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”] I have the following financial interests or Disclosure code relationships to disclose: Pfizer C, S Roche C Genentech C Ipsen C Novartis C BMS C 2

CARMENA investigated the role of CN SURTIME the sequence of CN

SURTIME and CARMENA included patients who require sunitinib Time to targeted therapy in patients with low-volume but non-resectable metastatic disease after CN N=28 from an institutional database of 202 primary mRCC patients Median timo to TT 14 months Bex et al., GU ASCO, J Clin Oncol 34, 2016 (suppl 2S; abstr 604)

Study design N E P Cycle 4 Cycle 1 (6 wk) Cycle 2 Cycle 3 H R Immediate E Nephrectomy C T O M Progression Progression status Progression status status every Y at week 16 at week 28 12 weeks R N E P H R Deferred E C Nephrectomy T Cycle 1 (6 wk) Cycle 4 Cycle 2 Cycle 3 (4 wk) Cycle 5 O M Y = Sunitinib = Progression status 4 weeks after CN 5

Baseline characteristics Immediate Deferred nephrectomy nephrectomy (N=50) (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 93.1 (37.8) 96.8 (31.3) (mm) 6

Progression-free survival (ITT) HR (95%CI)=0.88 (0.56, 1.37), p=0.569 Stratified by WHO performance status (0 versus 1) Immediate Deferred Progression-free status nephrectomy nephrectomy at w28 (±15 days) (N=50) (N=49) Progression-free 21 (42.0%) 21 (42.9%) at week 28 [95% CI] [28.2% – 56.8%] [28.8% – 57.8%] Deferred p-value (one-sided Fisher 0.61 Week 16 evaluation Week 28 evaluation (+/-15 days window) (+/-15 days window) exact test) Progression ≤ week 28 or 25 (50.0%) 24 (49.0%) Immediate treatment failure Not assessable 4 (8.0%) 4 (8.2%) 7

Overall Survival (ITT) Immediate Deferred nephrectomy nephrectomy Deferred HR (95%CI)=0.57 (0.34, 0.95), p=0.032 (N=50) (N=49) Stratified by WHO performance status (0 versus 1) Survival status Dead 35 (70.0) 28 (57.1) Reason of death Progression 30 25 Surgery related toxicity 1 0 Immediate Progression and surgery related 1 0 toxicity Cardiovascular disease 1 0 (not due to toxicity or progression) Other (not due to toxicity or 1 0 progression) Unknown 1 3 8

Overall Survival – Landmark analysis at week 16 100 90 80 Overall survival after week 16 (%) 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 Months Patients-at-Risk Excluded- 13 2 1 0 0 0 0 0 0 0 PD Immediate- 12 8 6 2 1 1 0 0 0 0 before w16 Deferred- 10 8 4 3 3 2 1 1 1 1 Immediate- 27 26 21 15 12 10 8 4 2 1 No PD before w16 Deferred- 32 31 26 23 19 17 12 8 6 3 Assessment of progression status at week 16 prior to planned CN in the deferred arm 9

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 Pembrolizumab 200 mg IV Q3W PLUS axitinib MK-3475- Merck Sharp & Dohme 840 PFS central clear cell 5 mg PO BID review component with 426/KEYNOTE-426 vs OS or without NCT02853331 ¹ sunitinib 50 mg PO QD 4/2 weeks sarcomatoid features Avelumab administered at 10 mg/kg IV Q2W in JAVELIN Renal 101 Pfizer 583 PFS, OS clear cell combination with axitinib, 5 mg PO BID component NCT02684006 ¹ vs sunitinib given at 50 mg PO QD 4/2 weeks NCT02420821 ¹ Atezolizumab as a fixed dose of 1200 mg via IV Hoffmann-La Roche 900 PFS investigator clear cell infusion on days 1 and 22 of each 42-day plus reviewed histology and/or bevacizumab 15 mg/kg via IV infusion on days OS in a component of 1 and 22 of each 42-day cycle participants with sarcomatoid vs detectable PD- carcinoma sunitinib given at 50 mg PO QD 4/2 weeks L1 Bristol-Myers Squibb 1070 Nivolumab 3 mg/kg combined with ipilimumab 1 PFS clear-cell Checkmate 214 mg/kg solutions IV Q3W for 4 doses then OS component NCT02231749 ¹ nivolumab 3 mg/kg solutions IV Q2W vs sunitinib given at 50 mg PO QD 4/2 weeks NCT02811861 ¹ Lenvatinib 18 mg PO QD, plus everolimus 5 mg PFS, OS Eisai Inc. 735 clear-cell PO, QD or lenvatinib 20 mg PO QD, plus component pembrolizumab 200 mg IV, Q3W vs sunitinib 50 mg PO QD 4/2 weeks

Check-SUR-STAM-MENA-PEDE phase III trial of all potential combinations with CN you ever dreamt of Nephrectomy R A IO + X N D O Metastatic M IO + X Nephrectomy clear cell RCC I ECOG 0-1 N = Z 1500 + A each T new I IO + X arm O N  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 Biswas et al, 2009; US NIH, 2010c.

Does CN have a future ? • For those who require VEGFR-TKI Indication Frequency Rationale • Patients with solitary or low Cure • oligometastasis not requiring (in NKI dataset 40/244 = Delay of systemic therapy immediate systemic therapy 16.4 %) • Intermediate risk patients probably 80 % of Identification of long-term without systemic progression intermediate risk patients survivors • during immediate TKI who constitute 60 % of RCC Potentially longer OS risk groups 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 CN not required unlikely metastases CR at metastatic sites CN advised in all May occur in a few only instances: cases • to stop treatment • potentially curative SD or PR but median CN may be of benefit: likely • OS substantially longer in case of symptoms • than in VEGFR-TT era potentially curative with 10-20 % ‘cured’ CR=complete remission; PR=partial remission; SD=stable disease; OS=overall survival; TT=targeted therapy