Who is this for?
This is for people with advanced (metastatic) clear-cell kidney cancer who are choosing a first treatment.
Modern first-line treatment is built around immunotherapy. There are two main strategies: combining two immunotherapy drugs (covered in our CheckMate 214 summary), or combining one immunotherapy drug with a targeted pill — the subject of this summary. Both are excellent; which suits a given person depends on several factors.
What kind of evidence is this?
This is a review of the three large phase III trials that established immunotherapy-plus-pill combinations as first-line treatment — KEYNOTE-426, CheckMate 9ER, and CLEAR — each of which compared a combination against the old standard pill, sunitinib. It also draws on a 2025 expert review of how these options are chosen in practice.
Background: two attacks are better than one
For over a decade, the first treatment for advanced kidney cancer was a single targeted pill such as sunitinib, which blocks the tumor’s blood supply. It helped, but rarely for long. Then immunotherapy arrived and changed everything.
Researchers reasoned that pairing an immunotherapy drug with a targeted pill might combine their strengths: the pill shrinks the tumor quickly and reliably, while the immunotherapy works toward a deeper, longer-lasting response. Three different combinations were each tested against sunitinib — and all three won.
The evidence: three winning combinations
Each combination was tested in its own large phase III trial, against sunitinib, in people with previously untreated advanced clear-cell kidney cancer across all risk groups:
- Pembrolizumab + axitinib (KEYNOTE-426)
- Nivolumab + cabozantinib (CheckMate 9ER)
- Pembrolizumab + lenvatinib (CLEAR)
Because no trial compared the combinations directly, they can’t be ranked with certainty — but their results point the same way.
Results: what they found
Across all three trials, adding an immunotherapy drug to a targeted pill beat sunitinib on every important measure.
Immunotherapy + pill vs sunitinib (across the three trials)
The tumor measurably shrank in most people on a combination — and completely disappeared in about 12–18%, versus only a few percent with sunitinib.
The cancer was kept from growing for much longer — median progression-free survival was roughly doubled.
Each combination improved overall survival compared with sunitinib, with roughly a 16–23% lower risk of death (hazard ratios 0.77–0.84).
The combinations look broadly similar. Pembrolizumab + lenvatinib produced the highest response rate and the longest time in check, but also tends to bring more side effects — a reminder that the “best on paper” number isn’t automatically the best choice for a given person.
Immunotherapy + pill, or two immunotherapies — how is the choice made?
Both are first-line standards, and there is no simple winner. An immunotherapy + pill combination shrinks the tumor quickly and in most people, which is valuable when someone has a lot of cancer or symptoms that need controlling soon. Two immunotherapies (nivolumab + ipilimumab) has a lower chance of shrinking the tumor up front, but offers the possibility of a deep, durable, sometimes treatment-free remission — and is favored in intermediate/poor-risk disease. The decision weighs risk group, how urgently a response is needed, side-effect profiles, and personal preference.
What are the side effects?
These combinations carry the side effects of both drugs. The targeted pill commonly causes high blood pressure, diarrhea, fatigue, and hand-foot soreness. The immunotherapy can cause immune-related inflammation of organs such as the thyroid, bowel, liver, or skin. A practical challenge is telling which drug is causing a given symptom, since managing them differs. Doses of the pill are often adjusted to keep side effects tolerable.
Are the three combinations really different?
They share the same design — an anti-PD-1 immunotherapy plus a blood-supply-blocking pill — and their results are in the same ballpark. They differ mainly in the specific pill (axitinib, cabozantinib, or lenvatinib), which changes the exact side-effect profile and dosing. Without head-to-head trials, oncologists choose based on those practical differences and their own experience, rather than a proven ranking.
Immunotherapy + targeted pill (first-line)
- KEYNOTE-426 — pembrolizumab + axitinib
- CheckMate 9ER — nivolumab + cabozantinib
- CLEAR — pembrolizumab + lenvatinib
The two-immunotherapy alternative
- CheckMate 214 — nivolumab + ipilimumab (our summary)
The bottom line
For advanced clear-cell kidney cancer, combining an immunotherapy drug with a targeted pill is a highly effective first treatment. Three such combinations — pembrolizumab + axitinib, nivolumab + cabozantinib, and pembrolizumab + lenvatinib — each beat the old standard pill on tumor shrinkage, time in check, and survival. They work across all risk groups and are especially useful when the tumor needs to be brought under control quickly. The main alternative, two immunotherapies together, trades a lower up-front response for the chance of a durable, treatment-free remission. There is no single “best” option — the right one depends on the person.
What this could mean for you
- Immunotherapy-based treatment is standard. A single targeted pill alone is no longer the first choice for advanced clear-cell kidney cancer.
- These combinations shrink the tumor in most people — useful if you have a large amount of cancer or symptoms that need controlling.
- There’s more than one good option. Immunotherapy + pill and two-immunotherapy approaches are both standards; the choice is individual.
- Ask about the side-effect trade-offs of the specific pill in each combination — they differ, and that often guides the decision.
Questions & comments
Have a question about this research? Ask below. Questions are read and answered by the site. We can’t give personal medical advice, but we’re glad to explain the research more clearly.