medwireNews: Overall survival (OS) is significantly improved with the first-line combination of pembrolizumab and axitinib relative to sunitinib in patients with advanced renal cell carcinoma (RCC), shows the KEYNOTE-426 trial.
The estimated 12-month survival rate in the phase III study was 89.9% for the 432 participants with untreated stage IV disease who were randomly assigned to receive pembrolizumab 200 mg every 3 weeks plus a twice daily dose of axitinib 5 mg, and was 78.3% for their 429 counterparts who were given sunitinib 50 mg/day on a 4 weeks on, 2 weeks off schedule.
This equated to a significant 47% reduced risk for death in favor of pembrolizumab–axitinib, report the researchers in The New England Journal of Medicine and at the 2019 ASCO Genitourinary Cancers Symposium in San Francisco, California, USA.
Progression-free survival – a co-primary endpoint – was also significantly improved with the combination of the PD-1 inhibitor and the VEGFR tyrosine kinase inhibitor, at a median of 15.1 months compared with 11.1 months for sunitinib, and a significant 31% reduced risk for progression or death with the combination.
And trial participants given pembrolizumab plus axitinib were significantly more likely to achieve an objective response than sunitinib-treated patients, with rates of 59.3% and 35.7%, respectively.
“Overall, we have not previously seen a renal cancer study which has improved response, progression-free survival, and overall survival,” said presenting author Thomas Powles (Queen Mary University of London, UK) in a press statement. “This is therefore a major step forward in renal cancer.”
He believes that “[p]embrolizumab plus axitinib should be a new standard therapy for first-line treatment of patients with [metastatic] RCC.”
The OS benefit afforded by the combination was observed in all subgroups, including in all International Metastatic Renal Cell Carcinoma Database Consortium risk and PD-L1 expression categories. But the investigators caution that the “subgroup analyses should be considered hypothesis-generating only” as the number of deaths accrued in certain subgroups over the median follow-up period of 12.8 months was small, leading to wide confidence intervals.
On the whole, the toxicity profile was “as expected” for the known profiles of each of three drugs, says the team, with the exception of a higher incidence of grade 3 or 4 liver enzyme elevations with the combination than previously seen with either pembrolizumab or axitinib alone.
The incidence of treatment-related adverse events (AEs) of grade 3 or worse was comparable between study groups, at 62.9% and 58.1% for the combination and sunitinib arms, respectively. Just under a third (30.5%) of participants in the pembrolizumab–axitinib group discontinued either drug due to toxicity, while 10.7% stopped taking both drugs; the rate of AE-related discontinuation in the sunitinib arm was 13.9%.
Commenting on the findings of this and the previously reported JAVELIN Renal 101 trial, pitting avelumab plus axitinib against sunitinib, Bernard Escudier (Gustave Roussy Cancer Campus, Villejuif, France) says that “[b]oth combinations are expected to become new standards of care and to be incorporated into future guidelines.”
He adds, however, that several unanswered questions remain, such as the nature of the precise role of axitinib in these regimens and which combination, out of pembrolizumab–axitinib, avelumab–axitinib, and the current standard of nivolumab–ipilimumab, “will be used in the future.”
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