Keytruda/Welireg Combo Improves Disease-Free Survival in Clear Cell Kidney Cancer

The combination of Keytruda (pembrolizumab) and Welireg (belzutifan) improved disease-free survival compared with Keytruda alone when given after surgery to patients with clear cell renal cell carcinoma at increased risk of recurrence.

These findings were presented at the 2026 Genitourinary Cancers Symposium by lead study author Dr. Toni Choueiri and represent the first time an adjuvant combination has shown a benefit over an active immunotherapy in this setting.

“LITESPARK-022 is the first adjuvant phase 3 trial in RCC to show a significant benefit for a combination treatment vs an active immunotherapy comparator,” Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, coleader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School, emphasized.

At the time of the analysis, the median disease-free survival had not yet been reached in either treatment group. However, patients who received both Keytruda and Welireg had better outcomes over time. At 12 months, approximately 92% of patients who received the combination remained free of recurrence compared with approximately 85% of those who received Keytruda alone.

At 24 months, those rates were approximately 81% versus 74%, and at 30 months they were approximately 76% versus 69%. Overall, the combination reduced the risk of recurrence or death by 28%.

Most patient subgroups benefited from the addition of Welireg. The only group that did not appear to benefit consisted of patients classified as high risk based on disease features, although the number of patients in this subgroup was smaller.

Overall survival data are not yet mature, meaning not enough events have occurred to determine whether the combination helps patients live longer. Survival rates at 12, 24 and 30 months were high in both groups, reflecting the early stage of follow-up.

Adjuvant Keytruda became a standard treatment for patients with high-risk disease after surgery because prior research showed it could delay recurrence and improve survival compared with placebo. However, approximately 40% of patients still experienced recurrence or death within 5 years, highlighting an ongoing need for more effective therapies. Welireg targets hypoxia-inducible factor 2 alpha, a pathway known to drive kidney cancer growth, and has already shown activity in advanced disease. Investigators therefore explored whether adding it earlier could further reduce recurrence risk.

Patients enrolled in the study had clear cell renal cell carcinoma removed by surgery within the previous 12 weeks, had not received prior systemic therapy and were fit enough for treatment. Participants were randomly assigned to receive Keytruda for approximately 1 year plus daily Welireg or Keytruda plus a placebo.

The study included 1841 patients. Treatment completion rates were similar between groups, with approximately 70% of patients finishing therapy. The most common reasons for stopping treatment were side effects, recurrence and patient choice.

Side effects were more common with the combination than with Keytruda alone, which is expected when two drugs are used together. Serious side effects occurred in approximately 52% of patients receiving the combination compared with approximately 30% of those receiving Keytruda alone. Side effects leading to treatment discontinuation occurred in approximately 12% versus approximately 9%.

Common side effects with the combination included anemia fatigue elevated liver enzymes diarrhea itching dizziness headache nausea joint pain thyroid changes rash shortness of breath and cough. Immune-related side effects occurred at similar rates in both groups.

Two side effects were notably more frequent with Welireg: anemia and low oxygen levels. Anemia occurred in approximately 84% of patients receiving the combination compared with approximately 12% of those receiving Keytruda alone. In some cases, anemia required treatment interruption dose reduction blood transfusions or medications that stimulate red blood cell production. Low oxygen levels occurred in approximately 7% of patients receiving the combination and were rare with Keytruda alone. Some patients required oxygen therapy.

Despite these differences, investigators reported that the safety profile was manageable and consistent with what is known about each drug individually. Only a small percentage of patients stopped both treatments because of side effects.

These results suggest that adding Welireg to adjuvant Keytruda may further reduce the risk of recurrence for patients with high-risk clear cell renal cell carcinoma following surgery. Longer follow-up is needed to determine whether the combination improves overall survival, but the disease-free survival benefit indicates a potential new standard option for patients who face a high risk of their cancer returning.

References

1. “Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study,” by Dr. Toni Choueiri. The Journal of Clinical Oncology.