Cytoreductive nephrectomy in renal cell

carcinoma: still required in the combined targeted and immunotherapy era ?

Urologists view

Axel Bex, MD, PhD

The Netherlands Cancer Institute

FOIU, 4 July 2018

Financial and Other Disclosures Off-label use of drugs, devices, or other agents: None or FILL IN HERE; including your

local regulatory agency, such as FDA, EMA, etc.

Data from IRB-approved human research is presented [or state: “is not”]

2

I have the following financial interests or

relationships to disclose: Disclosure code

Pfizer C, S

Roche C

Genentech C

Ipsen C

Novartis C

BMS C

CARMENA investigated the role of CN

SURTIME the sequence of CN

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 timo to TT

14 months

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

disease after CN

Study design

5

Progression status

at week 16 Progression status

at week 28

N E P H R E C T O M

Y

Cycle 1 (6 wk) Cycle 2 Cycle 3

Cycle 4

N E P H R E C T O M Y

Progression

status every

12 weeks

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

R

Immediate Nephrectomy

Deferred Nephrectomy

= Progression status 4 weeks after CN

= Sunitinib

Baseline characteristics

6

Immediate nephrectomy

(N=50)

Deferred nephrectomy

(N=49)

Median age (years) 60 58

Performance status (WHO)

- WHO 0 36 (72.0%) 31 (63.3%)

- WHO 1 14 (28.0%) 18 (36.7%)

Male 41 (82.0%) 39 (79.6%)

MSKCC intermediate risk 43 (86.0%) 44 (89.8%)

≥ 2 measurable metastatic sites 43 (86.0%) 46 (93.9%)

Mean (SD) primary tumor size (mm)

93.1 (37.8) 96.8 (31.3)

Progression-free survival (ITT)

7

Progression-free status at w28 (±15 days)

Immediate nephrectomy

(N=50)

Deferred nephrectomy

(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 (one-sided Fisher exact test)

0.61

Progression ≤ week 28 or treatment failure

25 (50.0%) 24 (49.0%)

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

HR (95%CI)=0.88 (0.56, 1.37), p=0.569 Stratified by WHO performance status (0 versus 1)

Week 1

6 e

valu

ation

(+

/-1

5 d

ays w

ind

ow

)

Week 2

8 e

valu

ation

(+

/-1

5 d

ays w

ind

ow

)

Immediate

Deferred

Overall Survival (ITT)

8

HR (95%CI)=0.57 (0.34, 0.95), p=0.032 Stratified by WHO performance status (0 versus 1)

Immediate nephrectomy

(N=50)

Deferred nephrectomy

(N=49)

Survival status

Dead 35 (70.0) 28 (57.1)

Reason of death

Progression 30 25 Surgery related toxicity 1 0 Progression 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 3

Immediate

Deferred

Overall Survival – Landmark analysis at week 16

9

Assessment of progression status at week 16 prior to planned CN in the deferred arm

0 6 12 18 24 30 36 42 48 54 60

0

10

20

30

40

50

60

70

80

90

100

Patients-at-Risk

13 2 1 0 0 0 0 0 0 0

12 8 6 2 1 1 0 0 0 0

10 8 4 3 3 2 1 1 1 1

27 26 21 15 12 10 8 4 2 1

32 31 26 23 19 17 12 8 6 3

Excluded-

Immediate-

Deferred-

Immediate-

Deferred-

Overa

ll s

urv

ival

aft

er

week 1

6 (

%)

Months

PD

before w16

No PD

before w16

Patient characteristics (1)

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

Conclusions from both SURTIME and

CARMENA

• Despite its limitations, CARMENA is a practice

changing trial and SURTIME complements the

results

• Patients with poor risk MSKCC should not

undergo CN

• Patients with intermediate MSKCC risk who

require systemic therapy should not undergo

immediate CN but receive sunitinib first

Finally, open questions remain

• Should CN be performed at a later stage in all patients

except those who progress (SURTIME) or only when

necessary (CARMENA)?

• First-line therapy with nivolumab plus ipilimumab will

replace sunitinib for intermediate and poor risk

patients.

• Will we need new studies or treat patients with primary

metastatic RCC with the tumour in place followed by

resection when necessary ?

Checkpoint inhibitor combination trials in

first-line: Changing the paradigm

Study Sponsor N Therapy Endpoint Subtype

MK-3475-

426/KEYNOTE-426

NCT02853331¹

Merck Sharp & Dohme 840 Pembrolizumab 200 mg IV Q3W PLUS axitinib

5 mg PO BID

vs

sunitinib 50 mg PO QD 4/2 weeks

PFS central

review

OS

clear cell

component with

or without

sarcomatoid

features

JAVELIN Renal 101

NCT02684006¹

Pfizer 583 Avelumab administered at 10 mg/kg IV Q2W in

combination with axitinib, 5 mg PO BID

vs

sunitinib given at 50 mg PO QD 4/2 weeks

PFS, OS clear cell

component

NCT02420821¹ Hoffmann-La Roche 900 Atezolizumab as a fixed dose of 1200 mg via IV

infusion on days 1 and 22 of each 42-day plus

bevacizumab 15 mg/kg via IV infusion on days

1 and 22 of each 42-day cycle

vs

sunitinib given at 50 mg PO QD 4/2 weeks

PFS investigator

reviewed

OS in

participants with

detectable PD-

L1

clear cell

histology and/or

a component of

sarcomatoid

carcinoma

Checkmate 214

NCT02231749¹

Bristol-Myers Squibb 1070 Nivolumab 3 mg/kg combined with ipilimumab 1

mg/kg solutions IV Q3W for 4 doses then

nivolumab 3 mg/kg solutions IV Q2W

vs

sunitinib given at 50 mg PO QD 4/2 weeks

PFS

OS

clear-cell

component

NCT02811861¹ Eisai Inc. 735 Lenvatinib 18 mg PO QD, plus everolimus 5 mg

PO, QD or lenvatinib 20 mg PO QD, plus

pembrolizumab 200 mg IV, Q3W

vs

sunitinib 50 mg PO QD 4/2 weeks

PFS, OS clear-cell

component

Check-SUR-STAM-MENA-PEDE phase III trial of all

potential combinations with CN you ever dreamt of

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

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

IO + X Nephrectomy

Does CN have a future ?

• For those who require 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 patients

who constitute 60 % of RCC

risk groups

• Identification of long-term

survivors

• Potentially longer OS

Remember: VEGFR-targeted therapy is non-curative !

Does CN have a future ?

• For immunecheckpoint combination therapy

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