The mTOR inhibitor everolimus failed to prove progression-free survival noninferiority compared with the VEGF-targeting tyrosine kinase inhibitor sunitinib when given as first-line treatment in patients with metastatic renal cell carcinoma (RCC), according to the results of the phase II RECORD-3 trial.
The results of the trial were presented by Robert John Motzer, MD, of Memorial Sloan Cancer Center, at the annual meeting of the American Society of Clinical Oncology (ASCO).
Everolimus is currently the standard therapy given to patients with metastatic RCC after they have progressed on sunitinib. In this study, Dr. Motzer and colleagues examined if first-line everolimus followed by sunitinib was a noninferior treatment sequence.
The primary objective of the study was to assess progression-free survival noninferiority of first-line everolimus compared with first-line sunitinib. The investigators also compared combined progression-free survival for the two sequences of treatment.
The open-label phase II trial included 471 patients without prior systemic therapy who were randomly assigned to first-line treatment with everolimus (n = 238) or sunitinib (n = 233). Patients continued on first-line therapy until they had evidence of progression and were then crossed over to the alternative therapy. Progression-free survival was defined as the time from patient randomization to progressive disease or death before the start of second-line treatment.
When looking at noninferiority of everolimus, the progression-free survival analysis showed that the study did not meet its primary objective.
“The estimated hazard ratio for progression-free survival first-line was 1.43, which did not satisfy the protocol-defined noninferiority margin,” Dr. Motzer said.
The median progression-free survival for sunitinib was 10.71 months compared with 7.85 months for everolimus.
The researchers also conducted a pre-specified analysis of progression-free survival by risk group and by predominant histology. The findings of both analyses were consistent with the primary analysis, showing benefit for sunitinib compared with everolimus.
The objective response rate for patients assigned everolimus was 8% compared with 26.6% with sunitinib. Nearly all responses seen were partial responses.
When the researchers examined the combined progression-free survival for the two sequences, results indicated that the median progression-free survival for patients assigned everolimus followed by sunitinib was 21.13 months compared with 25.79 months for sunitinib followed by everolimus.
“The analysis was limited, however, since only 207 of 471 patients on study crossed over to second line, and there were a relatively low number of second-line events,” Dr. Motzer said.
The median overall survival for first-line everolimus was 22.41 months compared with 32.03 months for first-line sunitinib. Dr. Motzer noted the number of early deaths on the everolimus arm and the fact that many of the patients were censored around the median. He added that it is likely that these numbers will change somewhat.
“However, there is a trend for longer overall survival for patients treated with sunitinib followed by everolimus standard sequence,” Dr. Motzer said. “The final overall survival analysis will be performed 3 years after last patient was randomized.”
More deaths occurred with first-line everolimus than with sunitinib; however, these deaths were not related to adverse events, but instead were related to early progression of disease.
In his discussion of the results, Toni Choueiri, MD, director of the kidney cancer center, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, said that the trial addressed an important question about drug sequencing and whether there is a place for a frontline mTOR inhibitor in an unselected metastatic RCC front-line population.
However, he also pointed out several weaknesses with the trial including the fact that the crossover data assumed patients were able to crossover. In fact, Dr. Choueiri said that he “strongly argued” that the progression-free survival data from first-line therapy, after crossover, and the overall survival data may not be reliable and is not relevant for patient care.
“There is a very high censoring around the median,” Dr. Choueiri said. “And there is an uncertainty how [combined PFS] was calculated for patients censored on first-line therapy.”
Overall, Dr. Choueiri said that this trial shows that VEGF-targeted therapy remains the standard of care in metastatic RCC. Moving forward, it will be important to identify tumors addicted to mTOR pathway signaling, as that might help predict longer time to progression on mTOR inhibitors.