How FDA combo Tx approval will change RCC treatment

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The approval of immune checkpoint inhibitor combination therapy may be the most significant advance in a decade for the treatment of metastatic renal cell carcinoma, an expert says.

However, the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) is indicated only in previously untreated, intermediate- to poor-risk patients, and is associated with some potentially serious toxicities that signal a need for careful monitoring, according to experts.

For urologists, the most important take-home message right now is that this immune checkpoint inhibitor regimen is effective for advanced kidney cancers with less-than-favorable prognostic risk, according to David F. McDermott, MD, of Dana-Farber/Harvard Cancer Center, Boston.

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“Combination immunotherapy is now in the front line for their patients, and for some, remissions are possible,” Dr. McDermott said in an interview with Urology Times. “It's an exciting new option that's going be broadly applied to patients with metastatic untreated kidney cancer.”

The FDA approval was based on data from the CheckMate 214 trial, results of which were recently published in the New England Journal of Medicine (April 5, 2018 [Epub ahead of print]).

That approval is “the most significant advance for the treatment of kidney cancer over the last 10 years,” CheckMate 214 investigator Hans Hammers, MD, PhD, said in a press release issued by UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, Dallas.

The clinical trial included 1,096 patients were randomized either to the PD-1 inhibitor nivolumab plus the anti-CTLA4 antibody ipilimumab, or to standard treatment with the VEGF tyrosine kinase inhibitor (TKI) sunitinib (Sutent). Investigators reported results according to prognostic group, assessed using criteria developed by the International Metastatic Renal Cell Carcinoma Database Consortium.

Next: Significantly higher rates of overall survival and objective response among intermediate-, poor-risk patientsAmong the intermediate- and poor-risk patients, nivolumab plus ipilimumab produced significantly higher rates of overall survival and objective response, according to investigators.

At a median follow-up of 25.2 months, the 18-month overall survival rate for intermediate- and poor-risk patients was 75% for the immunotherapy combination versus 60% for sunitinib, with a median overall survival not reached versus 26.0 months for standard therapy (p<.001). The objective response rate was 42%, compared to 27% for the control arm (p<.001), with a complete response rate of 9% versus 1%.

By contrast, outcomes in favorable risk patients did not seem to be any better in the immunotherapy arm, with a significantly higher objective response rate and significantly longer progression-free survival favoring the sunitinib arm, though longer-term follow-up data are awaited.

“For now, it's safe to say that VEGF TKIs will continue to be a standard option for those patients,” said Dr. McDermott, who also served as an investigator in CheckMate 214. “I think observation is also appropriate in those patients, too. If we're seeing a good risk patient in clinic, we often tell them, ‘We can just wait and watch and we'll treat you if your scans show growth.’ ”

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Dr. McDermott cautioned that clinicians and patients need to be attuned to the toxicities associated with immune checkpoint inhibitor therapy, which can be serious. In CheckMate 214, there were four deaths in the sunitinib group and eight in the nivolumab-plus-ipilimumab group that investigators said were related to treatment.

“The toxicities need to be diagnosed early and treated early, at which point they can be reversed,” Dr. McDermott said.

Dr. McDermott has received honoraria and consulting fees from Bristol-Myers Squibb, Pfizer, Merck Novartis, Eisai, Exelixis, Array BioPharma, and Genetech BioOncology, as well as grant support from Prometheus Laboratories. Dr. Hammers has received grants and personal fees from Bristol-Myers Squibb and personal fees from Pfizer and Exelixis.

Checkmate 214 was supported by Bristol-Myers Squibb and Ono Pharmaceutical.