Roger M. Perlmutter, MD, PhD
Combining the PD-1 inhibitor pembrolizumab (Keytruda) with the VEGF inhibitor axitinib (Inlyta) significantly improved survival versus sunitinib (Sutent) as a first-line treatment for patients with advanced or metastatic renal cell carcinoma (RCC), according to findings from the phase III KEYNOTE-426 trial.1
Merck (MSD), the manufacturer of pembrolizumab, announced in a press release that the study had met the coprimary endpoints of significant improvement in overall survival (OS) and progression-free survival (PFS), as well as the secondary endpoint of significantly improved objective response rate (ORR). The OS, PFS, and ORR benefits were observed with the combination across risk groups and regardless of PD-L1 expression level.
“Keytruda, in combination with the tyrosine kinase inhibitor Inlyta, resulted in significant and clinically meaningful improvements in overall survival, progression-free survival, and objective response in this phase III study. This marks the first time that combination treatment with an anti–PD-1 therapy has achieved the dual primary endpoints of overall survival and progression-free survival as first-line therapy in advanced renal cell carcinoma,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement.
“Fewer than 10% of those diagnosed with advanced renal cell carcinoma survive for 5 years, and hence there is significant need for improved therapies for this disease. We are very grateful to the investigators and patients for their involvement in this important study, the results of which will be filed with global regulatory authorities in the near future,” added Perlmutter.
The open-label phase III KEYNOTE-426 trial (NCT02853331) randomized 861 patients with advanced or metastatic RCC to frontline treatment with pembrolizumab (200 mg IV every 3 weeks) plus axitinib (5 mg orally twice daily) for up to 24 months, or sunitinib (50 mg orally once daily for 4 weeks followed by no treatment for 2 weeks, continuously). Merck noted that safety data for pembrolizumab and axitinib were consistent with earlier findings from studies of each agent.
Previously reported data from an open-label phase Ib single-arm clinical trial showed that antitumor activity with the combination of axitinib and pembrolizumab was superior to that expected from axitinib or PD-1/PD-L1 pathway inhibitor monotherapy in treatment-naïve patients with advanced RCC.2
In addition, fewer liver function test abnormalities and less fatigue were reported compared with other combinations of VEGF inhibitors and PD-1 checkpoint inhibitors, lead investigator Michael B. Atkins, MD, said when presenting the findings in February at the 2018 Genitourinary Cancers Symposium.
“The regimen was highly active,” he said, with 38 of 52 patients (73.1%) enrolled in the dose-finding and dose-expansion phases of the study having objective responses with the axitinib/pembrolizumab combination. Best overall response was a complete response in 4 patients (7.7%), partial response in 34 (65.4%), and stable disease in 8 (15.4%). The median progression-free survival was 20.9 months (95% CI, 15.4 to not evaluable). Median overall survival was not reached at a minimum follow-up of 17.6 months.
Prior studies in which VEGF inhibitors were combined with PD-1 checkpoint inhibitors were plagued by excess toxicity. Many of these toxicities were related to off-target effects of multitargeted tyrosine kinase inhibitors. The possibility that a more selective VEGF inhibitor would improve tolerability when combined with a PD-1 inhibitor while offering synergistic antitumor activity was the basis for the phase Ib study that Atkins reported at the symposium.
In the study, 11 treatment-naïve patients were enrolled in a dose-finding phase to estimate the maximum-tolerated dose and 41 in a dose-expansion phase. Axitinib at 5 mg was administered orally twice daily and pembrolizumab at 2 mg/kg was given intravenously every 3 weeks.
Tumors were assessed using RECIST v1.1 at baseline, week 12, and then every 6 weeks. The primary endpoint was dose-limiting toxicity during the first 2 cycles (6 weeks). “Per protocol, according to the investigators’ judgment, patients with evidence of disease progression experiencing what was thought to be clinical benefit were eligible for continued treatment,” said Atkins, deputy director, Georgetown-Lombardi Comprehensive Cancer Center.
To be included in the study, patients had to have treatment-naïve clear cell kidney cancer, prior nephrectomy, at least 1 measureable lesion by RECIST v1.1, an ECOG performance status of 0 or 1, and controlled hypertension.