木瓜直播

Updated results of CheckMate 214 revealed that nivolumab (Opdivo) plus ipilimumab (Yervoy) improved survival rates in previously untreated patients with advanced, poorer-risk renal cell carcinoma (RCC).

After median follow-up of 25.2 months, the 18-month overall survival (OS) rate in poor- and intermediate-risk RCC patients treated with the anti–PD-1/CTLA-4 combination was 75% versus 60% among those treated with sunitinib (Sutent), reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

"Approximately 75% of patients with advanced RCC have intermediate- or poor-risk disease and have worse outcomes than those with favorable-risk disease," the authors wrote in the New England Journal of Medicine.

In September 2017, manufacturer Bristol-Myers Squibb announced that the in the immunotherapy combination arm.

The CheckMate 214 trial randomized 1,096 advanced RCC patients 1:1 to treatment with either nivolumab plus ipilimumab or sunitinib, with the majority (847 patients) classified as intermediate- or poor-risk based on well-characterized clinical and laboratory risk factors.

Median OS among these poorer-risk patients was not reached with the immunotherapy combination versus 26 months with sunitinib for a hazard ratio for death of 0.63 (P<0.001). The immunotherapy combination also yielded better rates of objective response (42% versus 27%) and complete response (9% versus 1%) compared with sunitinib.

Exploratory analyses of 249 favorable-risk patients found that sunitinib seemed to perform better, with a higher objective response rate favoring the VEGFR tyrosine kinase inhibitor (52% versus 29% with nivolumab/ipilimumab).

The advantage seen with sunitinib, both in objective responses and progression-free survival (25.1 months versus 15.3 months with the immunotherapy combination) did not translate into a significant OS improvement in the favorable-risk subgroup, however.

"These results in favorable-risk patients should be interpreted with caution because of the exploratory nature of the analysis, the small subgroup sample, and the immaturity of survival data," the investigators wrote, noting that only 37 deaths had occurred at time of database lock.

The PD-1 inhibitor nivolumab was previously approved by the FDA for treating RCC in patients with advanced disease whose disease progressed following treatment with antiangiogenic therapy. The CTLA-4 inhibitor ipilimumab is approved for treating melanoma, most recently in combination with nivolumab for unresectable or metastatic disease.

Treatment-related adverse events of all grades were nearly universal across both arms of CheckMate 214, at 93% with nivolumab/ipilimumab and 97% with sunitinib. Grade 3 or 4 events with the immunotherapy combination, which has been an issue in melanoma patients, were less frequent compared with sunitinib (46% versus 63%) in this RCC sample.

"The frequencies of treatment-related gastrointestinal, skin, and hepatic adverse events were lower than those seen in a trial involving patients with melanoma," the study authors wrote, noting that the melanoma trial had a higher ipilimumab dose and lower nivolumab dose. "Dose delays, treatment with glucocorticoids, and prompt diagnostic work-up to rule out noninflammatory causes were used to manage toxic effects."

In an editorial that accompanied the study, Brendan D. Curti, MD, of Providence Health and Services in Portland, Ore., highlighted the improved response seen with nivolumab plus ipilimumab among poorer-risk patients, which did not seem to translate to the favorable-risk group. "It is notable that tumors with a greater number of mutations appeared more likely to have a response to checkpoint immunotherapy. This suggests that there may be a higher tumor mutational load and a broad, though ineffective, extant adaptive immune response in patients with intermediate-risk and poor-risk RCC as compared with patients with favorable-risk disease."

Indeed, better responses and survival were seen in patients with greater PD-L1 expression. Among the 776 poorer-risk patients treated with immunotherapy, and with quantifiable PD-L1 expression, those with a level of 1% or greater had an 18-month OS rate of 81% versus 74% among those with expression levels less than 1%.

"The goal of future immunotherapy development should be not just transient response or tumor control, but rather cure in a higher proportion of patients," concluded Curti. "The combination of ipilimumab and nivolumab is a step in the right direction."