Two pills hold advanced kidney cancer in check for longer

In Short. For people whose kidney cancer has kept growing despite immunotherapy, a newly approved two-pill combination held the disease back for longer than a drug they could already get, but a large trial could not show that it helps them live longer.

THE KIDNEYS filter the blood through tiny tubes, and the most common cancer to strike them, renal cell carcinoma, mostly starts in those tubes. It accounts for about nine in ten kidney cancers, and about 70% of those cases are of a type called clear-cell. When the cancer has spread beyond the kidney, or has grown in a way that surgery cannot remove, doctors call it advanced, and treatment turns to medicines.

The patients in question have already had one of those medicines, an immunotherapy. These drugs release a brake on the immune system (a pair of proteins called PD-1 and PD-L1) so that it attacks the tumor harder. In these patients the cancer grew anyway. Robert Motzer of Memorial Sloan Kettering Cancer Center, who led the trial and has consulted for both drugmakers, says doctors have had "limited options" to offer.

The new approach exploits a common fault. The most frequent genetic change in this kind of kidney cancer is the loss of a working gene called VHL. Its protein acts as a brake on another protein, HIF-2 alpha, marking it for destruction. Without that brake, HIF-2 alpha piles up and switches on genes for cell growth, new blood vessels and tumor growth. Belzutifan stops HIF-2 alpha from doing that job. Lenvatinib works from another side. It blocks the receptors for signals that tumors use to grow new blood vessels, along with several other growth signals.

On September 24th America's Food and Drug Administration (FDA) approved the two together, belzutifan as Merck's Welireg and lenvatinib as Eisai's Lenvima, for adults with advanced clear-cell kidney cancer that has grown after a PD-1 or PD-L1 drug. The approval rests on a phase 3 trial, LITESPARK-011, in which chance alone split 747 patients evenly (making it randomized) between a daily 120 mg of belzutifan plus 20 mg of lenvatinib, and a daily pill of cabozantinib.

Cabozantinib is already approved for advanced kidney cancer, so the pair had to beat a real treatment rather than a dummy pill. That makes cabozantinib an active comparator. Because the treatments were different pills, patients and doctors knew who was taking what, a design called open-label. That matters when judging from scans whether a cancer has grown, since knowing the treatment could nudge a borderline reading. So the scans were read by outside radiologists who did not know which treatment each patient got, a blinded independent central review.

The trial asked two main questions at once. One was how long patients went before their cancer measurably grew or they died, known as progression-free survival. The other was simply how long they lived, overall survival. For each, the trialists set in advance how big a difference had to be, given the trial's size, before chance became an unlikely explanation. A result that clears that bar has statistical significance.

Progression-free survival cleared it. The typical patient on the combination (the median, meaning half fared better and half worse) went 14.6 months before the cancer grew or they died, against 10.6 months on cabozantinib. Merck describes this as a 26% lower risk of the cancer growing or the patient dying. The share whose tumors shrank by a set amount was 53% on the combination and 40% on cabozantinib. Overall survival fell short of statistical significance at its final analysis. The median was 33.7 months against 28.6, but the plausible range of the effect ran from a 30% lower risk of death to a 3% higher one. A paper in the Lancet in August, based on an earlier look at the data, reached the same verdict on both questions.

The label warns that belzutifan can cause severe anemia (too few red blood cells) and dangerously low oxygen levels, and can harm an unborn baby. Taken with lenvatinib it can also weaken the heart. The trial excluded people who already had low oxygen, cancer in the brain or recent serious heart disease.

What the trial settles is practical. For adults whose clear-cell kidney cancer has grown after immunotherapy, and who resemble those who took part, the combination keeps the disease in check for longer and shrinks more tumors than cabozantinib does, as judged by blinded independent central review. It cannot say how the pair compares with other later treatments, because cabozantinib was the only rival, or whether it helps people who have not yet had immunotherapy, because none were enrolled. For patients weighing it now, it offers more time before the cancer grows, while a longer life remains possible but unproven.