First-line pembrolizumab + axitinib outdoes sunitinib in improving survival in advanced RCC
The combination of pembrolizumab and axitinib in the first-line setting yielded superior survival outcomes compared with sunitinib in patients with advanced renal cell carcinoma (RCC), according to results of the phase III KEYNOTE-426* trial.
“The significant [overall survival (OS)] advantage is particularly notable because it has not been achieved with first-line treatment of RCC with the use of anti-VEGF-based therapy administered alone or in combination,” said the authors.
“Pembrolizumab plus axitinib should be a new standard of care for first-line treatment of patients with advanced clear-cell RCC,” said study author Professor Thomas Powles from the Barts Cancer Institute and Queen Mary University of London, London, UK, who presented the findings at ASCO GU 2019.
A total of 861 adults with newly-diagnosed or recurrent stage IV clear-cell RCC who had not previously received systemic treatment for advanced disease were randomized to receive intravenous pembrolizumab (200 mg Q3W for up to 35 cycles) plus oral axitinib (5 mg twice/day; n=432, median age 62 years, 71.3 percent male) or oral sunitinib (50 mg once/day for the first 4 weeks of each 6-week cycle; n=429, median age 61 years, 74.6 percent male).
Of the 176 and 242 patients on pembrolizumab-axitinib and sunitinib, respectively, who discontinued treatment, 50 and 60.7 percent, respectively received subsequent therapy, with a majority receiving a VEGF or VEGF receptor inhibitor in the pembrolizumab-axitinib group (44.3 percent) and a PD-1 or PD-L1 inhibitor in the sunitinib group (37.6 percent).
Superior OS, PFS, and ORR
Patients were followed up for a median 12.8 months, at which time OS was superior among pembrolizumab-axitinib compared with sunitinib recipients (89.9 percent vs 78.3 percent, median survival not reached in either group, hazard ratio [HR], 0.53, 95 percent confidence interval [CI], 0.38–0.74; p<0.0001). [ASCO GU 2019, abstract 543, N Engl J Med 2019;doi:10.1056/NEJMoa1816714]
Progression-free survival (PFS) was also longer in pembrolizumab-axitinib compared with sunitinib recipients (15.1 vs 11.1 months, HR, 0.69, 95 percent CI, 0.57–0.84; p=0.0001).
“The benefits of pembrolizumab plus axitinib with respect to OS and PFS were observed in all subgroups examined, including all IMDC** risk and PD-L1 expression categories,” said the authors.
Pembrolizumab-axitinib recipients also had a superior objective response rate (ORR) compared with sunitinib recipients (59.3 percent vs 35.7 percent; p<0.0001; median duration of response, not reached vs 15.2 months), with 5.8 and 1.9 percent, respectively, having a complete response, 53.5 and 33.8 percent having a partial response, and 24.5 and 39.4 percent having stable disease.
Incidence of adverse events (AEs) of any cause were similar between pembrolizumab-axitinib and sunitinib recipients (98.4 percent vs 99.5 percent) as were treatment-related AEs (TRAEs; 96.3 percent vs 97.6 percent), specifically grade 3–5 TRAEs (62.9 percent vs 58.1 percent). Hypertension was the most common grade 3–5 AE in both pembrolizumab-axitinib and sunitinib recipients (22.1 and 19.3 percent, respectively). TRAEs led to treatment discontinuation in 25.9 and 10.1 percent of pembrolizumab-axitinib and sunitinib recipients, respectively, and there were four and seven TRAE-related deaths in these respective groups.
The most common grade 3–5 AEs of interest among pembrolizumab-axitinib recipients were hepatitis (2.3 percent) and colitis (1.9 percent), and among sunitinib recipients, severe skin reactions (0.7 percent).
The future of RCC treatment?
“The results really were quite astounding,” said study co-author Professor Brian Rini from the Cleveland Clinic, Cleveland, Ohio, US. “The robust activity from the phase I [trial] held up and it translated into a very impressive survival advantage. It’s the first time in kidney cancer ever in a front-line setting that all three of those endpoints [OS, PFS, and ORR] have been met,” he said. [https://ecancer.org/conference/1127-2019-genitourinary-cancers-symposium.php]
“[The pembrolizumab-axitinib combination] is going to … assume a large part of the standard of care. Broadly speaking, kidney cancer patients … are all going to get an [immune-oncology]-based combo. The days of giving TKI monotherapy … are pretty much over,” he said.