In separate head-to-head studies, nivolumab, an immune checkpoint inhibitor, and cabozantinib, a tyrosine kinase inhibitor, significantly improved outcomes compared with everolimus in patients with advanced renal cell carcinoma (RCC) whose disease progressed after previous treatment, according to study results presented at the 2015 European Cancer Congress in Vienna and published online simultaneously in the New England Journal of Medicine.


Nivolumab significantly prolonged overall survival and cabozantinib significantly improved progression-free survival.

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A monoclonal antibody, nivolumab blocks the interaction between the programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1). Interaction between PD-1 and PD-L1 or PD-L2 normally results in inhibition of the cellular immune response. The drug is approved by the FDA for treating metastatic melanoma that no longer responds to other drugs and for treating squamous non-small cell lung cancer. Cabazantinib targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, both of which have been implicated in the pathobiology of metastatic RCC or in the development of resistance to anti-angiogenic medications. It is approved by the FDA for the treatment of medullary thyroid cancer.


In the phase 3 international CheckMate 025 clinical trial, Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York, and colleagues studied 821 patients with advanced clear-cell RCC randomized to receive either nivolumab 3 mg/kg of body weight intravenously every 2 weeks or a 10-mg everolimus table orally once daily. All patients previously had received treatment with 1 or 2 regimens of anti-angiogenic therapy. The median overall survival, the study’s primary end point, was 25 months with nivolumab compared with 19.6 months with everolimus. Nivolumab recipients had a significant 27% decreased risk of death compared with everolimus recipients, a difference that met the prespecified criterion for superiority, the researchers reported.


In addition, results showed that nivolumab was associated with a significantly greater objective response rate than everolimus (25% vs. 5%). Median progression-free survival was 4.6 months with nivolumab and 4.4 months with everolimus, a non-significant difference between the treatments.


Grade 3 or 4 treatment-related adverse events (AEs) occurred in 19% of the nivolumab recipients compared with 37% of the everolimus recipients. The most common AE was fatigue in the nivolumab group (2% of patients) and anemia in the everolimus patients (8% of patients).


The trial was discontinued early in July when it became clear that overall survival was superior with nivolumab, with patients offered an opportunity to continue with nivolumab treatment or, for everolimus recipients, to switch to nivolumab.


“It is exciting to see the outcome of this study, as the results are significant and clinically meaningful to patients and healthcare professionals alike,” principal investigator Padmanee Sharma, MD, PhD, of the MD Anderson Cancer Center in Houston, said in an ECC press release. “They are likely to change the treatment of patients with advanced kidney cancer, whose disease has progressed on prior treatment. Although we cannot speculate at this time on when nivolumab might enter the clinic, we hope that this study will quickly lead to approval of nivolumab as a standard of care therapy for these patients.”


In the randomized, open-label, phase 3 METEOR trial, Toni K. Choueiri, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues compared cabozantinib with everolimus in 658 patients with RCC that had progressed after VEGFR-targeted therapy. Patients received either cabozantinib 60 mg daily or everolimus 10 mg daily. Median progression-free survival—the study’s primary end point—was 7.4 months with cabozantinib compared with 3.8 months with everolimus, a difference that translated into a significant 42% decreased risk of progression or death with cabozantinib versus everolimus. A significantly greater proportion of cabozantinib than everolimus recipients had objective tumor responses (21% vs. 5%).

“An early evaluation of overall survival from the ongoing METEOR trial has shown a strong trend indicating that survival may be improved in patients receiving cabozantinib compared to standard therapy,” Dr. Choueiri said in an ECC press release. “The final evaluation regarding survival will occur at a later time when the data have further matured with longer follow up of the patient population. Overall, these results should give new hope to patients diagnosed with advanced kidney cancer as cabozantinib may become a new treatment option.”