Could a new combination treatment change what comes next for advanced kidney cancer?

For people with advanced clear-cell renal cell carcinoma (ccRCC), treatment decisions can become more complicated when cancer progresses after immunotherapy. Immune checkpoint inhibitors have transformed care for many people with kidney cancer. Until now, there has been an important unanswered question: What is the best treatment option when the cancer starts growing again after immunotherapy?

Results from the phase III LITESPARK-011 clinical trial may help provide another answer.

The study compared a combination of belzutifan (Welireg) and lenvatinib (Lenvima) with cabozantinib (Cabometyx), an established treatment option for people with advanced clear-cell kidney cancer whose disease has progressed after previous treatment. Researchers found that the belzutifan-lenvatinib combination significantly extended the amount of time participants lived without their cancer progressing.

Understanding the treatment options studied

LITESPARK-011 included 747 adults with advanced, unresectable, locally advanced, or metastatic clear-cell renal cell carcinoma. All participants had previously received immunotherapy targeting PD-1 or PD-L1, and their cancer had progressed.

Participants were randomly assigned to receive one of two treatment approaches:

• Belzutifan plus lenvatinib, a combination of two targeted therapies
• Cabozantinib, a targeted therapy that is already used to treat advanced kidney cancer

The combination kept cancer from progressing longer

One of the study’s main goals was to measure progression-free survival, or the amount of time before the cancer grew or spread further.

Participants receiving belzutifan plus lenvatinib had a median progression-free survival of 14.8 months, compared with 10.7 months for those receiving cabozantinib.

In other words, the combination reduced the risk of disease progression or death by 30% compared with cabozantinib during the study period.

This is an important finding because there is still no single, clearly established standard treatment approach for everyone whose advanced clear-cell kidney cancer progresses after PD-1 or PD-L1 immunotherapy.

What about overall survival?

The study also looked at overall survival, meaning how long participants lived regardless of whether their cancer progressed.

At the time of this analysis, median overall survival was:

• 34.9 months with belzutifan plus lenvatinib
• 27.6 months with cabozantinib

While the numbers favored the belzutifan-lenvatinib combination, researchers can’t conclude that the combination helped participants live significantly longer than cabozantinib.

The study is ongoing, and participants continue to be followed. Longer follow-up may provide a clearer picture of how these treatments compare over time.

Why might combining these treatments work?

Belzutifan and lenvatinib work in different ways, which is one reason researchers were interested in studying them together.

Belzutifan targets a protein called HIF-2α. Changes involving this pathway play an important role in the development and growth of clear-cell renal cell carcinoma.

Lenvatinib targets several pathways that cancer cells can use to grow and develop new blood vessels.

By targeting different biological processes at the same time, researchers hope the combination can make it more difficult for cancer to continue growing.

Side effects remain an important consideration

As with any cancer treatment, potential side effects are an important part of treatment decisions.

Serious, or grade 3 or higher, treatment-related side effects occurred at similar rates in both groups:

• 84% of participants receiving belzutifan plus lenvatinib
• 83% of participants receiving cabozantinib

The most common serious side effect in both groups was high blood pressure.

Treatment-related side effects can vary from person to person and may depend on factors such as other health conditions, previous treatments, and the specific medications being used. Two treatment-related deaths occurred in the belzutifan-lenvatinib group, while one occurred in the cabozantinib group.

These findings are an important reminder that a treatment’s potential benefits must always be weighed alongside its possible risks and impact on quality of life.

What do these findings mean for patients?

The results of LITESPARK-011 suggest that belzutifan plus lenvatinib could become an important new treatment option for people with advanced clear-cell renal cell carcinoma that has progressed after PD-1 or PD-L1 immunotherapy.

The combination didn’t show a statistically significant overall survival benefit at this stage of the study, but it did significantly extend progression-free survival compared with cabozantinib.

More time without cancer progression can be a meaningful outcome, but it’s only one part of a larger treatment conversation. Patients and their care teams may also consider potential side effects, previous treatments, overall health, treatment goals, and quality of life.

Looking ahead

While additional follow-up is needed to better understand the long-term survival impact of belzutifan plus lenvatinib, the findings offer encouraging evidence that combining targeted treatments may help delay cancer progression for some patients.

As research continues, having more evidence-based treatment options could help make care increasingly personalized, allowing patients and their oncology teams to choose treatments based not only on what has worked before, but also on what may be most appropriate for the next stage of care.

Disclaimer: The information provided in this article is for informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Outcomes4Me is not acting as your caregiver, and any suggestions or guidance offered should not replace the advice of your healthcare provider or qualified medical professional. Always seek the guidance of your physician or other qualified health provider with any questions you may have regarding a medical condition.