November 2015, Vol. 2, No. 6

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Two New Options for Renal Cell Carcinoma

European Cancer Congress

Patients with advanced, pretreated renal cell carcinoma (RCC), who have limited treatment options, received good news from 2 important practice-changing trials presented as late-breakers at the recent 2015 European Cancer Congress (ECC)—CheckMate 025 and METEOR.

CheckMate 025 found a survival benefit for nivolu­mab over standard everolimus therapy in previously treated advanced RCC. This is the first trial to show a survival benefit for an immune checkpoint inhibitor after standard therapy has failed in this setting.

METEOR showed that cabozantinib nearly doubled progression-free survival (PFS) compared with standard everolimus in patients with advanced RCC that progressed with prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy.

Both studies were published separately online in The New England Journal of Medicine to coincide with presentation of results at 2015 ECC.

Experts at the congress said that these 2 trials would change the way RCC is treated.

CheckMate 025 Details

CheckMate 025 compared nivolumab with standard everolimus in 821 patients with advanced RCC who had received prior 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 10 mg/day.

Median overall survival (OS) was 25 months with nivolumab versus 19.6 months for standard everolimus (P = .002), representing a 27% reduction in risk of death favoring nivolumab. The benefit in survival associated with nivolumab was observed regardless of the level of programmed death-1 ligand 1 (PD-L1) expression in their tumors.

The trial was halted prematurely in June 2015 when the superior OS with nivolumab became evident. At that time, patients were offered the option of continuing on nivolumab or switching to nivolumab if they had been assigned to everolimus treatment at study 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 author Padmanee Sharma, MD, PhD, Scientific Director of the Immunology Platform and Professor at MD Anderson Cancer Center, Houston, TX.

The objective response rate showing tumor shrinkage was 25% for nivolumab versus 5.4% for everolimus (P <.001). Partial response rate was 24.1% versus 4.9%, respectively. Median PFS was similar, about 4 months in both groups. Stable disease was reported in 34.4% of those who received nivolumab versus 55.2% for everolimus.

Fewer grade 3/4 serious adverse events were reported in the nivolumab-treated group (19%) versus the everolimus-treated group (37%). The most frequently occurring adverse events with nivolumab were fatigue (33%), nausea (14%), and severe itching (14%). With everolimus, the most frequently occurring adverse events were fatigue (34%) and anemia (24%).

No treatment-related deaths occurred with nivolumab; 2 treatment-related deaths occurred 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,” Sharma said.

Regarding the lack of association with PD-L1 expression and survival seen in the trial, Sharma said, “This suggests that PD-L1 expression should not be used to determine which patients should be offered nivolumab.”

METEOR Details

The phase 3 METEOR trial showed that advanced kidney cancer patients treated with cabozantinib as second-line or later therapy had an almost twice as long PFS compared with 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 author Toni K. Choueiri, MD, Dana-Farber Cancer Institute, Boston, MA. “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, 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 must have received at least 1 prior VEGFR-targeted TKI and have had radiographic progression within 6 months after the most recent dose. No crossover was allowed.

Patients were randomized 1:1 to oral cabozantinib 60 mg/day or oral everolimus 10 mg/day and treated as long as benefit was observed or until the development of unacceptable toxicity.

The study met its primary end point of PFS. Median PFS was 7.4 months for cabozantinib versus 3.8 months for everolimus, representing a 42% reduction in risk of progression or death (P <.001).

Objective tumor responses were observed in 21% of the cabozantinib group compared with 5% of patients treated with everolimus.

A prespecified interim analysis showed a trend toward longer OS for cabozantinib versus everolimus (a 33% reduction in risk of death favoring cabozantinib; P = .005). This occurred despite more use of subsequent anticancer therapies in 47% of the everolimus group versus 38% in the cabozantinib group.

Median duration of treatment was 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: 60% for cabozantinib versus 25% for everolimus. However, discontinuation because of treatment-related adverse events was about 10% in both arms.

The most common adverse events with cabozantinib were diarrhea, fatigue, nausea, decreased appetite, palmar-plantar syndrome, and hypertension, consistent with those observed with other VEGFR TKIs in RCC. Higher rates of pneumonitis, peripheral edema, anemia, and hypoglycemia were observed with cabozantinib than with everolimus.

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