The role of cytoreductive nephrectomy for mRCC in 2020

Maarten Albersen Dept. of Urology UZ Leuvenwith assistance of: Eduard Roussel Alessandro Larcher

CASE Male, 55 YOMedical history: 2002 pneumonia & TB pleuritis No meds

• Presents with macroscopichematuria / cloth retention in 04/2019 > large tumor Rt kidneywith Mayo level 1 thrombus.

• Embolisation same night.• Free of symptoms.• CT thorax: multiple pulmonary and

pleural mets, bilateral.• IMDC: (before bleeding: 0 risk

factors)• What would be your advice on

MDT?

CASE 1. AS2. CN + AS3. Nivolumab (+- deferred CN)4. Nivolumab + Ipilimumab (+- deferred CN)5. Sunitinib (+- deferred CN)6. Axitinib + Pembrolizumab(+- deferred CN)

What is cytoreductive nephrectomy?Non-curative nephrectomy in mRCC with the goal of decreasing total tumorload.• Often + abdominal metastasectomy/LND• Upfront or delayed.• Goals:

• Tumor self-seeding principle: volume reduction• “abscopal effect” in 2% with metastatic reduction (due to relief of

immune-surpressive effects of primary: immunologic sink)• Better response with systemic therapy• Palliation (symptoms/paraneoplastic s)

Setting: mRCC

IMDC-Heng criteria Diagnosis-systemic therapy < 1 yearPS <80%Hemoglobin < LLNCalcium > ULNNeutrophils > ULNPlatelets > ULN

0 points: favorable OS = 20 months1 or 2 points = intermediate OS = 10 months>2 points = high risk = 4 months

0 points: favorable OS = 43,2 months1 or 2 points = intermediate OS = 22,5 months>2 points = high risk = 7,8 months

Heng J Clin Oncol 2009Motzer J Clin Oncol 2002

MSKCC-Motzer criteria Diagnosis-systemic therapy < 1 yearPS <80%Hemoglobin < LLNCalcium > ULNLDH > 1.5x ULN

Historical perspective: IFN era

Flanigan et al. NEJM 2001Mickisch et al. Lancet 2001> Flanigan et al. J Urol 2004

Prospective RCTLow metastatic loadPS: ECOG 0

TKI era

RetrospectiveInherent selection bias with CN

Choueiri et al. J Urol 2011Heng et al. Eur Urol 2014Hanna et al. JCO 2016

Choueiri 2011 Heng 2014 Hanna 2016

TKI eraOnly CN for patients with

life expectancy >12 months Max 3 IMDC criteria

Heng et al. Eur Urol 2014

EAU guidelines 2018

CARMENA

Primary endpoint: OSDesign: non inferiority (HR OS <1.20)N (powercalc): 576PI: Arnaud Méjean

Key eligibility CriteriamCCRCC Tx naiveMSKCC int/poor riskECOG PS 0-1

Randomization 1:1

N=450CN

Sunitinib50 mg QD 4/2

Subitinib50 mg QD 4/2

CNStratificationMSKCC risk groups

Centre

3-6 weeks

Stable disease: 18%

Mejean et al - NEJM 2018

N=226

N=224

CARMENA

Mejean et al - NEJM 2018

Major adverse events in favour of CN + Sunitinib (net reduction -10%, p=0.04)

CARMENA: limitations

Mejean et al - NEJM 2018 / Stewart et al. Eur Urol – 2017 / Motzer NEJM 2018 / Chouieri JCO 2017

Population at high risk:Survival rates poorer than expected (14-18 mos vs 21.8-26 mos in Motzer & Chouieri. 43% poor-risk

Slow accrual: • N= 450/576, accrual 0.7 pts/site/yr• Need to open UK centres: after accrual open in 26

sites around UK, only 14 patients were enrolled• Ideal patients for CN did not consent, underwent CN

outside of study, exlucions at investigators discretion

Sunitinib arm: 11/224 (5%) did not recieve Sunitinib38/213 (18%) underwent CN (median 11 months)

CN+ Sunitinib arm40/226 (18%) did not receive sunitinib16/186 (9%) did not receive CN

CARMENA: is this the patient we would typically do CN on?

Arora et al. Eur Urol - 2018

5 - 18 months survivaladvantage followingCN

Larcher et al - Eur Urol Oncol 2019

No survival advantageCARMENA

retrospective

Bhindi et al - Eur Urol 2019

CARMENA in current literature

ccRCC

nccRCC

CARMENA: subanalyses: delayed CN (OS)

Mejean et al ASCO 2019

48.5 mo15.7 mo

Response as a Litmus test

SURTIME

SURTIME

Primary endpoint: PFS ITT (sec:OS)N (powercalc): 458PI: Axel BexSponsor: EORTC

Key eligibility CriteriamCCRCC Tx naiveECOG PS 0-1

Randomization 1:1

N=99CN

Sunitinib50 mg QD 4/2

3 cycles

Subitinib50 mg QD 4/2

CN Sunitinib50 mg QD 4/2

Not eligble for CN due to progression: 29%

N=50

N=49

Bex et al. Jama Oncology 2018

StratificationWHO performance status

SURTIME

Bex et al. Jama Oncology 2018

Patients who:

Progress under TKIDo not benefit from CN

Safety: no increase of peri-operative outcomes in deferred CN

Safety of CN: YAU and Leuven cohorts

Neurologic: 3,4%

Wound/Skin: 3,4%

Gastrointestinal: 9,3%

Cardiopulmonary: 4,7%

Vascular/Lymphatic: 16,3%

Infectious/Metabolic: 17,4%

Postoperative complications CDC (1-5): 42%• High-grade postoperative complications CDC (3-5): 2,3%• Surgery-related mortality: 0%

Predictors for High-grade postoperative morbidity• Estimated intraoperative blood loss: HR 2.93 (1.20-7.15)

• CN case load: HR 0.13 (0.03-0.59)

Neurologic: 1,0%

Wound/Skin: 1,8%

Gastrointestinal: 4,5%

Cardiopulmonary: 5,3%

Vascular/Lymphatic: 9,1%

Infectious/Metabolic: 8,8%

Postoperative complications CDC (1-5): 29,5%• High-grade postoperative complications CDC (3-5): 6,1%• Surgery-related mortality: 1,4%

YAU (n=736) Leuven (n=86)

CARMENA: subanalyses: 1 IMDC risk factor

Mejean et al ASCO 2019

Median OS (months) ARM A: CN + Sunitinib (n=127)

ARM B: Sunitinib alone (n=139)

HR (95% CI) P-value

IMDC 1 risk factor 31.4 (17.3-45.5) 25.2 (19.6-35.4) 1.29 (0.85-1.98) 0.232

IMDC 2 risk factors 17.6 (13.7-21.5) 31.2 (20.5-40.4) 0.63 (0.44-0.97) 0.033

HR (95% CI) 1.68 (1.10-2.57) 0.88 (0.59-1.30)

P-value 0.015 0.515

UZ Leuven experience (E. Roussel & A. Verbiest)

CARMENA TKI (26)CARMENA CN-TKI (44)

TOO GOOD FOR CARMENACN+AS (49)

CARMENA practice changing: intermediate/poor risk with need for immediate TKI

There is still a population likely benefitting from CN

UZ Leuven experience (E. Roussel & A. Verbiest)

Patients with:

Lung only metsSingle site metsOligometastasis<3 IMDC criteria

May still benefit from CN

However, all these numbers are OUTDATED (2020)

New backbone in all risk groups:(TKI+) IO

IMDC analysis on CN in IO era (ASCO-GU20)inverse probability treatment weighted propensity scored analysis

Which patients got CN in IO era?

IMDC analysis on CN in IO era (ASCO-GU20)inverse probability treatment weighted propensity scored analysis

IMDC analysis on CN in IO era (ASCO-GU20)inverse probability treatment weighted propensity scored analysis

Perspective:

SummaryYES, the role of CN has drastically changed after CARMENA• No more upfront CN in intermediate (2 IMDC) and poor risk patients.• Deferred CN has become a valid option with response as litmus test.

Upfront CN still is recommended• In symptomatic patients• In IMDC 0-1 favourable/intermediate risk• In oligometastatic patients• In patients in which all tumor can be surgically resected• Probably in the same population combined with IO/IO-TKI

CASE Male, 56 YOMedical history: 2002 pneumonia & TB pleuritis No meds

10 months post-CN:Regression of lung mets (CR)

2 factors 1 factor

Response

Primary mCCRCC

MDT

Not immediately requiring IO/TKI

Oligometastasis

CN

AS Metastasis directed Tx

Progressive disease

Axi-Pembro

Ipi-Nivo / Axi-Pembro CN

IMDC poor IMDC intermediate

Deferred CN

IMDC intermediate / poor

IMDC favorable

Requiring and eligible for IO/TKI

Adapted from: Kuusk et al. Ther Adv Med Oncol 2019

Take home: