Authors

  1. Goodwin, Peter M.

Article Content

MADRID-A combination of the cytotoxic T-lymphocyte-associated protein 4 (CTLA 4) immune checkpoint inhibitor ipilimumab together with its immunotherapy cousin PD-1 inhibitor nivolumab was clearly superior to the tyrosine kinase inhibitor (TKI) sunitinib as first-line therapy for treating patients with intermediate- and poor-risk advanced or metastatic clear cell renal cell carcinoma (RCC), according to findings from the CheckMate-214 study announced at the ESMO 2017 Congress (Abstract LBA5).

  
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But good-risk patients with advanced RCC treated with sunitinib had superior objective response rate (ORR) and median progression-free survival (PFS) than good-risk patients treated with the immunotherapy combination.

 

"Nivolumab plus ipilimumab is going to become the treatment of choice for most of the patients we see with kidney cancer, except [for] the very good risk patients where we are going to continue to use TKI," said first author Bernard Escudier, MD, in the Department of Medical Oncology, Institut Gustave Roussy in Villejuif, France.

 

Patients at intermediate- and poor-risk had a greater ORR and prolonged median PFS when treated with the immunotherapy combination than those receiving sunitinib for their previously-untreated advanced or metastatic RCC.

  
Bernard Escudier, MD... - Click to enlarge in new windowBernard Escudier, MD. Bernard Escudier, MD

CheckMate-214 randomized 1,096 adults with clear-cell metastatic RCC and Karnofsky performance scores of at least 70 to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients). The primary endpoints of were ORR, PFS (assessed by an independent committee), and overall survival.

 

After 17.5 months of follow-up, ORR in patients with intermediate- and poor-risk disease was significantly greater (41.6%) for patients treated with nivolumab plus ipilimumab than for those on sunitinib (26.5%). In 9.4 percent of patients on combination therapy, the responses were complete (CR). In contrast, only 1.2 percent of patients treated with sunitinib had a CR. Median duration of response was not reached in the combination arm and was 18.2 months with sunitinib.

 

For the overall cohort of high- and intermediate-risk patients, the median PFS was 11.6 months with immunotherapy and 8.4 months with sunitinib-equivalent to a hazard ratio (HR) of 0.82.

 

Higher PD-L1 Expression

Escudier said there was greater benefit in patients with higher levels of PD-L1 expression at baseline. "In our study, PD-L1 positive patients do much better than PD-L1 negative patients, which is a surprise for us. So should we look at PD-L1 expression to select those patients who are going to benefit more from this combination? We still don't know," he explained.

 

In intermediate and poor risk patients grouped together who had baseline PD-L1 expressions of at least 1 percent and were treated with the combination, the ORR was more than double (58%) that of those taking sunitinib (25%). There was an even bigger disparity in median PFS-22.8 months with the combination and 5.9 months with sunitinib (HR 0.48).

 

Low Risk

Patients at favorable risk, however, had lower tumor PD-L1 expression and better ORR with the TKI (52% with sunitinib, 29% with nivolumab). And their median PFS was longer with the TKI (25.1 months with sunitinib; 15.3 months with immunotherapy).

 

Taking all 1,096 patients together regardless of risk, there was no significant difference between the two treatments.

 

Less Toxicity

Escudier noted toxicity with the immunotherapy combination was generally lower than with sunitinib. "If you look at grade 3-4 toxicity, it's not as much as you have with sunitinib. So quality of life, too, was better with the combination."

 

Manuela Schmidinger, MD, Professor of Medicine, Medical Oncologist at the Medical University of Vienna, Austria, said that "to some extent" this was a paradigm change in first-line treatment for metastatic RCC.

 

But although she regarded checkpoint inhibitor first-line treatment as a new standard of care, she did not think this was the final picture yet. She regarded other combinations under investigation in phase III trials such as immuno-oncology-VEGF-inhibitor regimens also as potential candidates for standard of care.

 

"Once we will be able to properly address the biology of a patient's individual tumor, we may pick out the best individual treatment among various first-line options," Schmidinger concluded.

 

Peter M. Goodwin is a contributing writer.

 

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