Written By | Health News Agencies
US regulators have approved Merck and Eisai's Welireg-plus-Lenvima regimen for advanced kidney cancer that has beaten immunotherapy
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For thousands of people with advanced kidney cancer, the bad news usually comes in the same way. The immunotherapy that had held the tumours in check for months, sometimes years, stops working. A scan shows new spots on the lungs, or old ones growing again. The next question is always the same: what now?
This week, American patients got a new answer.
On Thursday, 24 September, the US Food and Drug Administration approved a pairing of two tablets, belzutifan (sold as Welireg by Merck) and lenvatinib (sold as Lenvima by Japan's Eisai), for adults with advanced clear cell renal cell carcinoma whose disease has progressed after a PD-1 or PD-L1 immunotherapy drug. The companies announced the approval at 6.45 a.m. Eastern time the next morning.
According to the companies, it is the first approved combination of a HIF-2 alpha inhibitor, a drug that cuts the wires on a tumour's built-in "low oxygen" alarm, with a multi-targeted blood-vessel blocker. Both are taken by mouth, at home, once a day. No drips. No infusion chair.
And in a head-to-head trial against the drug most doctors reach for in this situation today, the combination kept the cancer from growing for longer and shrank tumours in more patients.
But, as with many cancer headlines, the details matter. The same trial found no statistically significant gain in the thing patients care about most: how long they live.
THE TRIAL THAT WON THE APPROVAL
The approval rests on a Phase 3 study called LITESPARK-011. It was a big, international effort: 747 patients at 184 medical centres in 25 countries, all with advanced clear cell kidney cancer that had already progressed on or after immunotherapy.
Half were randomly assigned to belzutifan (120 milligrams a day) plus lenvatinib (20 milligrams a day). The other half got cabozantinib (sold as Cabometyx by Exelixis), a powerful single tablet that has become a go-to option for patients once immunotherapy fails.
The trial was open-label, which means patients and their doctors knew which treatment they were getting. To guard against bias, the scans were read by a blinded independent panel.
The results, according to the FDA:
In plain terms: roughly four extra months of the cancer standing still, more tumours shrinking, and those shrinkages lasting much longer.
THE CATCH: NO PROVEN SURVIVAL BOOST
LITESPARK-011 had two main goals, not one. The first was progression-free survival, which it hit. The second was overall survival: whether people actually live longer.
It missed that one. In the final analysis, published data show a median overall survival of 33.7 months on the combination against 28.6 months on cabozantinib. That five-month gap sounds meaningful, and the numbers leaned in the combination's favour (hazard ratio 0.85). But the statistical confidence range crossed the line of no effect, so researchers cannot rule out that the difference was down to chance.
Merck and Eisai's own announcement says plainly that overall survival "did not meet statistical significance." The FDA's notice says the same.
Why does that happen? There are several possible reasons, and cancer specialists will debate them at the European Society for Medical Oncology (ESMO) Congress in Madrid, where the companies say the results will be presented. Patients whose cancer grows on one treatment go on to receive others, and those later drugs can blur survival differences. Cabozantinib is itself a strong drug. And trials can simply be too small to prove a modest survival gain.
What it does mean is that the new combination is not a proven life-extender. It is a proven way to hold the cancer back for longer, with more tumour shrinkage, which many patients value in its own right.
HOW THE DRUGS WORK: CUTTING THE TUMOUR'S OXYGEN ALARM
To understand why doctors are excited about belzutifan, you have to go back to a Nobel Prize. In 2019, William Kaelin, Sir Peter Ratcliffe and Gregg Semenza shared the Nobel Prize in Physiology or Medicine for discovering how cells sense and respond to oxygen. At the centre of that machinery is a family of proteins called hypoxia-inducible factors, or HIFs. When oxygen runs low, HIFs switch on genes that build new blood vessels and help cells survive.
In healthy cells, a protein made by the VHL gene acts like a garbage disposal, destroying HIF whenever oxygen levels are normal. In most clear cell kidney cancers, the VHL gene is broken. The garbage disposal stops working. HIF-2 alpha builds up, and the tumour behaves as if it is permanently starved of oxygen, sprouting blood vessels and growing aggressively.
Belzutifan blocks HIF-2 alpha from pairing up with its partner protein, effectively silencing that false alarm. The drug traces back to laboratory work at UT Southwestern Medical Center in Dallas, was developed by a spin-out called Peloton Therapeutics, and came to Merck when it bought Peloton in 2019.
Lenvatinib comes at the problem from a different angle. It is a tyrosine kinase inhibitor that jams the signals tumours use to grow new blood vessels (the VEGF receptors) and several other growth pathways.
Put together, one drug turns off the alarm and the other cuts the supply lines. "By bringing together two therapies that each target different pathways, WELIREG plus LENVIMA is now the first approved regimen of its kind," said Dr M. Catherine Pietanza, vice president of global clinical development at Merck Research Laboratories.
THE SIDE EFFECTS: A HEAVY LOAD
This is not a gentle treatment, and the prescribing information makes that clear.
In LITESPARK-011, serious adverse reactions occurred in 54% of patients on the combination. The most common serious ones included hypoxia, meaning dangerously low oxygen levels (6%), pneumonia (5%), low sodium (3.2%), acute kidney injury (3%), bleeding (2.7%), anaemia (2.7%), heart failure (2.4%) and diarrhoea (2.4%).
Fatal adverse reactions occurred in 5% of patients, including sepsis, pneumonia and respiratory failure.
Other numbers from the label tell the story of how hard the regimen can be to tolerate:
Belzutifan also carries a boxed warning, the FDA's strongest, about harm to an unborn baby. It can make some hormonal contraceptives stop working, so patients who could become pregnant are told to use non-hormonal contraception. The label says the combination's safety has not been established in people whose heart pumping capacity is already below 50%, and the trial excluded patients who already had low oxygen, active brain metastases or recent serious heart disease.
Doctors will be told to check oxygen saturation, blood counts and, often, heart function before and during treatment.
EXPERT PERSPECTIVE
The trial's principal investigator, Dr Robert Motzer, a kidney cancer specialist at Memorial Sloan Kettering Cancer Center in New York, framed the approval around a gap every oncologist knows well.
"While there has been much progress in the first-line treatment of advanced kidney cancer, we have limited options to offer patients if the disease progresses after treatment with a PD-1/PD-L1 immunotherapy," he said. The approval, he added, gives doctors "a new treatment option for patients who progress following treatment with anti-PD-1/PD-L1 therapy."
Eisai's Dr Corina Dutcus, senior vice president for oncology global clinical development, said the complexity of managing kidney cancer over time "makes every treatment decision meaningful."
Independent specialists are likely to weigh the trade-off carefully. On one side: a longer stretch of disease control, more responses and much more durable ones. On the other: no proven survival gain, a higher burden of side effects to monitor, and two drugs to manage instead of one. For a fit patient who wants the best chance of shrinking their tumours, the combination may be attractive. For an older or frailer patient, or someone with heart or lung problems, single-drug options such as cabozantinib, or belzutifan on its own, may remain the better fit.
WHY THIS MATTERS: THE SCALE OF KIDNEY CANCER
Kidney cancer is not rare. According to figures cited by Merck, there were an estimated 442,570 new cases and 144,871 deaths from kidney cancer worldwide in 2024. About nine in ten kidney cancers are renal cell carcinoma, and roughly 70% of those are the clear cell type targeted by this approval. The disease is about twice as common in men as in women.
Many kidney cancers are found by accident, on a scan done for something else. But about 32% of patients are diagnosed when the cancer has already spread to nearby tissue or distant organs.
Over the past decade, the first-line treatment of advanced kidney cancer has been transformed by immunotherapy, usually combined with another drug. Those regimens have helped many patients live longer. But most patients' cancers eventually find a way around them, and the "second-line" options after immunotherapy have been limited. That is the gap this approval targets.
A DRUG ON A WINNING STREAK
Belzutifan is quickly becoming one of Merck's most important cancer drugs outside of its blockbuster Keytruda.
It was first approved in the US in 2021 for tumours linked to von Hippel-Lindau disease, a rare inherited condition caused by faulty copies of the same VHL gene. It later won approval on its own for advanced clear cell kidney cancer after both immunotherapy and a blood-vessel blocker had failed. It has also been approved for a rare adrenal tumour called pheochromocytoma or paraganglioma, and, with Keytruda, as an "adjuvant" treatment given after surgery to lower the chance of kidney cancer returning in higher-risk patients.
This new approval moves belzutifan one step earlier in the advanced-disease pathway: straight after immunotherapy, rather than after two lines of therapy.
Lenvatinib, meanwhile, is already approved in kidney cancer with Keytruda as a first-line option and with everolimus after prior blood-vessel therapy.
WHAT THIS MEANS FOR YOU
If you or someone you love has advanced clear cell kidney cancer that has progressed on immunotherapy, here is what to know:
THE BOTTOM LINE
For patients whose kidney cancer has outrun immunotherapy, the approval of belzutifan plus lenvatinib is a real step forward: two pills that attack the tumour from two sides, keep it in check longer than the current standard, and shrink it in more than half of patients.
But it is not the knockout blow the "two pills, one punch" headline might suggest. The survival advantage the trial hoped for did not reach statistical significance, and the side effects are heavy enough that most patients need their doses adjusted.
Doctors will now have to match the right patients to the right option. For some, four extra months of the cancer standing still, and a better chance of tumours shrinking, will be worth the burden. For others, a gentler single drug may make more sense.
What is certain is that a discovery about how cells sense oxygen, first celebrated with a Nobel Prize seven years ago, has now produced another treatment option for people facing one of the hardest moments in cancer care.
