CARMENA: Targeted therapy not inferior to nephractomy in select patients with mRCC
BY NEIL Osterweil
Nephrectomy – either complete or partial surgical removal of a cancer-involved kidney – has been the standard of care for patients with metastatic renal cell carcinoma (mRCC) for nearly 20 years. But with the advent in 2005 of therapies that targeted vascular endothelial growth factor (VEGF) signaling, the therapeutic landscape for patients with mRCC began to change for the better.
Targeted therapies for mRCC include sunitinib and pazopanib, which are tyrosine kinase inhibitors (TKIs) directed against VEGF cell signaling, the antiangiogenic monoclonal antibody bevacizumab, and the mammalian target of rapamycin inhibitor temsirolimus.
Although retrospective studies and a systematic analysis of cohort studies have suggested a clinical benefit to combining targeted therapy with nephrectomy, data from prospective studies of the effects of nephrectomy and targeted therapies on overall survival have been hard to come by – until now.
The randomized phase 3 CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques) trial, presented at the 2018 annual meeting of the American Society of Clinical Oncology and published simultaneously online in the New England Journal of Medicine, demonstrated that, in patients with intermediate- or poor-risk mRCC, medical therapy with sunitinib alone was not inferior to nephrectomy and adjuvant sunitinib, the current standard of care.
Among 450 patients followed for a median of 50.9 months, median overall survival was 18.4 months with sunitinib alone, compared with 13.9 months in patients who received nephrectomy and adjuvant sunitinib. The stratified hazard ratio for death with sunitinib was 0.89, with the upper boundary of the 95% confidence interval of 1.10; this was below the prespecified limit of 1.20, so it met the primary endpoint of noninferiority of sunitinib alone.
The findings of the trial demonstrated that many patients with mRCC could be spared the potential risks and comorbidities associated with nephrectomy, according to Arnaud Méjean, MD, PhD, head of urology at Hôpital Européen Georges-Pompidou – Paris Descartes University in Paris and lead investigator on the study.
The decision to forgo nephrectomy is based on several factors unique to each patient, including size of the primary tumor and other risk factors, and the procedure can still be an essential component of care for certain patients, he said in an interview at the annual meeting of the American Society of Clinical Oncology.
The CARMENA trial was conducted using sunitinib as the therapeutic agent of choice because of clinical experience with this agent and the best available evidence at that time. Since the initiation of the trial, however, newer agents and combinations – such as the combination of the immune checkpoint inhibitors nivolumab and ipilimumab, or the TKI cabozantinib, which targets c-Met and VEGF receptor 2 – have shown greater efficacy than sunitinib alone. Yet given the difficulty of accruing patients for a randomized trial, it is doubtful that a study of the scope of CARMENA could be performed again, Dr. Mejean said.
Although the majority of patients who do undergo nephrectomy have a total resection because of the large size of the primary tumor, there are some patients who may still benefit from partial nephrectomy, and it may be possible with neoadjuvant therapy to shrink unresectable tumors to a size conducive to partial nephrectomy, Dr. Mejean acknowledges.
Brian I. Rini, MD, professor of hematology and medical oncology at the Cleveland Clinic Lerner College of Medicine agreed that neoadjuvant chemotherapy can make it possible for surgeons to perform less radical procedures. Targeted therapy in the adjuvant setting is somewhat controversial, but it may be recommended for patients with good performance status or other clinical features suggesting that they could benefit from a TKI, he said in an interview at the ASCO annual meeting.
The CARMENA trial results demonstrated that, in the metastatic renal cell carcinoma setting, patients with borderline presentations who might experience significant morbidities from surgery may have outcomes with sunitinib alone that are comparable to those with surgery followed by sunitinib.
One of the most important unanswered questions in the treatment of patients with mRCC is the utility of biomarkers such as the programmed death-1 ligand 1 (PD-L1), according to David Y.T. Chen, MD, associate professor of surgical oncology at the Fox Chase Cancer Center in Philadelphia. However, the CARMENA trial results give urologic oncologists confidence that some patients with mRCC can be safely managed without surgery, he said in an interview at the meeting.