Heng on Managing Toxicity and Sequencing With Belzutifan/Lenvatinib in RCC

The FDA approved belzutifan (Welireg) in combination with lenvatinib (Lenvima) on September 24, 2026, for adults with advanced renal cell carcinoma (RCC) with a clear cell component whose disease progressed following treatment with a PD-1 or PD-L1 inhibitor.¹ The recommended dosage is lenvatinib at 20 mg plus belzutifan at 120 mg once daily until disease progression or unacceptable toxicity.

The approval is based on the open-label, randomized, phase 3 LITESPARK-011 trial (NCT04586231), in which 747 patients were assigned 1:1 to belzutifan plus lenvatinib or cabozantinib (Cabometyx). Median progression-free survival (PFS) was 14.6 months (95% CI, 11.1-16.6) with the combination vs 10.6 months (95% CI, 9.2-11.1) with cabozantinib (HR, 0.74; 95% CI, 0.61-0.89; 1-sided P = .00095). Overall survival (OS), the trial's other dual primary end point, was not significantly different between arms at the second interim analysis (median, 34.9 vs 27.6 months; HR, 0.85; 95% CI, 0.68-1.05; 1-sided P = .061).² Grade 3 or worse treatment-emergent adverse events occurred in 84% of patients receiving belzutifan plus lenvatinib and 83% of those receiving cabozantinib, most commonly hypertension. The belzutifan prescribing information carries a boxed warning for embryo-fetal toxicity and warnings and precautions for anemia and hypoxia; for the combination, warnings and precautions also include cardiac dysfunction.¹

In an interview with Targeted Oncology^TM, Daniel Heng, MD, MPH, FRCPC, of the University of Calgary and an author of the LITESPARK-011 publication, discussed the unmet need addressed by the approval, considerations for prescribing, the next steps for research, and how the regimen may affect first-line sequencing.

Targeted Oncology: What unmet need does this FDA approval of belzutifan plus lenvatinib fill?

Daniel Heng, MD: I'm really excited that the FDA has approved belzutifan plus lenvatinib in the second- and third-line setting. What it does is give us the ability to use combination therapy. In the old days, when you used immunotherapy and it stopped working and you had to go on to something else, we would get a median PFS of 6 to 7 months, and response rates would be about 30%.

Now we have the LITESPARK-011 clinical trial, which looked at cabozantinib vs belzutifan plus lenvatinib. Cabozantinib had a response rate of 40%, and belzutifan plus lenvatinib has a response rate of 53%, so we're really increasing the ability to respond better, and that's what our patients need. The PFS is also extended; it's over 14 months instead of 10 months for cabozantinib. In the real world, when we use other therapies, it's as low as 6 or 7 months. I think this is a very exciting advance for our patients as we push the boundaries of PFS, ORR [objective response rate], and OS.

Are there any specific considerations when prescribing this regimen, or any contraindications?

Because it's combination therapy, there will be more toxicities than with single-agent therapy. Specifically with lenvatinib and belzutifan, we'll have the introduction of belzutifan [adverse] effects such as hypoxia and the potential need for transfusions or erythropoietin because of anemia. Those are some new things that we didn't have to think about before with this combination.

There is an interesting signal of maybe some cardiac toxicity, but it's quite low. I think it may be because we were doing a lot more echocardiograms than in real life, so that needs to be teased out a little more to understand how significant it truly is.

We've dealt with the hypoxia before because we've used belzutifan for VHL [von Hippel-Lindau disease], and we've used it in the third- and fourth-line setting. The interesting thing about belzutifan hypoxia is that it usually goes away if you take 5 deep breaths. The patient usually doesn't look dyspneic; they look fine, actually, but their O₂ saturation is low. Those are some differentiating features.

Honestly, when I first started using belzutifan several years ago, I would send everyone with hypoxia to the emergency [department] because I didn't know that the hypoxia could be managed by holding the drug for a week and then subsequently reducing [the dose]. Obviously, if a person is dyspneic, or if you're worried about a pulmonary embolism, then yes, you do have to send them to the emergency [department]. But those are some tricks I've learned over the years with belzutifan.

Regarding toxicity, is the safety profile in line with what oncologists are used to managing?

I think so. Oncologists are really good at using TKIs [tyrosine kinase inhibitors] because we've had a lot of history with them. Belzutifan is relatively newer, so we just have to look for the hypoxia and the anemia. If your patient is a regular patient with not too many comorbidities and no severe [chronic obstructive pulmonary disease (COPD)"} that requires oxygen, then I think they would be a candidate for belzutifan and lenvatinib.

How do you see the availability of this combination affecting sequencing choices?

When this becomes available worldwide, some of us will have to think about sequencing and what we use in the first line. For example, do we use more cabozantinib and nivolumab [Opdivo] or ipilimumab [Yervoy] and nivolumab in the first line so that we can use belzutifan and lenvatinib afterward, or do we stick with the same go-to medications that we use in the first line?

I think it will depend on where you're from. In Canada, we might not get this combination right away, whereas in the US you have it yesterday. So maybe in the US there may be some changes in what happens in the first line, whereas in Canada and other countries that are slower to adopt, we might not be changing our first-line therapy. I think it's really important to use your best first-line therapy first, though, because not everyone gets onto their second-line therapy, and similarly, not everyone gets onto their third-line therapy. We want to be very thoughtful about how we sequence things.

What do you see as the next step in this line of research?

The next step is to look at how this works in the real world. When we use belzutifan and lenvatinib, what benchmarks of ORR, PFS, and OS do we actually achieve? We also want to look at cardiotoxicity to see if there are any signals there or if it's just a red herring from doing more echocardiograms.

I think it will be really interesting to see how this evolves, because we'll probably have more combination therapies come up. There are other HIF-2α inhibitors being investigated, so are those better? Are they interchangeable? Can we use one after another? Those are great research questions that we're going to look into.

Watch the full interview with Dr Heng.

REFERENCES

1. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. FDA. September 24, 2026. Accessed October 7, 2026. https://tinyurl.com/3r6cvkex

2. Motzer RJ, McDermott R, Park SH, et al. Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial. Lancet. 2026;408(10557):808-820. doi:10.1016/S0140-6736(26)01089-5