Extended analysis of the phase III KEYNOTE-426 study upholds pembrolizumab plus axitinib as a preferred front-line regimen over sunitinib in patients with advanced sporadic renal cell carcinoma.¹ These updated results were presented during the ASCO20 Virtual Scientific Program by Elizabeth R. Plimack, MD, Chief of the Division of Genitourinary Medical Oncology and Director of Genitourinary Clinical Research at Fox Chase Cancer Center, Philadelphia.

Elizabeth R. Plimack, MD

At a minimum follow-up of 23 months, median overall survival was not reached with pembrolizumab plus axitinib vs 36.7 months with sunitinib, the former standard of care. This difference represents a 32% reduction in the risk of death in an intent-to-treat analysis (P < .001).

“These results continue to support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced renal cell carcinoma,” Dr. Plimack stated.

Earlier findings of KEYNOTE-426, published in 2019,² and discussed in more detail on page 37, found the combination significantly improved overall response rates, progression-free survival, and overall survival vs sunitinib as front-line therapy for advanced renal cell carcinoma. Based on these findings, the U.S. Food and Drug Administration (FDA) granted approval to the combination as front-line treatment.

Study Details

KEYNOTE-426 randomly assigned 861 patients with newly diagnosed or recurrent stage IV clear cell renal cell carcinoma in a 1:1 ratio to receive pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 cycles plus oral axitinib at 5 mg twice daily vs oral sunitinib at 50 mg once daily for the first 4 weeks of each 6-week cycle. Treatment was continued until disease progression, unacceptable toxicity, or patient withdrawal.

The median age of participants was 62 years. A total of 73% of patients were male, and 27% were female. Patients were stratified by risk group and geographic region. About 30% had favorable-risk disease, 56% had intermediate-risk disease, and 13% had poor-risk disease. About 60% had PD-L1–positive (combined positive score ≥ 1) disease. Three-quarters of patients had two or more metastatic sites.

Updated Results

With longer follow-up at a median of 23 months, the superiority of the combination regimen was upheld. In the pembrolizumab/axitinib arm, 22.8% were continuing treatment compared with 17.9% in the sunitinib arm. Discontinuation of therapy occurred in 72.7% and 82.1%, respectively.

After discontinuation of study treatment, 54.5% of patients in the pembrolizumab/axitinib arm and 69.3% of those in the sunitinib arm had subsequent therapy.

With longer follow-up, confirmed objective response rates were 60.2% with pembrolizumab plus axitinib vs 39.9% with sunitinib. Complete responses were seen in 8% of the combination arm vs 3% of sunitinib-treated patients. Partial response rates were 51.4% vs 36.8%, respectively. Stable disease rates were 23.1% vs 35%, respectively. Progressive disease rates were 11.3% vs 17.2%, respectively. The median duration of response was 23.5 months with the combination vs 15.9 months with sunitinib, respectively.

The rates of 1-year overall survival were 90% and 74% with the combination vs sunitinib, respectively. The 2-year overall survival rates were 79% vs 66%, respectively.

Median progression-free survival in the intent-to-treat analysis was 15.4 months with the combination vs 11.1 months with sunitinib, for a 29% reduction in the risk of disease progression or death (P < .0001). The 1- and 2-year progression-free survival rates were 60% with the combination and 38% with sunitinib and 48% and 27%, respectively.

No overall survival benefit for the combination was observed in patients with favorable-risk disease, but there was a progression-free survival and objective response rate benefit in these patients. The magnitude of overall survival benefit appeared to be more robust in patients with intermediate-risk or poor-risk disease. “There are several possible reasons for this,” suggested Dr. Plimack. “Perhaps patients with favorable risk-disease do not benefit from the addition of immune-based therapy. Another potential explanation is that patients with favorable-risk disease have a known excellent survival.”

Treatment-related adverse events of any grade were reported in 96.3% of the combination arm vs 97.6% of the sunitinib arm. There were more grade 3 to 5 treatment-related adverse events with the combination (66.9% vs 62.4%). There were four deaths in the combination arm and six deaths in the sunitinib arm. The most common immune-related adverse events were hypothyroidism and hyperthyroidism in the combination arm; about 15% of patients had grade 3 to 5 events for both.

A post hoc analysis found that achieving a complete response improved the chances of overall survival in both arms.

Additional Commentary

The KEYNOTE-426 trial discussant, Daniel Y. Heng, MD, MPH, singled out this abstract for discussion. Dr. Heng is a medical oncologist at the Tom Baker Cancer Centre, University of Calgary, Canada.

Daniel Y. Heng, MD, MPH

“There were no surprises in the updated analysis of KEYNOTE-426,” Dr. Heng said. “As in the primary analysis, the study was positive for overall survival, progression-free survival, and objective response rate [for pembrolizumab plus axitinib vs sunitinib].”

Dr. Heng continued: “The complete response rate in all risk groups was 9%, up from 6% in the previous analysis. This is respectable. The objective response rate in patients with favorable-risk disease was 32%, which is much higher than we would normally see (typically about 20%).”

Although making cross-trial comparisons is “dangerous,” Dr. Heng admitted, the combination of nivolumab plus ipilimumab is not as effective as sunitinib in favorable-risk disease, and the combination is approved for intermediate/poor-risk disease. “Sunitinib still outperforms nivolumab plus ipilimumab in patients with favorable-risk disease,” Dr. Heng noted. Regarding the combination of pembrolizumab plus axitinib, he said it should be given to all risk groups, based on the trial results.

Personal Preferences

Dr. Heng shared his personal preferences for first-line therapy in metastatic renal cell carcinoma. “I choose nivolumab plus ipilimumab for poor- and intermediate-risk disease in patients with no significant autoimmune history and in those with vascular endothelial growth factor (VEGF) contraindications. I would opt for pembrolizumab plus axitinib for more favorable- and intermediate-risk disease. This combination is associated with fewer immune-related toxicities than nivolumab and ipilimumab. This is a good choice for patients who can tolerate chronic VEGF therapy or have well-controlled autoimmune disorders.”

Dr. Heng concluded: “It is unknown whether we should use all our best therapies like a VEGF tyrosine kinase inhibitor and PD-1 inhibitor upfront or whether having access to a CTLA-4 inhibitor is more important first line. It remains to be seen which strategy is best, and we look forward to having more data through real-world evidence to assess this.” 

DISCLOSURE: KEYNOTE-426 was funded by Merck Sharp & Dohme. Dr. Plimack has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Flatiron, Genentech/Roche, Incyte, Infinity Pharmaceuticals, Janssen, Merck, Pfizer, and Seattle Genetics; has received institutional research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck Sharp & Dohme, Peloton Therapeutics, and Pfizer; and has institutional patents, royalties, or other intellectual property (U.S. Patent No: 14/588,503, filed 1/2/2015). Dr. Heng has served as a consultant or advisor to Astellas Pharma, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, and Pfizer and has received institutional research funding from Bristol Myers Squibb, Exelixis, Ipsen, Novartis, and Pfizer.

REFERENCES

1. Plimack ER, Rini BI, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma: Updated analysis of KEYNOTE-426. ASCO20 Virtual Scientific Program. Abstract 5001.

2. Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116-1127, 2019.