As reported in The Lancet Oncology by Thomas Powles, MD, PhD, and colleagues, extended follow-up of the phase III KEYNOTE-426 trial shows continued progression-free and overall survival superiority with pembrolizumab/axitinib vs sunitinib in the first-line treatment of advanced renal cell carcinoma.

The first interim analysis of the trial, performed at a median of 12.8 months, supported the April 2019 U.S. Food and Drug Administration approval of pembrolizumab in combination with axitinib in this setting. At that analysis, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab/axitinib group vs 78.3% in the sunitinib group (hazard ratio [HR] = 0.53, P < .0001) and median progression-free survival was 15.1 months vs 11.1 months (HR = 0.69, P < .001).

Thomas Powles, MD, PhD

The current analysis occurred after a median follow-up of 30.6 months.

Study Details

In the ongoing, international, open-label trial, 861 patients with advanced renal cell carcinoma showing clear-cell histology were randomly assigned to two treatment arms between October 2016 and January 2018. Patients received either pembrolizumab at 200 mg every 3 weeks for up to 35 cycles plus axitinib at 5 mg twice daily (n= 432), or sunitinib at 50 mg once daily for 4 weeks in each 6-week cycle.

Treatment continued until disease progression or unacceptable toxicity. Primary endpoints were overall survival and progression-free survival in the intent-to-treat population. The primary endpoints were met at the first interim analysis; thus, updated data are reported with nominal P values.

Extended Follow-up

At data cutoff at a median follow up of 30.6 months (range = 23.4–38.4 months), 72% of patients in the pembrolizumab/axitinib group and 81% in the sunitinib group had permanently discontinued treatment, with the primary reason in both groups being radiographic disease progression. Overall, 4% of the pembrolizumab/axitinib group completed the study-defined limit of 35 cycles of pembrolizumab.

Among the patients who discontinued study treatment, 54% vs 69% of patients received subsequent anticancer therapy, including VEGF or VEGFR inhibitors in 49% vs 46% and PD-1 or PD-L1 inhibitors in 8% vs 48%.

Overall and Progression-Free Survival

Median overall survival was not reached in the pembrolizumab/axitinib group vs 35.7 months (95% confidence interval [CI] = 33.3 months­–not reached) in the sunitinib group (hazard ratio [HR] = 0.68, 95% CI = 0.55–0.85, P = .0003), with estimated rates at 24 months of 74.4% (95% CI = 69.9%–78.2%) vs 65.5% (95% CI = 60.8%–69.8%).

Among the 138 (32%) vs 131 (31%) patients with a favorable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, overall survival at 2 years was 85.3% vs 87.7% (HR = 1.06,  95% CI = 0.60–1.86, P = .58). Among 294 vs 298 patients with intermediate (238 vs 246) or poor (56 vs 52) IMDC risk scores, 24-month overall survival was 69.2% vs 55.8% (HR = 0.63, 95% CI = 0.50–0.81, P = .0001).

Median progression-free survival was 15.4 months (95% CI = 12.7–18.9 months) vs 11.1 months (95% CI = 9.1–12.5 months), with a hazard ratio of 0.71 (95% CI = 0.60–0.84, P < .0001); estimated rates at 24 months were 37.6% (95% CI = 32.7%–42.5%) vs 26.5% (95% CI = 21.8%–31.4%). 

Among patients with IMDC favorable-risk scores, progression-free survival at 24 months was 44.6% vs 35.3% (HR = 0.79, 95% CI = 0.57–1.09, P = .078). Among patients with IMDC intermediate- or poor-risk scores, progression-free survival at 24 months was 34.3% vs 22.7% (HR = 0.69, 95% CI = 0.56­–0.84, P = .0002). 

Confirmed objective response was observed in 60% of the pembrolizumab/axitinib group, including complete response in 9%, vs 40% of the sunitinib group, including complete response in 3% (P < .0001). Median durations of response were 23.5 months (95% CI = 19.4–29.0 months) vs 15.9 months (95% CI = 13.8–20.4 months), with an estimated 47% vs 38% of responders having an ongoing response at 24 months.

Adverse Events

No new safety signals were observed with extended follow-up. Total exposure was 7,715.4 person-months in the pembrolizumab/axitinib group vs 6,036.4 person-months in the sunitinib group. Treatment-related adverse events of any grade occurred in 96% vs 98% of patients.

After adjustment for exposure, the rate of treatment-related adverse events of any grade was 63 events per 100 person-months vs 97 events per 100 person-months. The most common treatment-related grade ≥ 3 adverse events (≥ 10% in either group) were hypertension (22% vs 20%), alanine aminotransferase (ALT) increase (13% vs 3%), and diarrhea (11% vs 5%). As was observed in the first interim analysis, the incidence of grade 3 or 4 ALT elevations (13%) and aspartate aminotransferase elevations (7%) in the pembrolizumab/axitinib group was higher than previously observed with either agent alone. No new treatment-related deaths were observed.

The investigators concluded, “With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support … first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.”

Dr. Powles, of Barts Cancer Centre, Barts Cancer Institute, London, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co. For full disclosures of the study authors, visit thelancet.com.