Two Contenders for Second-Line Treatment of Advanced Renal Cell Carcinoma

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Robert J. Motzer, MD

Bernard J. Escudier, MD

Nivolumab represents a new standard of care for patients with advanced renal cell carcinoma treated with prior VEGF [tyrosine kinase inhibitor] therapy. We think it is a good choice for second-line therapy.

—Robert J. Motzer, MD
Our preliminary results suggest that cabozantinib may help overcome treatment resistance and provide new hope to patients with this aggressive cancer.

—Bernard J. Escudier, MD

Options for second-line therapy of advanced/metastatic renal cell carcinoma are expanding. Updates from the CheckMate 025 and METEOR ­trials presented at the 2016 Genitourinary Cancers Symposium solidify the value of both nivolumab (Opdivo, an immune checkpoint inhibitor) and cabozantinib (Cometriq, a small-molecule inhibitor of tyrosine kinases) as second-line therapy.1,2

Nivolumab is already U.S. Food and Drug Administration (FDA)-approved for treating metastatic renal cell carcinoma. Cabozantinib is FDA-approved for the treatment of thyroid cancer. There is debate in the oncology community about which of these drugs would be the preferred second-line option, if cabozantinib were to be approved for this indication.

CheckMate 025 Subgroup Analysis

CheckMate 025 was a pivotal study designed to compare nivolumab vs everolimus (Afinitor) in 821 previously treated patients with metastatic renal cell carcinoma. The study met its primary endpoint, showing a significant survival advantage for nivolumab, improved overall response rates, fewer grade 3 and 4 adverse events, and improved quality of life. Based on these results, nivolumab was approved as second-line therapy after one or two prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor therapies.

Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC), New York, updated attendees on key subgroup results as well as results according to prior number and type of therapy.

“Nivolumab should be considered as second-line therapy after a first-line VEGFR [tyrosine kinase inhibitor]. This agent improved quality of life over everolimus. The duration of response makes it an attractive choice, as does the consistent survival benefit seen in all subgroups,” Dr. Motzer stated.

Previously reported results showed improved overall survival regardless of the level of programmed cell death ligand 1 (PD-L1) expression. The new key subgroup analyses based on MSKCC risk score, number and site(s) of metastases, prior therapy, and details of prior therapy all favored nivolumab over everolimus.

Key Findings

Nivolumab was favored for overall survival in all MSKCC risk groups, with the largest benefit observed in the poor-risk group. Nivolumab also outperformed everolimus regardless of the number, type, and site of metastasis, including lung, bone, and liver.

“Bone and liver metastases are associated with poor prognosis. Bone metastases are especially problematic in patients treated with a VEGFR [tyrosine kinase inhibitor]. A survival benefit for nivolumab was seen for both bone and liver metastases,” he said.

Similarly, nivolumab was associated with more favorable survival compared with everolimus in all subgroups for prior systemic therapy, including sunitinib and pazopanib (Votrient). More than 60% of patients had received sunitinib as first-line therapy, and in this group, there was a 19% improvement in survival for nivolumab recipients. Median overall survival was 23.6 months for nivolumab vs 19.8 months for everolimus.

In the 30% of patients on first-line pazopanib, nivolumab improved survival by 40%. Median survival was not yet reached for nivolumab vs 17.6 months for everolimus. In both the sunitinib- and pazopanib-pretreated groups, about 60% of patients were alive after 18 months on nivolumab.

Median overall survival was lower for patients who were treated in the first line for less than 6 months compared with those treated for more than 6 months. Nivolumab was favored in both subgroups.

About 75% of patients had received one prior VEGFR tyrosine kinase inhibitor therapy prior to enrollment. Among these patients, nivolumab improved survival by 21%: Median overall survival was 23.6 months with nivolumab vs 19.9 months for everolimus.

“Nivolumab represents a new standard of care for patients with advanced renal cell carcinoma treated with prior VEGF [tyrosine kinase inhibitor] therapy. We think it is a good choice for second-line therapy,” Dr. Motzer said. “We have developed a new standard of care with a new type of agent, and our patients will benefit for many years to come.”

METEOR Subgroup Analysis

The METEOR trial compared cabozantinib vs everolimus in patients with metastatic renal cell carcinoma. At the first interim analysis, cabozantinib significantly improved progression-free survival, and a strong trend was observed toward improved overall survival vs standard treatment with everolimus.

“Current treatments can provide some benefit to patients with advanced kidney cancer, but we need treatments that are more effective and can overcome treatment resistance. Our preliminary results suggest that cabozantinib may help overcome treatment resistance and provide new hope to patients with this aggressive cancer,” said lead author Bernard J. Escudier, MD, Chair of the Genitourinary Oncology Committee at the Institut Gustave Roussy, Villejuif, France.

“I predict that cabozantinib will become the drug of choice after PD-1 or PD-L1 failure,” he told listeners.

Cabozantinib targets MET and AXL, which are associated with poor prognosis and resistance to a VEGFR tyrosine kinase inhibitor. Thus, its mechanism of action is theoretically attractive for patients who have disease progression on first-line therapy with a VEGFR tyrosine kinase inhibitor.

METEOR enrolled 658 patients with advanced kidney cancer previously treated with one or two lines of therapy (with a VEGFR tyrosine kinase inhibitor or checkpoint inhibitor). Patients were randomly assigned to receive either cabozantinib or everolimus (both drugs are oral agents) and treated until loss of benefit or intolerable toxicity. No crossover was allowed in the study. 

Second-Line Therapy for Kidney Cancer

  • Two large phase III trials showed impressive progression-free survival results for nivolumab and cabozantinib as second-line therapy for metastatic renal cell carcinoma.
  • Final survival results are needed for the cabozantinib trial.
  • Some experts predict that cabozantinib will be the preferred option for second-line therapy, whereas others believe nivolumab is presently the preferred option.

Key Findings

Progression-free survival for the first 375 patients enrolled in the trial was reported at the interim analysis. Median progression-free survival was 7.4 months on cabozantinib vs 3.8 months on everolimus (P < .001), representing a 42% reduction in risk of disease progression favoring cabozantinib.

Cabozantinib was favored across all subtypes for progression-free survival, regardless of risk category, metastatic sites, and number and type of prior treatments. In an exploratory analysis of progression-free survival, cabozantinib appeared to be even more effective in patients with bone metastasis, those previously treated with first-line sunitinib, and those who experienced treatment failure on prior checkpoint inhibitor therapy.

Progression-free survival was quite robust with cabozantinib in patients for whom sunitinib was their only prior tyrosine kinase inhibitor: Median progression-free survival was 9.1 months in the cabozantinib group. “This has never been seen before,” Dr. Escudier said.

Only 32 patients had prior checkpoint inhibitor therapy, so the improved progression-free survival data in this small subgroup were hypothesis-generating and need further study, he noted.

Side effects commonly reported with cabozantinib included diarrhea, fatigue, nausea and vomiting, and hand-foot syndrome. Common side effects reported with everolimus included fatigue, anemia, decreased appetite, cough, and dyspnea.

Patients are increasingly being treated with nivolumab as second-line therapy, Dr. Escudier said, adding that it was too early to say that cabozantinib would be the preferred option. The results in subgroups would need to be replicated in larger numbers of patients, in his opinion.

Final overall survival results will be presented at the ASCO Annual Meeting in June.  ■

Disclosure: Dr. Motzer is a consultant for Pfizer; has received research funding (institutional) from Bristol-Myers Squibb, Eisai, Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer; and travel expenses from Bristol-Myers Squibb and GlaxoSmithKline. Dr. Escudier has served in a consulting or advisory role for AVEO, Bayer, GlaxoSmithKline, Novartis, and Pfizer.


  1. Motzer RJ, Sharma P, McDermott DF, et al: CheckMate 025 phase III trial: Outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. 2016 Genitourinary Cancers Symposium. Abstract 498. Presented January 9, 2016.
  2. Escudier BJ, Motzer RJ, Powles T, et al: Subgroup analyses of METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma. 2016 Genitourinary Cancers Symposium. Abstract 499. Presented January 9, 2016.

 Corrections were made to this article on February 11, 2016.

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