Combination immunotherapy could be a new standard of care for some patients with advanced renal cell carcinoma (RCC), suggest the results of a large randomized phase 3 trial
In the trial, both overall survival and objective response rates were significantly higher with nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb) as compared to sunitinib (Sutent, Pfizer) in patients with intermediate- and poor-risk advanced RCC.
The 18-month overall survival rate was 75% with nivolumab plus ipilimumab vs 60% with sunitinib; the objective response rate was 42% vs 27%.
The findings were initially presented at the European Society of Medical Oncology 2017 Congress and were reported by Medscape Medical News at that time. They have now been published online in the New England Journal of Medicine.
“The study showed improvement in response and overall survival compared to sunitinib for patients with intermediate or poor features, comprising about 80% of patients with metastatic RCC,” said lead author Robert Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.
“In this group, nivolumab plus ipilimumab should be a new treatment option — pending regulatory approval — and a new standard of care,” he told Medscape Medical News. “The benefit was seen in the entire kidney cancer population as well, but in the small subset of patients with favorable-risk disease, the sunitinib group had higher response rates. So sunitinib will be regarded by most as the option of choice for favorable-risk patients.”
The combination of nivolumab plus ipilimumab has already been investigated in several tumor types, and response rates tend to be better than those of either agent used alone. The combination has been approved for the treatment of advanced melanoma.
The combination has also demonstrated antitumor activity in untreated and previously treated patients with advanced RCC, the authors note.
Significant Improvement in Survival and Response
The cohort included 1082 patients with previously untreated clear-cell advanced RCC who were randomly assigned to receive treatment with nivolumab plus ipilimumab (n = 547) or with sunitinib (n = 535). In the intent-to-treat population, 423 patients had intermediate-risk disease, and 416 patients had poor-risk disease.
The coprimary end points were overall survival, objective response rate, and progression-free survival in the group at intermediate or poor risk.
In the intermediate- and poor-risk group, the 12-month overall survival rate was significantly better in the nivolumab plus ipilimumab arm compared with that in the sunitinib arm: 80% vs 72% (hazard ratio for death, 0.63; 99.8% confidence interval, 0.44 – 0.89; P < .001).
The median overall survival was not reached with nivolumab plus ipilimumab. It was 26.0 months with sunitinib.
A complete response was observed in 40 patients (9%) in the nivolumab plus ipilimumab arm and in 5 patients (1%) in the sunitinib arm. Among the intermediate- and poor-risk patients, 81% in the nivolumab plus ipilimumab arm demonstrated a duration of response of at least 1 year; 70% of patients in the sunitinib arm demonstrated a duration of response of at least 1 year. The median duration of response not reached in the nivolumab plus ipilimumab arm; it was 18.2 months in the sunitinib arm.
For progression-free survival, the median was 11.6 months with nivolumab plus ipilimumab and 8.4 months with sunitinib, but the difference between groups did not meet the prespecified threshold (P = .009) for statistical significance (hazard ratio for disease progression or death, 0.82; P = .03).
The authors assessed outcomes for the entire intent-to-treat population (patients with favorable, intermediate, or poor risk). The 12-month overall survival rate was 83% for immunotherapy vs 77% with sunitinib; the 18-month overall survival rate was 78% vs 68%.
The median overall survival was not reached for the nivolumab plus ipilimumab arm; it was 32.9 months for the sunitinib arm. The rate of independently assessed objective response was 39% with nivolumab plus ipilimumab and 32% with sunitinib (P = .02; not significant per the prespecified 0.001 threshold).
Median progression-free survival rates were similar for both groups: 12.4 with nivolumab plus ipilimumab and 12.3 months with sunitinib (hazard ratio for disease progression or death, 0.98; P = .85).
Favorable Risk Favors Sunitinib
The subgroup of patients who were considered to be at favorable risk did worse with immunotherapy than with sunitinib. An exploratory analysis found that in this small subgroup (n = 249), response rates were higher and progression-free survival was longer with sunitinib than with the combination of nivolumab and ipilimumab.
The 12-month overall survival rate was 94% with nivolumab plus ipilimumab and 96% with sunitinib. The 18-month overall survival rates were 88% and 93%, respectively (the hazard ratio for death favored sunitinib: 1.45; 99.8% CI, 0.51 – 4.12; P = .27). The objective response rate was 29% with nivolumab plus ipilimumab vs 52% with sunitinib (P < .001). The median progression-free survival was 15.3 months vs 25.1 months (hazard ratio for disease progression or death, 2.18; 99.1% CI, 1.29 – 3.68; P < .001), favoring sunitinib.
The rate of complete response, however, was 11% with nivolumab plus ipilimumab and 6% with sunitinib.
“It is important to evaluate and better understand the underlying tumor biology of each of these groups to better define what is driving response to nivolumab plus ipilimumab and to sunitinib,” said Motzer. “We have not compared the combination to nivolumab alone, although cross-study comparisons favor the nivolumab/ipilimumab combination in producing tumor responses.”
Patients who received the immunotherapy combination had fewer grade 3-4 adverse events than those who received sunitinib (46% vs 63%), but there were more discontinuations (22% with immunotherapy vs 12% with sunitinib) and more treatment-related deaths (8 patients vs 4 patients). Overall, treatment-related adverse events of any grade occurred in 93% of patients in the immunotherapy group vs 97% of those treated with sunitinib.
Curative Treatments Needed
In an accompanying editorial, Brendan Curti, MD, from the Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, writes that it is “notable that tumors with a greater number of mutations appear more likely to have a response to checkpoint immunotherapy.”
This may account for the better response with immunotherapy seen in some patients but not others. There may be a “higher tumor mutational load and a broad, though ineffective, extant adaptive immune response in patients with intermediate- and poor-risk renal-cell carcinoma as compared with patients with favorable-risk disease,” says Curti.
But importantly, the combination of ipilimumab and nivolumab is a step in the right direction when it comes to improving treatment in RCC. He notes that for the past quarter century, treatment has evolved from “infrequently effective cytokine-based immunotherapy to active but rarely curative TKI [tyrosine kinase inhibitor] treatment, and now to more effective immunotherapy that in some clinical settings is superior to TKIs.”
However, with current therapies, there is still only a small probability of complete response or cure. “The goal of future immunotherapy development should be not just transient response or tumor control, but rather cure in a higher proportion of patients,” Curti emphasizes.
The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Patients treated at the Memorial Sloan Kettering Cancer Center were supported in part by a Memorial Sloan Kettering Cancer Center support grant/core grant. Dr Motzer received grant support from Bristol-Myers Squibb during the conduct of the study; has received grant support and personal fees from Pfizer, Novartis, Eisai, and Exelixis and grant support from Genentech/Roche outside the submitted work. Several coauthors have disclosed relationships with industry, as noted in the original article. Dr Curti has received grants, personal fees, and nonfinancial support from BMS and Prometheus, grants from MedImmune and Viralytics, and personal fees from Eisai outside the submitted work.
N Engl J Med. Published on March 21, 2018. Full text, Editorial
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