KEYTRUDA-WELIREG combination wins FDA approval for high-risk kidney cancer after surgery
Approval is based on Phase III LITESPARK-022 trial results showing a 28% reduction in the risk of disease recurrence, metastasis or death in patients with clear cell renal cell carcinoma.
The U.S. Food and Drug Administration (FDA) has approved Merck’s anti-PD-1 therapies, KEYTRUDA (pembrolizumab) and KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph), each in combination with WELIREG (belzutifan), for the adjuvant treatment of certain adults with renal cell carcinoma containing a clear cell component.
The approval covers patients with clear cell renal cell carcinoma (ccRCC) at intermediate-high or high risk of recurrence following kidney removal surgery (nephrectomy), or after nephrectomy and surgical removal of metastatic lesions.
The decision marks the first approval of WELIREG in earlier-stage ccRCC and the first approval of combination regimens involving a PD-1 inhibitor and a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.
A PD-1 inhibitor is a type of immunotherapy that helps the immune system recognise and attack cancer cells. HIF-2α inhibitors target cellular pathways that can support tumour growth under low-oxygen conditions.
Phase III trial findings
The approval was based on results from the Phase III LITESPARK-022 trial, a randomised, double-blind study involving 1,841 patients.
A Phase III trial is a late-stage clinical study that compares a new treatment against standard therapy or placebo in a large patient population to assess effectiveness and safety.
The trial showed that KEYTRUDA combined with WELIREG significantly improved disease-free survival, the study’s primary endpoint, compared with KEYTRUDA plus placebo.
Disease-free survival refers to the length of time after treatment during which a patient remains free of cancer recurrence or progression.
According to Merck, the combination reduced the risk of disease recurrence, metastasis or death by 28% compared with KEYTRUDA plus placebo (HR=0.72; 95% CI 0.59-0.87; p=0.0003).
The estimated 24-month disease-free survival rate was 81% in the KEYTRUDA-WELIREG group, compared with 74% in the KEYTRUDA-placebo group. Median disease-free survival had not been reached in either treatment arm at the time of the interim analysis.
Overall survival data were not yet mature.
Merck said the study is the first global Phase III trial to demonstrate an improvement in disease-free survival over KEYTRUDA monotherapy in the adjuvant treatment setting for ccRCC.
New option for patients
“Patients with earlier-stage renal cell carcinoma at high risk of recurrence after surgery may see their cancer return, frequently as metastatic disease,” said Dr Toni K. Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School.
“The results of this trial demonstrated the ability of pembrolizumab in combination with belzutifan to reduce the risk of disease recurrence, metastasis, or death by 28%, which represents an important new option for these patients to help keep their clear cell renal cell carcinoma from coming back,” he said.
Dr M. Catherine Pietanza, vice president of global clinical development at Merck Research Laboratories, said improved disease-free survival could have a significant impact on patients’ lives.
“These approvals demonstrate Merck’s commitment to pursuing innovative treatment options that may help these patients experience longer periods without disease,” she said.
Bryan Lewis, chief executive officer and co-founder of KidneyCan, said the approval of the KEYTRUDA and WELIREG combination represented an important step for patients with earlier-stage renal cell carcinoma.
Safety findings
The safety analysis included 915 patients who received WELIREG plus KEYTRUDA and 913 patients who received placebo plus KEYTRUDA.
Serious adverse reactions occurred in 30% of patients receiving the combination therapy. The most commonly reported serious adverse reactions included pneumonia, hypoxia, pneumonitis, arrhythmia, diarrhoea and acute kidney injury.
Fatal adverse reactions occurred in 1.1% of patients receiving the combination, including cases of sepsis.
The most common adverse reactions and laboratory abnormalities reported with WELIREG plus KEYTRUDA included decreased haemoglobin levels, increased liver enzyme levels, fatigue, decreased lymphocyte counts and increased alkaline phosphatase levels.
Merck noted that WELIREG carries a boxed warning that exposure during pregnancy can cause embryo-foetal harm. The drug can also cause severe anaemia and severe hypoxia, requiring monitoring during treatment.
The study’s primary efficacy endpoint was investigator-assessed disease-free survival, while overall survival was an additional outcome measure.
Merck said it continues to investigate WELIREG in renal cell carcinoma and selected solid tumours across different treatment settings as part of its broader clinical development programme.
