Cytoreductive nephrectomy in renal cell carcinoma: still required - - PowerPoint PPT Presentation

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”]

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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

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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

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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 16 evaluation (+/-15 days window) Week 28 evaluation (+/-15 days window)

Immediate Deferred

Overall Survival (ITT)

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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 Progression and surgery related toxicity 1 Cardiovascular disease (not due to toxicity or progression) 1 Other (not due to toxicity or progression) 1 Unknown 1 3

Immediate Deferred

Overall Survival – Landmark analysis at week 16

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

6 12 18 24 30 36 42 48 54 60 10 20 30 40 50 60 70 80 90 100

Patients-at-Risk

13 2 1 12 8 6 2 1 1 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-

Overall survival after week 16 (%) 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

• r 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

• ligometastasis 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

• nly

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