The combination of pembrolizumab (Keytruda) and axitinib (Inlyta) was associated with a significantly longer progression-free and overall survival compared with sunitinib (Sutent) in treatment-naïve patients with clear cell metastatic renal cell carcinoma.
Thomas Powles, MBBS, MRCP, MD
The combination of pembrolizumab (Keytruda) and axitinib (Inlyta) was associated with a significantly longer progression-free and overall survival (OS) compared with sunitinib (Sutent) in treatment-naïve patients with clear cell metastatic renal cell carcinoma (RCC), according to findings from the phase III KEYNOTE-426 study that were presented during a presscast ahead of the 2019 Genitourinary Cancers Symposium.1
Treatment with the combination led to a 47% reduction in the risk of death versus sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P <.0001). The median OS was not reached in either arm. The median progression-free survival (PFS) was 15.1 months (range, 12.6-17.7) for pembrolizumab/axitinib and 11.1 months (range, 8.7-12.5) with sunitinib. With the combination, there was a 31% reduction in the risk of disease progression (HR, 0.69; 95% CI, 0.57-0.84; P = .0001).
Based on these data, the FDA granted a priority review designation to a supplemental biologics license application for the combination of pembrolizumab and axitinib as a frontline treatment for patients with advanced RCC in February 2019.
“The combination of pembrolizumab and axitinib had significantly longer overall survival, with a reduction in the risk of death by 47%, a longer progression-free survival, and higher response rates than sunitinib in this patient population,” lead study author Thomas Powles MBBS, MRCP, MD, said during the presscast. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
Earlier phase Ib findings from an open-label, single-arm study previously showed that the combination of pembrolizumab and axitinib had superior antitumor activity compared with what is expected from either agent alone in treatment-naïve patients with advanced RCC.2 Data showed that the combination had a tolerable safety profile and elicited a 73% objective response rate (ORR).
In the open-label KEYNOTE-426 study (NCT02853331), 861 patients with newly diagnosed or recurrent stage IV clear cell RCC were randomized 1:1 to receive pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 cycles plus axitinib at 5 mg orally twice daily or sunitinib at 50 mg orally once daily for the first 4 weeks of each 6-week cycle. Treatment was administered until disease progression, unacceptable toxicity, or if patients dropped out of the trial.
The median age was 62; 73% of patients were male and 27% were female. Patients were stratified by geographic region and by International Metastatic Renal Cell Carcinoma Database Consortium risk group as having favorable-, intermediate-, or poor-risk disease.
The coprimary endpoints were OS and PFS; secondary endpoints were ORR, duration of response (DOR), patient-reported outcomes, and safety.
To be eligible for enrollment, patients had no prior systemic treatment for advanced disease, had a Karnofsky performance status ≥70, measurable disease per RECIST v1.1 criteria, provision of a tumor sample for biomarker assessment, and adequate organ function.
At a median follow-up of 12.8 months, results showed that the 12- and 18-month OS rates were higher with pembrolizumab/axitinib than sunitinib, at 89.9% versus 78.3% and 82.3% versus 72.1%, respectively. The 12-month and 18-month PFS rates were also higher with pembrolizumab and axitinib (59.6% and 41.1%) compared with sunitinib (46.2% and 32.9%). The survival benefits were observed irrespective of PD-L1 status or risk group, explained Powles, who is professor of genitourinary oncology, lead, Solid Tumour Research, Barts Cancer Institute, director, Barts Cancer Centre.
Additionally, the ORR was 59.3% (95% CI, 54.5-63.9) with the combination and 35.7% (95% CI, 31.1-40.4) with sunitinib (P <.0001). The median DOR was not reached (range, 1.4+ to 18.2+) in the pembrolizumab/axitinib arm and was 15.2 months (1.1+ to 15.4+) for sunitinib. Treatment is ongoing in 59.0% of patients on the immunotherapy/TKI arm and in 43.1% of those on the sunitinib arm.
Regarding safety, the incidence of all-grade adverse events (AEs) was comparable between the 2 arms, at 96.3% with the combination and 97.6% with sunitinib. Grade 3 to 5 AEs were higher with pembrolizumab/axitinib (62.9%) versus sunitinib (58.1%). A total of 0.9% of AEs led to death in the combination arm versus 1.6% in the sunitinib arm. Moreover, 25.9% of patients who were treated with pembrolizumab/axitinib discontinued treatment of either drug, compared with 10.1% of patients who discontinued sunitinib. A total 8.2% of patients discontinued treatment with both pembrolizumab and axitinib.
“This is a very significant trial and it’s going to have an impact on patient management going forward, as it works through the regulatory process,” said ASCO expert Robert Dreicer, MD, MS, MACP, FASCO, who moderated the presscast. “Metastatic kidney cancer has very low survival rates and there have been few significant advances in treating this advanced form of the disease. These findings may help provide a new option for patients.”