CARMENA: Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma

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Méjean A, et al. "Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma". New England Journal of Medicine. 2018. 379(5):417-427.
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Clinical Question

In patients with metastatic renal cell carcinoma, is treatment with sunitinib inferior to treatment with nephrectomy and sunitinib when comparing overall survival?

Bottom Line

Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal cell carcinoma who were classified as having intermediate or poor-risk disease.

Major Points

Current evidence is limited in regards to the place of medical vs surgical treatment of metastatic renal cell carcinoma. This study presents a long running trial aimed to address this evidence need. Randomising patients to either cytoreductive nephrectomy and sunitinib or sunitinib alone, this study showed that sunitinib was not inferior to nephrectomy with sunitinib. The primary endpoint assessed was overall survival. Additionally, there was no significant difference between the groups for response rate and progression free survival.

Guidelines

The EAU guidelines currently make the following recommendations:

  • Offer cytoreductive nephrectomy to favourable- and intermediate-risk patients with metastatic RCC.
  • Do not offer cytoreductive nephrectomy in IMDC poor-risk patients with ≥ 4 risk factors.
  • Perform immediate cytoreductive nephrectomy in patients with oligometastases when complete resection can be achieved
  • Offer deferred cytoreductive nephrectomy to intermediate-risk patients with clear-cell metastatic RCC who require systemic therapy with sunitinib.

The level of evidence supporting each of these recommendations is weak. [1]


Design

  • Trial type: prospective, multicentre, open label, randomised, phase 3 trial
    • CN + sunitinib 226
    • Sunitinib 224
  • Setting:79 centres in France, other centres in Europe (425 patients from France, 14 from UK, 10 from Norway, 1 from Sweden)
  • Enrollment: enrolled September 2009-September 2017
  • Mean follow-up: median of 50.9 months, range 0-86 (yet specifies minimum of 24 months in methods section).
  • Analysis: intention to treat with per protocol as supplementary
  • Primary outcome: overall survival

Population

Inclusion Criteria

  • Age ≥ 18 years
  • WHO score 0 - 1
  • Biopsy (primary tumour or metastases) confirming the diagnosis of clear cell carcinoma or preponderant (>50%)
  • Documented metastatic disease
  • Absence of prior systemic treatment for kidney cancer including AA
  • Tumour amenable to nephrectomy (partial or total) in the opinion of the patient’s urologist. Patients presenting with an inferior vena cava thrombosis can be included.
  • Patients for which the indication of Sunitinib is considered according to the recommendations rules given by national health authorities of participating countries. The prescription of Sunitinib in the circumstances of the study is considered as a standard treatment.
  • Platelets ≥ 100 x 109/L, haemoglobin > 9 g/dl, neutrophils >1.5 x 109/L;
  • Bilirubin <= 2 mg/dL, aspartate transaminase (ASAT) and alanine transaminase (ALAT) <= 2.5 times the upper normal limit (UNL) or <= 5 times UNL for patients with liver metastases
  • Patients of child bearing age should use contraceptive methods
  • Patient able to follow the procedures outlined in the protocol as far as the planning of visits and examinations are concerned.
  • Life expectancy ≥ 3 months
  • Written informed consent
  • Patient with Social Security System Insurance

Exclusion Criteria

  • Prior systemic treatment for kidney cancer (including Anti Angiogenic)
  • Pregnant or breast feeding women
  • Acute coronary syndrome or episode of myocardial infarction or severe or unstable angina within the last 6 months as well as severe diabetes with severe peripheral arteriopathy or deep phlebitis not treated with low molecular weight heparin or arterial thrombosis within the last 3 months
  • Curative anticoagulating
  • Medical, general or psychiatric difficulties which, in the opinion of the Investigator, would make it inappropriate for trial entry
  • Brain metastases
  • Preliminary radiotherapy for kidney cancer
  • Previous history of gastric disease or malabsorption, syndrome compromising the absorption of Sunitinib
  • Experimental treatment within the 28 days preceding inclusion
  • Other cancer within the previous 5 years (except for insitu skin carcinoma and treated localised prostate cancer with undetectable PSA)
  • Medical pathology or psychiatric (acute or chronic) pathology or biological disorder which could be aggravated by the study or by the administration of AA or can interfere with the interpretation of the results or any reason that could appear for the investigator
  • Sunitinib hypersensibility


Baseline Characteristics

Characteristics were well matched across the groups. Below is listed the nephrectomy-sunitinib demographics:

  • Age (range and median): 63 (33–84)
  • Male sex — no. (%) 169 (74.8)
  • MSKCC risk category — no./total no. (%) Intermediate risk 125/225 (55.6) ; Poor risk 100/225 (44.4)
  • ECOG performance-status score — no. (%): 0 130 (57.5) ; 1 96 (42.5)
  • Fuhrman grade of renal-cell carcinoma — no./total no. (%): 1 or 2 77/150 (51.3) 3 or 4 73/150 (48.7)
  • Tumor–node–metastasis stage — no./total no. (%) 71/207 (34.3) (NB 25.8% in comparator group)
  • Tumor stage
    • T1 5/67 (7.5) (NB 7/49 (14.3) in comparator group)
    • T2 13/67 (19.4) (NB 13/49 (26.5) in comparator group)
    • T3 or 4 47/67 (70.1) (NB 25/49 (51.0) in comparator group)
    • Tx 2/67 (3.0)
  • Node stage
    • N0 23/66 (34.8)
    • N1 13/66 (19.7) (NB 6/49 (12.2) in comparator group)
    • N2 7/66 (10.6) (NB 13/49 (26.5) in comparator group)
    • Nx 23/66 (34.8)
  • Median primary tumor size (range) — mm 88 (6–200)
  • Median no. of metastatic sites (range) 2 (1–5)
  • Median tumor burden (range) — mm 140 (23–399)
  • Location of metastases — no./total no. (%)
  • Lung 172/217 (79.3)
  • Bone 78/217 (35.9)
  • Lymph nodes 76/217 (35.0)
  • Other 78/217 (35.9)


Interventions

  • Group A – Nephrectomy, with Sunitinib commenced between 3-6 weeks post-op – Cycle of 50mg daily for 28 days, then 14 days off every 6 weeks
  • Group B – Sunitinib only – Cycle of 50mg daily for 28 days, then 14 days off every 6 weeks


Outcomes

Primary Outcomes

Overall survival
HR 0.89 (95% CI 0.71-1.10, upper limit of non inferiority <1.20)

Secondary Outcomes

Annual rate of death from any cause
1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)
Annual rate of cardiovascular death
0.79% vs. 0.56% (HR 1.35; 95% CI 1.04-1.76; P=0.02)

Subgroup Analysis

Survival stratified by disease severity:

  • Median survival longer in Sunitinib alone
    • Intermediate: 23.4 : 19.0
    • Poor: 13.3 vs 10.2
  • Hazard rations for death
    • Intermediate: 0.92 (95% CI 0.58-1.24)
    • Poor: 0.86 (95% CI, 0.62-1.17)

Adverse Events

Generally, the incidence of adverse events was similar between groups.

  • 4 post operative deaths (with in 1 month post op) in nephrectomy group
  • post operative complications 82/210 patients
    • 15.9% grade III or higher
  • 30.6% of patients required dose reduction (predominantly to manage adverse events.) Same in both groups
  • total patients reporting adverse events
    • 61 patients (32.8%) in the nephrectomy group
    • 91 (42.7%) in Sunitinib alone
  • Most commonly reported adverse events for sunitinib group
    • Asethnia (37), hand foot syndrome (20), anaemia (16), neutropenia (15)

Note only adverse events grade 3 and above reported.

Criticisms

  • Only poor and intermediate risk groups studied
  • Trial was closed early due to poor recruitment (sample size target not met)
  • Slow acrual may suggest selective referral for treatment or selective patient consenting
  • 17% cross over each way (patients in the nephrectomy group did not have sunitinib – 15%; patients in the sunitibinib only group underwent nephrectomy (17%)
  • 7% did not undergo nephrectomy in the nephrectomy group; 4.9% did not receive sunitinib in the sunitinib only group
  • Sunitinib is nolonger the best in class drug. This reflects the fact that trials comparing medical treatments are faster to conduct than those involving surgery.
  • Poor analysis strategy. The trial protocol was varied after accrual had ceased to include a per protocol analysis. The reason for two different per protocol analyses is unclear.


Funding

Supported by Assistance Publique–Hôpitaux de Paris (Clinical Research and Innovation Delegation), by a grant (PHRC-K 2007) from the Programme Hospitalier de Recherche Clinique Cancer– Ministère de la Santé, and by an unrestricted grant from Pfizer.

Further Reading


A commentary on the difficulty of answering this clinical question with reference to the SURTIME study [2]

Commentary on the CARMENA study in the NEJM [3]