What Is It, and Why Does It Matter?
The FDA has approved Welireg (belzutifan), a prescription oral medicine, to be used as an adjuvant therapy with Keytruda (pembrolizumab) or Keytruda Qlex (pembrolizumab/berahyaluronidase) for certain adults who have kidney cancer (renal cell carcinoma [RCC]) with a clear cell component (ccRCC) and have had kidney removal surgery (nephrectomy). This combination treatment is for people who have an intermediate-to-high or high risk of the cancer returning after nephrectomy, including those with a small amount of the cancer that had spread (metastases).
RCC is the most common form of kidney cancer, with ccRCC accounting for roughly 70% of RCC diagnoses. In 2026, more than 80,000 people are expected to be diagnosed with kidney cancer in the U.S., with over 15,000 patients projected to die from the disease, highlighting the need for effective post‑surgery (adjuvant) options.
The goal of this combination therapy is to reduce the risk of the cancer coming back. Welireg is a hypoxia-inducible factor-2-alpha (HIF-2α) inhibitor that works by blocking HIF-2α, a protein that promotes survival and growth of kidney cancer cells, especially during low-oxygen conditions or when the VHL (von Hippel-Lindau) gene does not function properly. Keytruda is an immunotherapy medicine that blocks the PD-1 receptor, a protein found on T cells (a type of white blood cell), helping the immune system recognize and kill cancer cells. When used together after surgery, the combination both disrupts cancer cells' survival pathways in a low-oxygen environment and boosts the body's immune response against cancer.
First approved in 2021, Welireg is also used for advanced ccRCC after prior treatments, for certain tumors associated with von Hippel-Lindau disease, and for rare adrenal-related tumors (pheochromocytoma or paraganglioma) that are advanced or cannot be removed with surgery.
This approval matters as it is the first time Welireg has been approved for use in earlier‑stage ccRCC and the first approval for a novel post‑surgery adjuvant therapy that combines an HIF-2α inhibitor and PD-1 immunotherapy. This unique combination may help reduce the chance of your ccRCC from coming back while giving you a choice between intravenous or under‑the‑skin dosing for Keytruda.
Why Was It Approved?
The FDA's approval was based on data from a clinical study that assessed how well the combination treatment worked in 1,841 adult patients who'd already had kidney removal surgery for ccRCC and were either at an intermediate-to-high or high risk for cancer recurrence or had surgically removed metastases with no evidence of cancer.
Patients received either Welireg plus Keytruda or a placebo plus Keytruda as adjuvant treatment after surgery. Treatment was continued until cancer recurrence, unacceptable side effects, or for up to 54 weeks for Welireg or 12 months for Keytruda.
The main outcome was disease-free survival (DFS), meaning the time until the cancer returned or spread or death occurred. In an interim analysis, Welireg plus Keytruda significantly improved DFS, compared with the placebo plus Keytruda, based on 186 events in the Welireg group, compared with 246 events in the placebo group. The risk for cancer recurrence or death was 28% lower in the Welireg group versus the placebo group (hazard ratio, 0.72). The median DFS had not been reached in either group. Data on overall survival was immature at the time of this interim analysis.
Common side effects and lab changes in patients who received Welireg plus Keytruda included low hemoglobin level (anemia) and lymphocyte counts, higher levels of liver enzymes, elevated alkaline phosphatase, and tiredness. Serious adverse events included pneumonia, low oxygen level (hypoxia), lung inflammation (pneumonitis), abnormal rhythm of the heart, diarrhea, and acute kidney injury. Deaths from side effects, including sepsis, occurred in 1.1% of patients.
What Do I Need to Know?
You take Welireg by mouth once daily at the same time each day, with or without food, and swallow the tablet whole. If you miss a dose, take it as soon as you remember that day. Do not take extra tablets. If you vomit after a dose, do not replace it, and take the next dose at the usual time.
You receive Keytruda intravenously every three or six weeks or Keytruda Qlex as an under‑the‑skin injection on the same schedule. Treatment continues for about a year or stops sooner if the cancer returns or side effects are not tolerable.
Welireg can cause anemia and low oxygen levels. Before starting and during your treatment, your health care team will perform certain tests to check your blood counts, hemoglobin and oxygen levels, and liver function. Tell your health care provider about your full medical history, especially if you have severe kidney or liver problems or have had organ, tissue, or donor stem cell transplants (including corneal graft).
Let your health care provider know about all the medicines – including prescription and over‑the‑counter medicines, vitamins, and herbal products – that you use. Some medicines that block the enzymes UGT2B17 or CYP2C19 can raise Welireg levels and may increase the risk of side effects or how severe they can get. Welireg can also lower the level of certain medicines that rely on CYP3A4 enzymes. So your health care provider may either avoid these combinations or adjust doses if they must be used together.
Both Welireg/Keytruda and Keytruda Qlex can harm a fetus, so you will need to have a pregnancy test before treatment. Let your health care provider know if you are pregnant or planning to get pregnant.
Taking Welireg together with hormonal contraceptives may make birth control less reliable and could increase the chance of breakthrough bleeding. Review your birth control method with your health care provider before and during treatment. Men with partners who could become pregnant should use effective birth control while taking Welireg and continue for a week after the last dose. Do not breastfeed during treatment and for a week after the last dose.
Use birth control during treatment with Keytruda or Keytruda Qlex and for four months after your last dose, and avoid breastfeeding for the same duration.
Keytruda can cause your immune system to attack normal organs, so your health care provider may advise periodic lab tests to monitor your liver, kidney, and thyroid function during treatment. Infusion- or injection-related reactions can also occur. Do not use Keytruda Qlex if you are allergic to berahyaluronidase alfa, hyaluronidase, or any ingredients of Keytruda Qlex. Your health care provider will also monitor you closely and may adjust or pause treatment or give you medicines such as corticosteroids or hormone replacements to manage side effects.
Contact your health care provider at once if you develop new or worsening shortness of breath, dizziness, or other signs of low oxygen levels; diarrhea or severe belly pain; dark urine or yellowing of your skin or eyes; easy bruising or bleeding; or severe skin reactions.