1. Mahmood rasheed Hematology/oncology fellow VCU Massey cancer center
Results from the CARMENA Trial: Sunitinib Alone versus Sunitinib with Nephrectomy in Metastatic Renal Cell Carcinoma
Mahmood rasheed
Hematology/oncology fellow
VCU Massey cancer center

2. Background: Renal Cell Carcinoma
4% of all adult malignancies in US, 63,000 new cases 2017, prevalence ~730,000.
Metastatic disease at presentation in ~35%, treated with systemic therapy.
Available systemic therapies have radically changed over time.
Rationale for and role of cytoreductive nephrectomy in this setting has evolved over time.

3. Evolution of Systemic RCC Treatment
1980’s-1990s: Cytokine Immunotherapy
1980’s: High dose IL-2, IFN-alpha
1992: FDA approval for HDIL-2
~5-7% durable CR
Use limited by frequent and severe toxicities

4. Evolution of Systemic RCC Treatment 1990s-2000s: Targeted Therapies
Less toxic than HDIL-2 or IFNa, easier to administer.
Compared with cytokine therapy, these improved PFS, ORR, and quality of life.
Negligible CR rates.
No OS benefit except for temsirolimus (select poor- prognosis patients).

5. Evolution of Systemic RCC Treatment
2010s: Modern Immunotherapy

6. Cytoreductive Nephrectomy before Targeted Therapies
Pre-systemic therapy era:
Palliation of symptoms
Rare spontaneous regression of metastatic disease observed after nephrectomy (<1% of cases).
Cytokine therapy era:
Less response in primary tumor than metastases
Possibility of survival benefit through potentiating response to cytokine therapy, debulking overall tumor mass, and eliminating source of new metastases.
Two RCT’s evaluating OS benefit:
EORTC 30947: Nephrectomy + IFN versus IFN alone (n=85). Median OS 18mo vs 7mo.
SWOG 8949: Same design, n=246. Median OS 11mo vs 8.1mo.
Modest survival benefits, small n size, long time to accrue.
Published in 2001, first targeted therapy approved shortly after publication - unclear applicability of findings

7. Retrospective Support for Cytoreductive Nephrectomy
Targeted Therapy Era
Numerous retrospective studies suggesting OS benefit with nephrectomy + targeted therapy versus targeted therapy alone
Petreli et al (2016)
Meta-analysis of 12 studies, 39,953 patients
Demonstrated survival benefit with nephrectomy - HR for death 0.46 favoring nephrectomy

8. Retrospective Support for Cytoreductive Nephrectomy
MDACC Database Retrospective (Culp et al 2007)
Retrospective study of 566 patients (456 with nephrectomy and without) who received systemic therapy at MDACC.
7 independent preoperative predictors of inferior OS after nephrectomy: elevated LDH, low albumin, symptomatic metastases, liver metastases, retroperitoneal adenopathy, clinical tumor stage T3-T4.
Higher risk of death correlated positively with number of risk factors; surgical patients with ≥4 risk factors did not benefit from nephrectomy.

9. Retrospective Support for Cytoreductive Nephrectomy
Heng et al
IMDC database analysis
1658 patients (982 with nephrectomy, 676 without) treated with any targeted therapy (72% sunitinib)
Median OS 20.6mo with nephrectomy vs 9.6mo without.
Those with ≥4 IMDC risk factors did not benefit from surgery, and those with life expectancy <12mo had only marginal benefit from nephrectomy.
EORTC (SURTIME):
Multinational prospective study, patients randomized to sunitinib and immediate vs deferred nephrectomy
99 patients (of planned 380) accrued over 6 years period at 19 institutions.
ESMO 2017: PFS unaffected, median OS 32.4mo vs 15.1mo favoring deferred nephrectomy, but severely underpowered to draw definitive conclusions.

10. CARMENA
Study Design
Multicenter open-label trial designed to demonstrate the non-inferiority of sunitinib alone versus nephrectomy followed by sunitinib in patients with metastatic RCC.
Inclusion criteria:
Biopsy-proven metastatic clear cell RCC
Resectable primary tumor
ECOG PS 0-1
No brain metastases
Adequate organ function
Exclusion criteria:
Prior systemic therapy
Medically unfit for nephrectomy

11. Study Design Stratified by risk according to MSKCC prognostic model:
Randomized 1:1 to undergo nephrectomy followed by sunitinib treatment or to receive sunitinib alone
Sunitinib 50mg daily for weeks 1-4 of 6 week cycle, dose reductions/interruptions permitted as needed.
Patients started sunitinib within 3-6 weeks post- nephrectomy, sunitinib group started treatment within 21 days of randomization.

12. Study Design Endpoints: Primary: overall survival Secondary:
PFS
ORR (CR + PR rates by RECIST criteria)
Post-operative morbidity/mortality
Adverse events on treatment by CTCAE
"Clinical benefit" - percentage of patients with CR, PR, or SD for more than 12 weeks
Statistics:
Non-inferiority trial designed to show non-inferiority for death at a HR of ≤1.20 with 95% confidence interval.
Planned to enroll 576 patients for 456 observed deaths, to accrue over 4 year period (10 patients per month across 92 centers)
Over an 8 year period, 450 patients were enrolled (average patients per center per year).
At a planned interim analysis (326 deaths) trial was closed due to poor accrual, trial committee deemed results from interim analysis adequate to meet trial objectives.

13. Results: Patients
17%!
Significant issues with patient crossover
7.1%

14. Results: Patients
No favorable-risk patients – MSKCC intermediate-poor only.
44.5% (nephrectomy) and 41.5% (sunitinib) with poor risk disease.
Higher T-stage (70% vs 50%) in the nephrectomy-sunitinib group
Average number, size, distribution of metastatic disease balanced, but extent of metastatic burden fairly high – 40% of disease volume from metastases versus primary tumor.
High proportion of patients with bone metastases (35.9% and %)

15. Subgroup
Median OS (SUN vs CN-SUN)
HR for Death
[95% CI]
All Patients
18.4 vs 13.9 months
0.89 [0.71 to 1.10]
MSKCC Intermediate-risk
23.4 vs months
0.92 [ ]
MSKCC Poor-risk
13.3 vs months
0.86 [ ]

17. Oncologic Outcomes in Sunitinib Arm of Recent RCC Trials
Enrolled Patient Population
Median OS in Sunitinib arm
PFS
ORR
Checkmate 214 (2018)
IMDC int-poor risk
26mo
8.4mo
27%
CABOSUN (2017)
21.8mo
8.2mo
12%
COMPARZ (2013)
Any risk
29.3mo
9.5mo
25%
CARMENA (2018) – Nephrectomy Arm
Any risk (but only MSKCC int-poor enrolled)
18.4mo
7.2mo
27.4%
CARMENA (2018) – Sunitinib only Arm
23.4mo
8.3mo
29.1%
Median OS in MSKCC intermediate risk – 33.6mo, MSKCC poor risk – 15.2mo (Tamada et al, Oncotarget 2018)

20. G3-4 adverse events in sunitinib group in CheckMATE 214 (63%), CABOSUN (68%)

22. Postoperative death in the month after nephrectomy in 4/210 patients in the
nephrectomy–sunitinib group. Not reported in the “sunitinib only” group.
82/210 (40%) patients with post-operative complications, 13/82 (16%) requiring procedural intervention or resulting in critical illness, organ dysfunction, or death.
Rates of complications fairly similar between upfront nephrectomy group and in the “sunitinib only” group.

23. The Good
Prospectively confirm prior retrospective observations that high-risk patients likely do not benefit from cytoreductive nephrectomy.
The Bad
Very poor accrual led to premature closure and underpowered study
Clear lack of clinical equipoise leading to patients most likely to benefit from surgery not being enrolled:
Disproportionately higher risk disease in enrolled patients (MSKCC risk features, bone metastases, higher metastatic burden)
Imbalance between arms (T3-4 in 70% in nephrectomy arm versus 50% of sunitinib only arm) also skews results to favor sunitinib only.
Significant crossover between groups (17.0% of the no-surgery group got surgery, 7% of the surgery group didn’t get surgery).
Sunitinib no longer ideal comparator given superior efficacy of newer treatments (better PFS with cabozatinib, OS with ipi/nivo, likely superior outcomes with combinatorial regimens)
Discussion

24. Common approach to metastatic RCC
While this study attempts to provide valuable prospective data on the merits of CN, I do not see it as practice changing overall.

25. Thank You