Renal cell cancer: Integrating novel agents into a therapeutic

algorithm Robert Dreicer, M.D., FACP Chairman Department of Solid Tumor Oncology Taussig Cancer InstituteCleveland ClinicProfessor of Medicine Cleveland Clinic Lerner College of Medicine

Metastatic Renal Cell Carcinoma: Initial Therapy Considerations Role of cytoreductive nephrectomy Sequential therapy Combination therapy Metastatic Kidney cancer as a

chronic disease?

Flanigan RC, et al. J Urol 171:1071 2004

Cytoreductive Nephrectomy: Current Status Debulking nephrectomy has become a standard of

care in selected patients Combined analysis of two prospective trials

demonstrated an overall survival (OS) advantage for the nephrectomy group (mean survival, 13.6 v 7.8 months for the interferon alone arm)

Appropriate candidates: ECOG performance status of 0 or 1 Resectable primary tumor representing the majority of

tumor No evidence of rapidly progressing extrarenal disease No prohibitive medical comorbidities

Cytoreductive Nephrectomy: Current Status Two randomized trials are ongoing Metastatic RCC patients randomized to

upfront nephrectomy or not followed by sunitinib for all patients

Second study is identical with the exception of delayed nephrectomy in patients initially randomly assigned to sunitinib

RCC (Clear Cell) Treatment Algorithm: 2012Setting Patients Therapy

(level 1evidence)

Other Options

(≥ level 2)

Untreated

Good/ Intermediate

risk

Sunitinib

Bevacizumab + IFN

HD IL-2

Pazopanib

Sorafenib

Clinical trial

Observation

Poor risk Temsirolimus Sunitinib

Clinical trial

Cytokine-refractory

Sorafenib Sunitinib

Bevacizumab

VEGF-R refractory

Everolimus

Axitinib

Clinical trial

Sunitinib

Sorafenib

mTOR-refractory Clinical trial Clinical trial

*Adapted from M Atkins, ASCO 2006 & R Bukowski ASCO 2007

Developed as empiric necessity As drugs came on line, they were used as salvage

therapy i.e. sorafenib followed by sunitinib Choice of initial therapy increasingly seen as

not as important given therapeutic paradigm However, some patients have bad disease and

don’t get a second line therapy The absence of data doesn’t mean it doesn’t matter

Sequential Therapy

Sequential Therapy

Sequenced monotherapy has activity in RCC Patients with the most favorable underlying biology will

have the greatest absolute overall survival as they will receive multiple active treatments

Toxicity matters Significant numbers of patients long-term

responders

A consensus definition of ‘treatment-refractory’ RCC and identification of prognostic factors would aid in the interpretation of clinical results

A critical question for sequential therapy in RCC is an understanding of the mechanism of resistance which could guide the choice of next treatment:

Target a different pathway Target the same pathway in a different way Target the same target, but more potently Take a drug holiday, then restart same drug

Sequential Therapy

* Inhibitory concentrations (kinase IC50 in nanomoles) for relevant targets

VEGFR1

VEGFR2

VEGFR3

PDGFRα

PDGFRβ

KIT FLT3 RET

Sorafenib NA 90 100 50-60 80 68 46 100-150

Sunitinib 10 4 10 5-10 10 13 1-10 100-200

Pazopanib 10 30 47 71 84 72 >1000 >1000

Axitinib 1.2 0.2 0.3 5 1.6 1.7 >1000 >1000

AV-951 0.21 0.16 0.24 1.7 1.6

BAY 73-4506 16 5 46 NR 74 7 440 1

ABT-869 3 3 35 31 48 13

The spectrum and potency of VEGF-R inhibitors is not identical

Selecting Salvage Therapy

Level 1 evidence Two phase III trials

Everolimus Axitinib

RRAANNDDOOMMIIZZAATTIIOONN

2:12:1

Everolimus Phase III

Everolimus 10 mg QD + BSC(n = 272)(n = 272)

Placebo + BSC(n = 138)(n = 138)

Disease Progression

• Metastatic RCC (clear cell component)

• Prior VEGF-R TKI with RECIST PD ≤ 6 months: sunitinib (50%), sorafenib (25%) or both (25%) (other tx. permitted)

• MSKCC favorable (30%), intermediate (55%), or poor risk (15%)

Hazard ratio = 0.30 95% CI [0.22, 0.40]

Median PFSEverolimus: 4.0 moPlacebo: 1.9 mo

Axitinib vs Sorafenib as Second-line Therapy for Metastatic Renal Cell Carcinoma: Results of the Phase 3 AXIS Trial

Treatment-refractory metastatic RCC

Axitinib 5 mg BID†

1:1

Sorafenib 400 mg BID

Randomization stratified by ECOG PS and type of prior treatment

†Starting dose 5 mg BID with option for dose titration to 10 mg BID

Rini B, et al. Lancet 2011 378:9807

Rini B, et al. Lancet 2011 378:9807

Management of Advanced RCC: Current Status More than 5 years into the “novel agent”

paradigm in RCC, some sobering thoughts We don’t cure folks Toxicity/cost are issues Drug holidays Timing of therapy ( does everyone need treatment

immediately) The treatment should not be worse than the disease

Accurate assessment of disease progression Not always what the radiology report states

Disparity in Reporting of Progression in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib According to Radiology and Medical Oncology The medical records of a subset of mRCC

patients treated at the Cleveland Clinic who had received sunitinib for > 6 months were retrospectively reviewed

All Radiology reports from post-baseline scans (every 2 cycles) were reviewed for text in the body or conclusion of the Radiology report consistent with disease progression (specifically the terms ‘progressive’, ‘new’ and/or ‘interval enlargement/worsening’)

Ali H, et al. GU ASCO 2012

Disparity in Reporting of Progression in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib According to Radiology and Medical Oncology 47 patients were identified with characteristics

typical of an mRCC population The majority of patients were reported by Radiology

to have progression of existing metastatic sites only, with 21% of patients having both existing site progression and new metastatic disease

The median lag between Radiology’s report of PD and Med Onc was 2.8 months (range 0-12.6+ months), with 5 patients not yet considered to have progressed by Med Onc

In almost 50% of cases the Med Onc call was >3 months later than Radiology

Ali H, et al. GU ASCO 2012

Management of Advanced RCC: Current Status Level 1 evidence to help drive decision making for

front-line and second line therapy is available Optimal front line therapy for good/intermediate risk

patients remains unclear (some data is coming- phase III pazopanib vs sunitinib)

Optimal therapy for non clear cell remains undefined Combination therapy remains investigational: its

more toxic than you would think, don’t try this at home

"It's not what you don't know that hurts you; it's what you know that just ain't so."

Satchel Paige