy (similar to INTORSECT patients)

3.9 (3.6-4.3)n=1151

13.0 (12.2-14.7)n=1157

3rd line therapy (all pts) 4.0 (3.4-4.5)n=425

12.1 (10.7-13.9)n=455

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=14018.0 (11.8-24.0)

n=147Ko et al BJC 2014

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

Harshman et al Lancet Oncol 2012

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

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

Iacovelli et al EJC 2013

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 Nephrectomy3245 mRCC patients

982/1658 (59%) CytoreductiveNephrectomy

676/1658 (41%)No nephrectomy

EXCLUDED 1587 (49%) w/ nephrectomy

prior to metastases

2569 (79%) patients with nephrectomy

FINAL NUMBERS

Overall Survival

Cytoreductive nephrectomy

No Cytoreductive nephrectomy

Median OS 20.6 vs 9.5 months (p<0.0001)Adjusted HR 0.60 (95%CI 0.52-0.69, p<0.0001)

Ove

rall

Sur

viva

l

Months Since Initiation of Targeted Therapy

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

Incremental BenefitOverall Survival (Months)

No CN OS (Months)

CN OS (Months)

P-value

< 24 7.1n=456

12.3n=480

<0.0001

<18 6.7n=430

10.0n=395

<0.0001

<12 5.5n=366

7.3n=290

<0.0001

<9 4.5n=303

5.5n=218

0.0027

<6 3.2n=230

4.0n=151

0.0084

<3 2.1n=118

2.2n=71

0.9429

Incremental BenefitOverall Survival (Months)

No CN OS (Months)

CN OS (Months)

P-value Incremental Benefit

(Months)< 24 7.1

n=45612.3

n=480<0.0001 +5.2

<18 6.7n=430

10.0n=395

<0.0001 +3.3

<12 5.5n=366

7.3n=290

<0.0001 +2.2

<9 4.5n=303

5.5n=218

0.0027 +1.0

<6 3.2n=230

4.0n=151

0.0084 +0.8

<3 2.1n=118

2.2n=71

0.9429 +0.1

Incremental BenefitOverall Survival (Months)

No CN OS (Months)

CN OS (Months)

P-value Incremental Benefit

(Months)

Hazard Ratio Adjusted for IMDC Criteria

< 24 7.1n=456

12.3n=480

<0.0001 +5.2 0.72 (0.62-0.85) p<0.0001

<18 6.7n=430

10.0n=395

<0.0001 +3.3 0.85 (0.72-1.00) p=0.0498

<12 5.5n=366

7.3n=290

<0.0001 +2.2 0.97 (0.81-1.17) p=0.7614

<9 4.5n=303

5.5n=218

0.0027 +1.0 0.98 (0.79-1.20) p=0.8108

<6 3.2n=230

4.0n=151

0.0084 +0.8 1.02 (0.80-1.31) p=0.8561

<3 2.1n=118

2.2n=71

0.9429 +0.1 1.03 (0.72-1.46)p=0.8782

Using IMDC Prognostic Factors# of IMDC Criteria

MetNo 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

biomarkersTHANK YOU!

daniel.heng@albertahealthservices.ca