VIENNA, Austria—A pair of studies indicate that two new drugs can significantly extend both overall and progression-free survival among patients with advanced renal cell carcinoma, researchers reported here at the European Cancer Congress. Patients treated with nivolumab achieved a median overall survival of 25 months compared with 19.6 months with everolimus, said Padmanee Sharma, MD, PhD, Professor of Genitourinary Medical Oncology and Immunology at the University of Texas MD Anderson Cancer Center.
“The risk of death was reduced by 27 percent in patients in the nivolumab-treatment group compared with those in the everolimus group,” she said at a news conference sponsored by the meeting organizers. In the Bristol-Myers Squibb-sponsored CheckMate 025 study, 21 percent of the patients on nivolumab achieved an objective response to therapy—including four patients who had a complete response—compared with five percent of patients receiving everolimus. (Everolimus is the current standard of care for patients with metastatic renal cell carcinoma.)
And, treatment with the tyrosine-kinase inibitor cabozantinib showed it could nearly double progression-free survival when compared with everolimus among similar patients, reported Toni K. Choueiri, MD, Clinical Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and principal investigator for that study, called METEOR.
Patients assigned to the cabozantinib-treatment group achieved a median progression-free survival of 7.4 months compared with 3.8 months for patients assigned to everolimus, Choueiri said at the news conference, at which results of both studies were detailed. He said the difference in outcome translated to a 42 percent reduction in the rate of disease progression or death for cabozantinib (P>0.001).
The METEOR researchers also conducted a prespecified overall survival analysis that indicated treatment with cabozantinib resulted in a 33 percent reduction in the risk of death (P=0.005), but under the statistical rules for such an interim analysis, the result was not considered statistically significant. “We have to wait for these results to further mature,” Choueiri said.
While the CheckMate 025 population of metastatic renal cancer patients limited to two the number of previous regimens a person could have had to be eligible for the trial, the trial with cabozantinib was more open, he noted: There was no limit on the number of previous regimens the patient may have been on.
CheckMate 025 was halted early after a planned interim analysis that occurred after 398 deaths had been recorded. The assessment on an independent data monitoring committee determined that the study met its primary endpoint, demonstrating superior overall survival for nivolumab, Sharma said.
“Immunotherapy has long been believed to have the potential to make an impact in kidney cancer, but until now we had not been able to demonstrate such a significant survival benefit. We have a real opportunity to change clinical practice for patients when other therapies have failed. Through studies such as CheckMate-025, we are learning to target the patients' immune systems to fight cancer rather than targeting the tumor itself. This is a new way forward.”
The researchers suggested that for patients who were responding to treatment and were not experiencing unmanageable toxicity they could be taking the agents indefinitely.
Among patients who showed a response, the impact was “durable,” Sharma said. This ongoing response was observed among 44 percent of those treated with nivolumab and 36 percent of those treated with everolimus. More than 12 months later, 31 percent and 27 percent of patients treated with nivolumab and everolimus, respectively, continued to show a response.
For some patients, even after treatment with nivolumab ended, response to the drug continued. “The immune system has a memory, so even when treatment has stopped, the body continues to exhibit a long-term response—meaning these patients can live normal lives without progressive disease,” she said.
Both studies are now available online ahead of print in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1510665 and DOI: 10.1056/NEJMoa1510016)
Both nivolumab (Opdivo, Bristol-Myers Squibb) and cabozantinib (Cometriq, Exelixis) are approved for other cancer treatments. Nivolumab is indicated for melanoma and lung cancer patients; cabozantinib is indicated for use in progressive medullary thyroid cancer.
Perspective from Martine Piccart
Asked for her perspective, Martine Piccart, MD, PhD, Professor of Oncology at Université Libre de Bruxelles and Director of Medicine at Jules Bordet Institute—and Chair of the meeting, who moderated the news conference—said she would likely use nivolumab in her advanced renal cancer patients because the drug showed a substantial improvement in overall survival. “When we tell patients that a drug is going to improve survival, they are going to be able to cope with a lot of side effects,” she said.
“That is not the same as telling the patients that this drug will extend a little bit the control of the disease. When it doesn't impact your overall survival, then toxicities are much more important. I would wait for using cabozantinib until they get the mature overall survival results.”
She added, “Many drugs get approval on very small improvements in overall survival, but I think that a five-month increase in overall survival is clinically meaningful.”
Piccart also noted that use of the drugs was likely to be slowed by their costs. “These are very expensive drugs,” she said. Hence, she suggested that substantial benefit such as seen with nivolumab in overall survival would have to be demonstrated to get the drugs to patients who need them.
CheckMate 025 Trial Details
In the Phase III open-label CheckMate 025 trial, Sharma and colleagues enrolled 821 patients, assigning 410 to receive nivolumab in an intravenous 3 mg/kg dose every two weeks. The other 411 patients were treated with 10 mg a day of oral everolimus. Patients were treated until progression or if the treatment proved intolerable.
Clinicians could opt to treat patients after disease progression if they still felt the patient was receiving clinical benefit, Sharma explained. Patients were eligible if they had been diagnosed with clear cell renal cell carcinoma and had disease progression despite treatment with one or two prior anti-angiogenic regimens.
The safety analysis of the study indicated that Grade 3 or 4 adverse events were less often observed among the patients on nivolumab than among patients on everolimus, she said. Of those on nivolumab, 76 patients (19% of the group receiving the drug) had Grade 3 or 4 events—most frequently fatigue, anemia, pneumonitis, and diarrhea.
A total of 145 patients (37%) on everolimus had Grade 3 or 4 adverse events—most frequently fatigue, stomatitis, anemia, diarrhea, and decreased appetite. “There were no treatment-related deaths among the patients on nivolumab,” she said.
In METEOR, Choueiri and colleagues enrolled 650 patients diagnosed with clear cell histology, who had measurable disease and whose disease had progressed on a prior vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor within six months of enrollment. No limit to the number of prior therapies made a patient ineligible for the study. Patients who had treated brain metastases were also eligible to participate. The patients were given 60 mg of cabozantinib once daily or 10 mg of everolimus once daily.
In a post-hoc subset analysis of patients who had received sunitinib, the most commonly used first-line therapy as their only prior VEGF receptor inhibitor, the median progression-free survival for 76 such cabozantinib-treated patients was 9.1 months compared with 3.7 months for the 77 everolimus-treated patients who fit this post-hoc criteria. This corresponds to a 59% reduction in the rate of disease progression or death for patients treated with Cabozantinib, Choueiri reported.
“In the METEOR trial, cabozantinib significantly improved progression-free survival as compared with everolimus, a commonly used standard of care, in both the full study population for the primary endpoint analysis as well as in the subgroup of patients previously treated with sunitinib only. Cabozantinib was also associated with a safety profile similar to those of other VEGF receptor inhibitors used to treat renal cell carcinoma.”
He suggested that it could be possible that nivolumab and cabozantinib could be given concurrently to patients since the agents had different mechanisms of action. He said adverse events would need to be assessed to determine how likely that type of combination would be.