Vienna, Austria—Patients with advanced, pretreated renal-cell carcinoma (RCC) who have limited treatment options got good news from 2 important practice-changing trials, CheckMate 025 and METEOR, which were presented as late-breaking abstracts at the 2015 European Cancer Congress (ECC). CheckMate 025 showed a survival benefit for nivolumab (Opdivo) over standard therapy with everolimus (Afinitor) in patients with previously treated advanced RCC. This is the first trial to show a survival benefit for an immune checkpoint inhibitor after standard therapy has failed. METEOR showed that cabozantinib (Cometriq) nearly doubled progression-free survival (PFS) compared with standard everolimus in patients with advanced RCC whose disease progressed with previous vascular endothelial growth factor (VEGF) receptor (VEGFR)-targeted therapy.
Both studies were published online to coincide with the presentation of their results at the 2015 ECC meeting (Motzer RJ, et al. N Engl J Med. 2015;373:1803-1813; Choueiri TK, et al. N Engl J Med. 2015;373:1814-1823).
At 2015 ECC, experts said that these 2 trials would change the way RCC is treated.
CheckMate 025 compared nivolumab with standard everolimus in 821 patients with advanced RCC who received previous treatment with a VEGFR-targeted tyrosine kinase inhibitor (TKI). Patients were randomized to receive nivolumab 3 mg/kg intravenously every 2 weeks or oral everolimus 120 mg daily.
The median overall survival (OS) was 25 months with nivolumab versus 19.6 months for standard everolimus (P = .002), representing a 27% risk reduction for death. The benefit in survival associated with nivolumab was observed regardless of the level of PD-1 ligand 1 (PD-L1) expression.
The trial was halted prematurely in June 2015 when the superior OS with nivolumab became evident. At that time, the patients were offered the option of continuing with nivolumab or switching to nivolumab if they had been assigned to everolimus at the study’s initiation.
“CheckMate 025 is the first and only study in which immunotherapy with a checkpoint inhibitor, used after prior treatment has failed, has shown a benefit in overall survival among patients with advanced kidney cancer for whom treatment options are currently limited,” said lead investigator Padmanee Sharma, MD, PhD, MA, Scientific Director, Immunotherapy Platform, and Professor, M.D. Anderson Cancer Center, Houston.
The objective response rate showing tumor shrinkage was 25% for nivolumab versus 5.4% for everolimus (P <.001). The partial response rates were 24.1% and 4.9%, respectively. The median PFS was similar, at approximately 4 months in both groups. Stable disease was reported in 34.4% of the patients who received nivolumab versus in 55.2% of those who received everolimus.
Grade 3 or 4 serious adverse events were lower with nivolumab than with everolimus (19% vs 37%, respectively). No treatment-related deaths occurred with nivolumab compared with 2 deaths in the everolimus arm.
“Results of this trial are likely to change treatment of patients with advanced RCC whose disease has progressed despite prior treatment. Although we cannot speculate on the time when nivolumab becomes available in the clinic, we hope that this study will quickly lead to approval of nivolumab as standard therapy for these patients,” Dr Sharma said.
Regarding the lack of association with PD-L1 expression and survival seen in the trial, Dr Sharma said, “This suggests that PD-L1 expression should not be used to determine which patients should be offered nivolumab.”
The phase 3 METEOR trial showed that patients with advanced kidney cancer who received cabozantinib as second-line or later therapy had almost twice as long of a PFS duration as patients receiving standard everolimus therapy.
Moreover, an interim analysis showed a trend toward improved OS favoring cabozantinib, but longer follow-up is needed to establish a significant survival benefit.
“This study can change the standard of care for patients with advanced kidney cancer who have received prior standard therapy targeting the VEGF receptor,” said lead investigator Toni K. Choueiri, MD, Director, Kidney Cancer Center, Dana-Farber Cancer Institute, Boston. “Cabozantinib is a new option for second-line therapy of RCC.”
Resistance to currently FDA-approved TKIs for the treatment of RCC is a major challenge. Cabozantinib, which is approved for the treatment of advanced thyroid cancer, is an oral multitargeted TKI designed to overcome resistance by targeting MET and AXL, as well as VEGFR, which have been implicated in resistance and poor prognosis.
METEOR enrolled 658 patients diagnosed with advanced RCC and clear-cell histology from 173 centers in 26 countries; all patients received ≥1 previous VEGFR-targeted TKIs and had radiographic progression within 6 months after the most recent dose. No crossover was allowed.
The patients were randomized 1:1 to oral cabozantinib 60 mg daily or to oral everolimus 10 mg daily and received treatment as long as benefit was observed or until the development of unacceptable toxicity. The median PFS was 7.4 months for cabozantinib versus 3.8 months for everolimus, representing a 42% reduction in risk for progression or death (P <.001). Objective tumor responses were observed in 21% of the cabozantinib group compared with 5% of the patients in the everolimus group.
A prespecified interim analysis showed a trend toward longer OS with cabozantinib versus everolimus (a 37% risk reduction for death), despite an increase in subsequent anticancer therapies used in 47% of patients in the everolimus group versus 38% in the cabozantinib group. The median durations of treatment were 7.6 months for cabozantinib and 4.4 months for everolimus.
One downside of cabozantinib was the need for more frequent dose reductions for adverse events, which occurred in 60% for cabozantinib versus 25% for everolimus. However, discontinuation as a result of treatment-related adverse events was approximately 10% in both arms. The most common adverse events with cabozantinib were diarrhea, fatigue, nausea, decreased appetite, palmar-plantar syndrome, and hypertension, which was consistent with those observed with other VEGFR TKIs in RCC. Higher rates of pneumonitis, peripheral edema, anemia, and hypoglycemia were observed in patients receiving cabozantinib than in those receiving everolimus.