RCCSURGERY IN METASTATIC DISEASE

Prof. Alessandro Volpe

University of Eastern Piedmont

Maggiore della Carità Hospital, Novara, Italy

DISCLOSURE OF INTEREST

None

• Tumour resection is curative only if all tumour

deposits are excised. This includes patients

with the primary tumour in place and single-

or oligo-metastatic resectable disease

• For most patients with metastatic disease,

cytoreductive nephrectomy (CN) is palliative

and systemic treatments are necessary

Evidence of a ‘stage shift’

• Sweden: from 23 % in 2005 to 15 % in 20101

• Germany: 17 % in 20131

• Netherlands: 18 % in 20111

• USA: 11 % in 20152 (National Cancer Database)

1 Thorstenson et al. Scand J Urol 2013, Report of Dutch Integral Cancer Centres 2013, RCC working group Germany,

SEER data USA 2 Patel et al,, Clinical stage migration and survival for RCC in the United States, Eur Urol Oncol 2018

Flanigan, Clin Cancer Res 2004: “Up to one third of patients with

renal cell carcinoma will present with metastatic disease”

15 years ago

just after SWOG 8949 and EORTC 30947

• N=94 with primary mRCC

• N=38 (40 %) considered irresectable

• N=36 (38 %) had a WHO ≥2

• N=20 (21 %) underwent CN

“ Only 1/5th fulfilled criteria for CN”

Present situation

BAUS nephrectomy registry 2012 (n=6042, 80 % complete)

•From all nephrectomies registered in the UK in 2012 only 4.6 % were cytoreductive (n=279)

•CN performed by 141 surgeons in 90 centres.

•On average each surgeon performed 1.97 CN or 3.1 CN per centre

Jackson et al., Perioperative Outcomes of Cytoreductive Nephrectomy in the UK in 2012. BJU Int. 2014

Tsao et al., SEER database on utilization of cytoreductive nephrectomy WJUR 2012

Conti et al., SEER evaluation of utilization of CN and survival Int J Cancer 2014

Introduction of targeted therapy

Morbidity of CN

• Individual prediction of 30-day mortality after partial or radical

nephrectomy according to age and stage strata (n=12,283)

T1-2N0M0

% 30 day mortality

(95%CI)

T3-4N0-2M0

% 30 day mortality

(95%CI)

T1-4N0-2M1

% 30 day mortality

(95%CI)

Age (years)

≤49 0.1 (0–0.4) 0.6 (0.1–1.9) 2.9 (1.2–5.9)

50–59 0.1 (0–0.5) 0.6 (0.2–1.8) 2.9 (1.4–5.6)

60–69 0.2 (0.05–0.5) 0.8 (0.3–1.6) 3.6 (2.0–6.3)

70–79 0.4 (0.1–0.7) 1.5 (0.7–2.6) 7.0 (4.0–11.0)

≥80 0.6 (0.1–1.5) 2.4 (0.8–4.9) 10.5 (4.3–23.0)

Cloutier, et al. Eur Urol 2008

4 months

20 %

SWOG trial of nephrectomy plus interferon

versus interferon alone

20 % of patients who underwent

surgery died within the first 4 months !

Figure from: Flanigan et al., Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for

metastatic renal-cell cancer. NEJM 345(23):1655-1659, 2001

• Multi-Institutional retrospective analysis of 141

patients after CN

• Systemic therapy 70% (98/141)

• No Systemic therapy due to* 15 % (20/141)

(*rapid progression & perioperative death)

Kutikov et al, Use of systemic therapy and factors affecting survival for patients undergoing

cytoreductive nephrectomy. BJUI 106(2):218-223, 2010.

Retrospective studies published until 2016 on survival

after CN versus no CN

Bex et al., Eur Urol 70: 901-905, 2016

Limitations of retrospective studies

Unfavourable tumor biology

Rapid disease progression

Probably never considered

for cytoreductive

nephrectomy

Cytoreductive

nephrectomy

Favourable tumor biology

with slow progression

•Low metastatic volume

•No sarcomatoid features

•Good performance

•MSKCC/IMDC intermediate

Patient population A Patient population B

SELECTION IS KEY

TUMOR FEATURES

CN in low volume mRCC

• Potentially curative

• Prolongs potentially PFS

• May substantially delay

targeted therapy

ECOG Performance status

• A preoperative ECOG status ≥ 2 was the only

significant risk factor associated with failure to

undergo cytoreductive nephrectomy followed by

immunotherapy (P = 0.043).

Walther et al., Cytoreductive surgery prior to IL-2 based therapy in patients with mRCC. Urology 42(3):250-7, 1993

SELECTION IS KEYPATIENT FEATURES

Heng et al., External validation and comparison of the IMDC prognostic model with other models

The Lancet Oncology 14 (2)141-8, 2013

Individual factors• Karnofsky performance < 80 %• anemia• thrombocytosis• neutrophilia• hypercalcemia• time from diagnosis to treatment < 1 year

SELECTION IS KEYVALIDATED PROGNOSTIC SCORES

No survival benefit in poor risk patients

Noe et al., J Clin Oncol 31, 2013 (suppl; abstr e15525)

2-year OS:

Intermediate:

25.5% (95% CI 18-34%)

Poor:

2.9% (95 % CI 0.05-14%)

Courtesy Dr Daniel Heng, presented at ASCO GU 2014

Pretreatment MSKCC IMDC in primary mRCC (n=1658)

(n=154 patients at the NKI)

Median OS

- intermediate risk:

17 months (95% CI 11.3-22.6)

- poor risk:

6 months (95% CI 3.4-8.5)

Estimate life expectancy

Adequate life expectancy turnspotential significance into relevance

Courtesy Dr Daniel Heng, presented at ASCO GU 2014

SURTIME, a EORTC-GU 30073 Phase III Study

Investigating the Sequence of Nephrectomy and Sunitinib

� Primary end point: PFS

� Secondary end points: OS, association with prognostic gene

and protein expression profiles

Nephrectomy

Sunitinib

50 mg/day

(schedule 4/2)

Nephrectomy

Sunitinib

50 mg/day

(schedule 4/2)

Patients with

synchronous

mRCC and

primary tumor

in situ

RANDOMIZATION

N = 458

Biswas et al, 2009; US NIH, 2010d.

esmo.org

IMMEDIATE VERSUS DEFERRED CYTOREDUCTIVENEPHRECTOMY IN PATIENTS WITH SYNCHRONOUS

METASTATIC RENAL CELL CARCINOMA (MRCC) RECEIVING SUNITINIB.

The European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30073 SURTIME.

A. Bex*, P. Mulders, M. Jewett, J. Wagstaff, R. Van Velthoven, P. Laguna, L. Wood, H.H.E. van Melick, P. Soetekouw,

J.B. Lattouf, T. Powles, I. De Jong, S. Rottey, B. Tombal, S. Marreaud, S. Collette, L. Collette, J. Haanen

*The Netherlands Cancer Institute, Amsterdam, The Netherlands, on behalf of the EORTC Genitourinary Cancer Group

Clinical trial identification NCT01099423

OBJECTIVE / ENDPOINTS / SAMPLE SIZE (2)

• Due to poor accrual (64 patients after 3 years recruitment), a revised statistical design had been submitted before the end of accrual to the Independent Data Monitoring Committee (IDMC) and approved the following changes:

• Primary endpoint: Progression-free rate (PFR) at 28 weeks, using RECIST v1.1

• Sample size: Based on the PFR at 7 months (28 weeks) in the sunitinib arm in the pivotal trial comparing sunitinib and interferon-alpha, in which 90% of the patients had a nephrectomy1, a PFR at 28 weeks of 70% was assumed for the immediate arm in trial 30073. To show an increase in the PFR at 28 weeks from 70% in the immediate arm to 90% in the deferred arm (H0: no difference versus H1: increase of 20% in the PFR), based on a one sided Fisher Exact test at 5% with 80% power in the intention-to-treat population, 98 patients were needed.

1Motzer et al.,N Engl J Med 2007; 356: 115-124.

21

STUDY DESIGN

Progression status at week 16

Progression status at week 28

NEPHRECTOMY

NEPHRECTOMY

Cycle 1 (6 wk) Cycle 2 Cycle 3 Cycle 4

NEPHRECTOMY

NEPHRECTOMY

Progression

status every

12 weeks

Cycle 4 Cycle 5Cycle 1 (6 wk) Cycle 2 Cycle 3 (4 wk)

R

Immediate Nephrectomy

DeferredNephrectomy

22

= Progression status 4 weeks after CN

= Sunitinib

RECRUITMENTRandomized patients

N=99

Immediate surgery

N=50

Deferred SurgeryN=49

NephrectomyN=46

NephrectomyN=34

Pre-surgical sunitinibN=48

Postop sunitinib N=40

Postop sunitinib N=26

Allocated treatment not started (n=1)

Allocated treatment not started (n=4)

No postop sunitinib (n=8)

No postop sunitinib (n=6)

Treatment stopped (n=22)Treatment ongoing (n=4)

Treatment stopped (n=34)Treatment ongoing (n=6)

No Surgery (n=8)Surgery off protocol (n=6)

10 not eligible 8 not eligible

23

• From 14/07/2010 to 24/03/2016 (ie 5.7 years):

• 99 patients randomized

• by 19 institutions

• from 4 countries (the Netherlands, Canada, United Kingdom, Belgium).

• As of May 5, 2017, median follow-up is 3.3 years (95% CI: 2.8, 3.8).

ADVERSE EVENTS AND SAFETY (1)

24

Immediatenephrecto

my(N=46)

Deferrednephrecto

my(N=48)

Number of patients with AE’s*

- grade ≥1 45 (97.8%) 48 (100.0%)

- grade ≥3 24 (52.2%) 28 (57.3%)

Number of patients with SAE’s

17 (37.0%) 17 (35.4%)

Number of SAE’s 32 24

*ALL adverse events, recorded according to CTCAE, version 4.0SAE were reported according ICH GCP and the EU Directive 2001/20/EC definition and requirements $ arterial embolization due to hematuria

Safety of pre-surgical sunitinib

Deferrednephrect

omy(N=48)

Delay of nephrectomy > 2 weeks- Logistical reasons- Treatment unrelated comorbidity- Sunitinib related

8 (16.6%)5 (10.4%)1 (2.0%)2 (4.2%)

Inability to perform surgery due to progression of primary tumour

-

Emergency intervention duringpretreatment$

1

25

SAFETY (2) - SURGICAL ADVERSE EVENTS

Immediatenephrecto

my

Deferrednephrecto

my$

Type of surgical complication:

- In-hospital mortality 2* 1

- Number of patients with prolongation of hospitalization (>20days) and/or readmission (within 30 days after

surgery)

6 3

- Number of patients (events) with intraoperative complication (including

vascular and organ damage# and

blood-loss grade 3)

• Grade ≥3

• Grade 5

14 (23)

8 (11)

1 (1)

9 (11)

6 (6)

-

- Number of patients with postoperative adverse events within 30 days after surgery#

• Grade ≥3

• Grade 5

7

1

7

1

$median days after sunitinib 4.5 (range 1.0-63.0), *1 death during surgery; # grade 3 or more according to CTCAE, version 4.0 and judged by physicians as likely related to surgery

PROGRESSION-FREE SURVIVAL - INTENTION TO TREAT -

Progression-free status at w 28 (±15 days)

Immediate

nephrectomy

(N=50)

Deferrednephrect

omy(N=49)

Progression-free at week 28

21 (42.0%)

21 (42.9%)

[95% CI][28.2% –

56.8%]

[28.8% –

57.8%]

p-value (Fisher exact test) >0.99

Progression before or at week 28, or treatment failure

25 (50.0%)

24 (49.0%)

Not assessable 4 (8.0%) 4 (8.2%)

26

Deferred

Immediate

HR [95% CI]: 0.88 [0.59-1.37]P=0.569 stratified by PS 0 vs 1

OVERALL SURVIVAL - INTENTION TO TREAT-

Immediate

nephrectomy

(N=50)

Deferrednephrect

omy(N=49)

Survival status

Dead 35 (70.0) 28 (57.1)

Reason of death

Progression 30 25Surgery related toxicity 1 0Progression and surgery

related toxicity 1 0

Cardiovascular disease (not due to toxicity or progression)

1 0

Other (not due to toxicity or progression)

1 0

Unknown 1 327

Deferred

Immediate

HR [95% CI]: 0.57 [0.34-0.95]P=0.032 stratified by PS 0 vs 1

PROGRESSION-FREE SURVIVAL AND OVERALL SURVIVAL- PER PROTOCOL -

28

Per protocol population: All patients who are eligible and have started their allocated treatment (excluding 18 ineligible patients and 5 who did not proceed to allocated treatment).

Deferred

Immediate

HR [95% CI]: 0.99 [0.60-1.62]P=0.965 stratified by PS 0 vs 1

Deferred

Immediate

HR [95% CI]: 0.71 [0.40-1.24]P=0.225 stratified by PS 0 vs 1

CONCLUSIONS

29

• The trial accrued poorly and therefore results are mainly exploratory.

• The sequence of CN and sunitinib did not affect the PFR at 28 weeks.

• The sample size precludes definitive conclusions from other endpoints, although an OS signal

was seen for deferred CN.

• The survival in the deferred arm is comparable to data reported from previous single-arm

phase II studies of presurgical sunitinib or pazopanib 1-3.

• The deferred CN approach appears to select out patients with inherent resistance to systemic

therapy. This confirms previous findings from single-arm phase II studies1-3.

• The deferred CN approach initiates therapy quickly, does not lead to inability to perform CN

and surgery appears safe after sunitinib.

1Powles et al., JAMA Oncol 2016, 10:1303-130; 2Powles et al., Eur Urol 2011, 60:448-5 ; 3Bex et al., Urology2011, 78:832-7

2018 Version

CARMENA Phase III Study of Sunitinib Only vs.

Nephrectomy Followed by Sunitinib

� Primary objective: Is sunitinib alone non-inferior to nephrectomy plus sunitinib in terms of OS?

� Note: NO stratification in MSKCC or IMDC risk

Nephrectomy

Sunitinib

50 mg/day

(schedule 4/2)

Sunitinib

50 mg/day

(schedule 4/2)

R

A

N

D

O

M

I

Z

A

T

I

O

N

N = 576

Metastatic

clear cell RCC

ECOG 0-1

Patient characteristics (1)

Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

Overall <br />survival (ITT)

Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

Overall survival (ITT)

Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

Secondary nephrectomy in Arm B (sunitinib alone)

Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

SURTIME and CARMENA included patients who

require sunitinib

N=28 from an institutional

database of 202 primary

mRCC patients

Bex et al., GU ASCO, J Clin Oncol 34, 2016 (suppl 2S; abstr 604)

Median time to TT

14 months

Time to targeted therapy in patients with low-volume but non-resectable

metastatic disease after CN

Which are the current indications for cytoreductive

nephrectomy?

Role of surgery for metastases

Does CN have a future ?

• VEGFR-TKI

Indication Frequency Rationale

Patients with solitary or

oligometastasis not requiring

immediate systemic therapy

low

(in NKI dataset 40/244 =16.4 %)

• Cure

• Delay of systemic therapy

Intermediate risk patients

without systemic progression

during immediate TKI

probably 80 % of intermediate

risk pts who constitute 60 %

of RCC risk groups

• Identification of long-term

survivors

• Potentially longer OS

Courtesy of Dr. A. Bex

CYTOREDUCTIVE NEPHRECTOMY

Personal view

• Favourable / low intermediate risk pts

– IMDC 0-1

– Good PS, young age, no symptoms, low volume met disease

• Poor / high intermediate risk pts

– IMDC ≥ 2

– Poor PS, symptomatic, brain mets, high volume met disease

• Poor risk pts

CNx

+ ev. metastasectomy

+ surveillance/TT-IO

TT/IO

+ deferred CNx if durable CR

TT/IO

Does CN have a future ?

• Immunotherapy

Scenario Rationale of CN Probability

CR of primary and

metastases

CN not required unlikely

CR at metastatic sites only CN advised in all instances:

•to stop treatment

•potentially curative

May occur in a few cases

SD or PR but median OS

substantially longer than in

VEGFR-TT era with 10-20%

‘cured’

CN may be of benefit:

•in case of symptoms

•potentially curative

likely

CR=complete remission; PR=partial remission; SD=stable disease; OS=overall survival; TT=targeted therapy

Courtesy of Dr. A. Bex

� Primary objective: Is IO + X alone superior to nephrectomy plus IO +

X or IO + X plus nephrectomy in terms of OS?

� Stratification by IMDC risk factors

Nephrectomy

IO + X

IO + X

R

A

N

D

O

M

I

Z

A

T

I

O

N

N = 1500 + each new arm

Metastatic

clear cell RCC

ECOG 0-1

IO + X Nephrectomy

Courtesy of Dr. A. Bex

CONCLUSIONS

• Primary mRCC is heterogenous and selection is key

• Immediate and deferred cytoreductive nephrectomy

after systemic treatment is safe and effective in selected

cases

• Systemic therapy is the maynstay of therapy for the

majority of patients

• Patients with poor/intermediate prognosis are best

treated primarily with targeted agents/IO

• Stratification of intermediate risk category is warranted

• Further RCTs on cytoreductive nephrectomy + TT/IO are

awaited