Key Ideas

Frontline treatment of advanced renal cell carcinoma (RCC) now centers on a choice between dual immunotherapy and immunotherapy-TKI combinations, each with different tradeoffs in response rate versus durable remission. HIF-2α inhibition, led by belzutifan, has emerged as the most significant new mechanism in RCC in the past five years, and T-cell engagers and radioligand therapy are the next frontier.

From TKI Monotherapy to Immunotherapy Combinations

Before 2005, advanced metastatic kidney cancer carried a grim prognosis, with roughly 5% of patients alive at five years. Tyrosine kinase inhibitors (TKIs) targeting the VEGF pathway, introduced starting in 2005, meaningfully extended disease control for many patients through about 2015, though with substantial toxicity of their own.

Immunotherapy then re-entered the picture (having previously been used in a limited way with high-dose IL-2 decades earlier). The CheckMate 214 trial established ipilimumab plus nivolumab as a frontline option against sunitinib, improving progression-free survival, overall survival, and response rate versus the TKI sunitinib. Ten-year follow-up data show a durable tail on the progression-free survival curve: roughly 20% to 30% of patients treated with ipilimumab-nivolumab remain without disease progression years later, off all therapy (since treatment was capped at two years, and sometimes stopped earlier for toxicity), meaning these patients are effectively treatment-free with no evidence of active metastatic disease.

Three large phase 3 trials then tested combining a TKI with a PD-1 or PD-L1 inhibitor against sunitinib: axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab. All three combinations improved progression-free survival, overall survival, and response rate compared with sunitinib, with response rates reaching up to 70% and disease control rates as high as 90%, generally higher than what is seen with dual immunotherapy.

The logical next question, whether combining all three drug classes together (TKI plus dual immunotherapy) could do even better, was tested in the COSMIC-313 trial, adding cabozantinib to ipilimumab-nivolumab. The triplet showed a slightly longer progression-free survival but no overall survival benefit, at the cost of substantially more liver toxicity and diarrhea. As a result, this triplet is not widely used even in higher-risk patients.

Choosing Between Dual Immunotherapy and Immunotherapy-TKI: A Genuine Toss-Up

No trial has directly compared ipilimumab-nivolumab against a TKI-immunotherapy combination, so the choice between these remains a matter of clinical judgment and shared decision-making rather than settled evidence. Some patterns are worth noting: response rates run considerably higher with TKI-immunotherapy combinations (roughly 61% to 71%) than with ipilimumab-nivolumab (around 40%), while complete response rates are fairly similar between approaches, in the range of 12-18% for all combinations. The chance that disease progression will be a patient's best response on treatment (meaning the treatment simply does not work for them) is slightly higher with ipilimumab-nivolumab (about 18%) than with the TKI-immunotherapy combinations (  5%-12%).

Factors favoring a TKI plus single immunotherapy include symptomatic metastases where a patient cannot tolerate a period of possible progression, since that could risk critical organ damage or leave a patient too unwell to receive second-line therapy, and major underlying autoimmune disease, where a PD-1 inhibitor alone may carry less risk than adding ipilimumab. Factors favoring dual immunotherapy include a preference (supported by patient survey data) for the possibility of a more durable, complete response even at some cost to upfront tumor shrinkage; sarcomatoid features on pathology, where immunotherapy in general appears to work particularly well; a longer life expectancy independent of the cancer, since the survival advantage associated with dual immunotherapy plays out over a roughly ten-year horizon; and significant comorbidities such as hypertension or cardiovascular disease that make chronic TKI therapy especially challenging.

After Progression on Frontline Therapy: TKIs Remain the Default, Not Immunotherapy

For patients who progress after immunotherapy-based frontline treatment, the standard options are switching TKIs (cabozantinib, lenvatinib, axitinib) or belzutifan, a HIF-2α inhibitor.

An important and well-established point: two separate randomized trials, CONTACT-03 (cabozantinib with or without atezolizumab) and TiNivo-2 (tivozanib with or without nivolumab), both found essentially identical progression-free and overall survival whether or not a checkpoint inhibitor was added to the TKI, in patients who had recently progressed on prior PD-1 therapy. Continuing or resuming immunotherapy after progression on checkpoint blockade does not appear to add benefit, and should generally be avoided once a patient has progressed on PD-1 therapy, since it does not benefit the patient and adds cost without benefit. A caveat: these trials mainly enrolled patients whose immunotherapy exposure was in the treatment line immediately preceding the study drug; for patients with a much longer interval since their last PD-1 exposure (for example, after cycling through multiple subsequent TKIs over several years), it remains uncertain whether disease biology has shifted enough to justify reconsidering immunotherapy, and this scenario is addressed cautiously in some guidelines.

A smaller, single-institution study from MD Anderson comparing lenvatinib-everolimus against cabozantinib in the second line suggested a longer duration of response and progression-free survival favoring lenvatinib-everolimus, without an overall survival difference, an important reminder that using two drugs instead versus one carries added toxicity for a benefit that may not extend survival.

HIF-2α Inhibition: The Newest Breakthrough Mechanism in RCC

Clear cell RCC carries VHL deficiency, which stabilizes HIF-2α and drives downstream hypoxia-response genes, including VEGF, providing a therapeutic target upstream of the VEGF pathway itself. Belzutifan, a HIF-2α inhibitor, was first approved for VHL-associated tumors and later, based on the LITESPARK-005 trial, for later-line clear cell RCC after prior PD-1/PD-L1 and VEGF-TKI therapy, showing improved progression-free survival compared with everolimus.

Belzutifan's side-effect profile is meaningfully different from that of TKIs: it does not cause the hypertension or gastrointestinal toxicity common with VEGF-targeted TKIs, which matters considerably for patients who have already cycled through multiple TKIs and are worn down by chronic low-grade side effects. Its distinct toxicities are anemia and hypoxia, both generally manageable with early dose reduction; erythropoiesis-stimulating agents are an option but is less preferred in our practice versus simply adjusting the dose. When tolerated, belzutifan can provide durable disease control, with some patients continuing years on treatment, offering a genuine TKI-free interval, valuable for a patient population that has otherwise been tied to TKI therapy as a backbone for roughly two decades.

The LITESPARK-011 trial tested whether combining belzutifan with lenvatinib could improve on cabozantinib alone, and found an improvement in progression-free survival, at the cost of added toxicity (notably more anemia and fatigue) and, so far, no overall survival benefit (though the data remain immature). This combination is not yet FDA approved. If approved in the future, the tradeoff to weigh will be whether the combination's added efficacy is worth losing the TKI-free interval that belzutifan alone can offer; that decision depends on how much disease burden a given patient has and how they weigh response rate against durability and quality of life.

A next-generation HIF-2α inhibitor, casdatifan, is furthest along among competitors, now being tested in the phase 3 PEAK-1 trial, in combination with a TKI, suggesting the field may continue moving toward doublet and even triplet combinations built around HIF-2α inhibition.

What's on the Horizon: T-Cell Engagers and Radioligand Therapy

T-cell engager therapy, a class of drugs with no prior track record in RCC, is now in early clinical development targeting ENPP3, a protein highly expressed in clear cell RCC and largely absent from normal tissue. Using a priming, step-up dosing schedule similar to that used for T-cell engagers already approved in multiple myeloma and small cell lung cancer, early phase 1 data show a manageable toxicity profile (cytokine release syndrome as a class effect, plus a high rate of at least low-grade skin rash, both of which resolve over time), an objective response rate of at least 25%, and a disease control rate of 70%, with some patients now remaining on treatment for over a year. Patients may have a preference for staying on this therapy, even with stable disease, to avoid returning to TKI-related toxicity. This same ENPP3 target is also being explored in other cancers, including papillary RCC, colorectal cancer, and non-small cell lung cancer.

Separately, radioligand therapy directed at CA9, a marker expressed on clear cell RCC and already used diagnostically in pathology, is advancing along a theranostic pathway (a paired diagnostic and therapeutic approach similar to what has been used in prostate cancer). Early studies have shown that a CA9-targeted diagnostic imaging agent can specifically identify kidney tumors on PET imaging, and a corresponding actinium-based therapeutic version is now opening for study at the University of Chicago for patients with refractory RCC.

For Patients

Treatment for advanced kidney cancer (renal cell carcinoma) now offers several strong frontline options, generally either two immunotherapy drugs together, or one immunotherapy drug combined with a targeted pill called a TKI (tyrosine kinase inhibitor). Both approaches work well, but in somewhat different ways: the TKI-immunotherapy combinations tend to produce a higher chance of the cancer shrinking, while the two-immunotherapy combination offers a smaller but real chance of a long-lasting, complete response that may allow some patients to eventually stop all treatment. Which is the better starting point depends on individual factors like how much the cancer is causing symptoms, other health conditions, and personal preference, and is a discussion to have with a kidney cancer specialist.

An important practical point: if a patient's cancer has progressed while on immunotherapy, continuing or restarting immunotherapy afterward generally does not provide additional benefit, according to well-designed clinical trials, so switching to a different type of drug (usually a TKI, or the newer HIF-2α inhibitor described below) is typically the better approach.

A newer type of pill, called a HIF-2α inhibitor (belzutifan is the first approved example), works through a different mechanism than TKIs and causes different side effects, mainly anemia and low blood oxygen rather than high blood pressure or stomach upset. For patients who have grown tired of TKI side effects, this can provide meaningful relief and a break from that particular set of side effects, sometimes for a year or more.

Looking ahead, newer types of treatment, including drugs that direct the immune system's T cells to attack kidney cancer cells directly, and radioactive drugs that specifically target kidney cancer cells (similar to an approach already used in prostate cancer), are showing early promise in clinical trials, offering hope for continued improvement in outcomes.

Anyone with advanced kidney cancer should discuss with their care team the tradeoffs between the different frontline treatment approaches, and ask whether any newer therapies or clinical trials might be appropriate as the disease progresses.

Key Takeaways

  • Frontline advanced RCC treatment now centers on choosing between dual immunotherapy (ipilimumab-nivolumab) and TKI-immunotherapy combinations; no head-to-head trial exists, so the choice depends on individual patient factors and shared decision-making.

  • Adding a a TKI to dual immunotherapy (cabozantinib to ipilimumab-nivolumab, tested in COSMIC-313) improved progression-free survival only modestly, with more toxicity and no overall survival benefit, and is not widely used.

  • Two separate randomized trials (CONTACT-03 and TiNivo-2) confirmed that adding or continuing immunotherapy after progression on checkpoint blockade does not improve outcomes; switching to a different mechanism (typically a TKI) is standard after progression on PD-1-based therapy.

  • Belzutifan, a HIF-2α inhibitor, represents the most significant new treatment mechanism in RCC in the past five years, with a distinct side-effect profile (anemia, hypoxia) that spares patients the hypertension and GI toxicity common with TKIs, and can provide a valuable TKI-free treatment interval.

  • Combining belzutifan with lenvatinib (LITESPARK-011) improves progression-free survival over cabozantinib alone but adds toxicity without a clear overall survival benefit so far, and is not yet FDA approved.

  • T-cell engager therapy and CA9-targeted radioligand therapy represent genuinely new treatment classes now in early clinical development for RCC, a disease that has had no prior track record with either approach.

References

  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma (CheckMate 214), long-term follow-up.

  2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma (CheckMate 9ER).

  3. Choueiri TK, Powles T, Albiges L, et al. Cabozantinib plus nivolumab and ipilimumab versus nivolumab and ipilimumab alone in advanced renal cell carcinoma (COSMIC-313).

  4. Pal SK, Albiges L, Tomczak P, et al. Cabozantinib plus atezolizumab versus cabozantinib alone after progression on immune checkpoint inhibitors (CONTACT-03).

  5. Choueiri TK, Motzer RJ, Barthelemy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy after an immune checkpoint inhibitor in RCC (TiNivo-2). Lancet. 2024.

  6. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus in advanced renal cell carcinoma (LITESPARK-005).

  7. Choueiri TK, et al. Casdatifan (AB521), a next-generation HIF-2α inhibitor, phase 3 PEAK-1 trial in clear cell renal cell carcinoma.