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Pembrolizumab/axitinib RCC survival benefit sustained in long-term results


The frontline combination of pembrolizumab (Keytruda) plus axitinib (Inlyta) continued to show a survival benefit over single-agent sunitinib (Sutent) in patients with renal cell carcinoma (RCC), according to 3.5-year follow-up data from the phase 3 KEYNOTE-426 trial presented at the 2021 ASCO Annual Meeting.1

At a median follow-up of 42.8 months, the median overall survival (OS) was 45.7 months (95% CI, 43.6–not reached) with pembrolizumab/axitinib compared with 40.1 months (95% CI, 34.3-44.2) with sunitinib (HR, 0.73; 95% CI, 0.60-0.88; P <.001). The median progression-free survival (PFS) was 15.7 months (95% CI, 13.6-20.2) versus 11.1 months (95% CI, 8.9-12.5), respectively (HR, 0.68; 95% CI, 0.58-0.80; P <.0001).

“With a median follow-up of 42.8 months, KEYNOTE-426 represents the longest follow-up of a checkpoint inhibitor combined with a VEGF/VEGFR inhibitor for first-line clear cell RCC,” said lead study author Brian I. Rini, MD, a professor of medicine and the inaugural chief of Clinical Trials at Vanderbilt-Ingram Cancer Center.

“Results of the final analysis of KEYNOTE-426 continue to support pembrolizumab plus axitinib as standard of care for patients with previously untreated advanced clear cell RCC,” added Rini.

The international, open-label, phase 3 KEYNOTE-426 study (NCT02853331) included 861 patients aged ≥18 years with treatment-naïve, advanced RCC. All patients had clear cell histology. Patients were randomized between October 24, 2016, and January 24, 2018, to either pembrolizumab plus axitinib (n = 432) or single-agent sunitinib (n = 429).

Baseline characteristics were well balanced across the study arms. “This was a typical frontline RCC population,” said Rini. In the combination arm, the median age was 62 years (range, 30-89), 71.3% of patients were male, and IMDC risk categories were favorable for 31.9%, intermediate for 55.1% and poor for 13%.

Previous nephrectomy had been received by 82.6% of the combination arm, and 72.9% of patients in this arm had ≥2 sites of metastases. Regarding PD-L1 status, 59.5% of 407 evaluated patients in the pembrolizumab/axitinib arm had a combined positive score ≥1.

In the combination arm, patients received pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 cycles plus axitinib at 5 mg orally twice daily. In the control arm, patients were treated with 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. OS and PFS were the primary study end points.

The follow-up range for the data reported at the ASCO meeting was a minimum of 35.6 months to a high of 50.6 months. At the time of follow-up, 14.5% of patients in the combination arm were still receiving treatment, compared with 9.4% of patients in the sunitinib arm.

In the combination arm, 58.4% of patients received subsequent anticancer therapy, compared with 73% in the sunitinib arm. In the pembrolizumab/axitinib arm, “About 20% received a PD-1/PD-L1 inhibitor, nearly 90% received some form of VEGF inhibition, and one-third of patients received other therapies,” said Rini. These rates were 74.4%, 68.7%, and 22.8%, respectively, in the control arm.

Objective response rate at 42.8 months was 60.4% in the combination arm compared with 39.6% in the sunitinib arm. The complete response and partial response rates were 10% versus 3.5% and 50.5% versus 36.1%, respectively.

The median time to response was 2.8 months with the combination versus 3.0 months with sunitinib. The median duration of response was 23.6 months versus 15.3 months, respectively.

Regarding safety, Rini said, “The safety profile was comparable between arms and no new safety signals emerged.”

Updated safety data showed treatment-related adverse events (TRAEs) across all grades occurred in 96.3% of the combination arm compared with 97.6% of patients in the sunitinib arm. “The only addition to this from previous presentations is proteinuria has now reached 20% overall incidence in the pembrolizumab plus axitinib arm,” said Rini.

The rates of grade 3 to 5 TRAEs were 67.8% versus 63.8%, respectively. There were 4 patient deaths in the pembrolizumab/axitinib arm compared with 7 in the sunitinib arm.

Based on prior data from the KEYNOTE-426 trial, the FDA approved pembrolizumab plus axitinib in April 2019 for use in the frontline setting for patients with advanced RCC.


1. Rini B, Plimack R, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426. J Clin Oncol 39, 2021 (suppl 15; abstr 4500). doi: 10.1200/JCO.2021.39.15_suppl.4500

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