LITESPARK-022 PRO Data Further Support Adjuvant Belzutifan Plus Pembrolizumab in ccRCC

Patient-reported outcomes (PROs) from the phase 3 LITESPARK-022 trial (NCT05239728) help contextualize the treatment burden of adding belzutifan (Welireg) to adjuvant pembrolizumab (Keytruda) in patients with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence after surgery, according to Thomas Powles, MBBS, MRCP, MD.¹

A PRO analysis of LITESPARK-002, which was presented at the 2026 Kidney Cancer Research Summit (KCRS), included patients given pembrolizumab plus belzutifan and those treated with pembrolizumab plus placebo. No clinically meaningful changes from baseline to week 84 were observed in either group per assessments with both the Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease-Related Symptoms (FKSI-DRS) and EORTC QLQ-C30. Analysis via FKSI-DRS showed no clinically meaningful deterioration in either arm, with LSM changes from baseline of –0.67 for the belzutifan combination vs –0.76 for the placebo combination (difference, 0.10; 95% CI, –0.28 to 047). Clinically meaningful deterioration was not observed in either group across QLQ-C30 assessments for global health status/quality of life (QOL; difference, −0.23; 95% CI, −1.95 to 1.49), physical function difference, 0.71; 95% CI, –0.66 to 2.09), and role function (difference, 0.72; 95% CI, –1.27 to 2.71).

“The addition of belzutifan to pembrolizumab as a standard of care is an important step towards improving outcomes in [RCC],” Powles said in an interview with OncLive^®.

Prior data from LITESPARK-022 supported the June 2026 FDA approval of belzutifan in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) for the adjuvant treatment of adult patients with RCC with a clear cell component at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.² Data supporting the approval showed that the combination improved disease-free survival (DFS) vs pembrolizumab plus placebo (HR, 0.72; 95% CI, 0.59-0.87; P < .003).

In an interview with OncLive®, Powles, a professor of genitourinary oncology at Barts Cancer Institute, Queen Mary University of London, and director of Barts Cancer Centre at St Bartholomew’s Hospital in London, United Kingdom, discussed the PRO findings from LITESPARK-022, explained how they add to the body of evidence for the combination of belzutifan plus pembrolizumab, and dived into adjuvant treatment navigation in RCC.³

OncLive: What did the LITESPARK-022 PRO data presented at KCRS 2026 reveal about adding belzutifan to adjuvant pembrolizumab in RCC?

Powles: QOL data in the adjuvant setting are a complex issue. We know that pembrolizumab monotherapy is associated with a significant and clinically meaningful OS advantage compared with placebo in intermediate-high–risk patients [as demonstrated in the phase 3 KEYNOTE-564 trial (NCT03142334)].³ We also know that in LITESPARK-022, when you add belzutifan for a year on top of [pembrolizumab], you get an EFS advantage—a delay or reduction in the risk of the cancer coming back in the future. [Those data] were also clinically meaningful, [although] we do not yet have [mature] OS data from that study. It is tracking in the right direction, but the initial look [at OS] was early.

We saw more frequent adverse effects with the addition of belzutifan. We know that immune checkpoint inhibition is sometimes associated with long-term toxicity, ranging from endocrine disorders to respiratory and other problems. The question is: did the addition of belzutifan have a big impact on QOL? Was that increase in AEs reflected in the QOL data?

The AEs most frequently associated with belzutifan are anemia and hypoxia, and both are reversible when we stop the drug. For patients who are coming into harm’s way with those AEs events, we either dose reduce or stop. In both circumstances, you can see a reduction in the AEs.

When we looked at the QOL data, we could show some short-term impact associated with [belzutifan plus pembrolizumab], but quite modest. In [measuring] QOL, you have to get quite a significant drop for [changes] to reach clinically meaningful levels, and we did not see that across the board, although there was a trend toward it. When you stop [belzutifan], any potential adverse impact goes away.

We looked at different parameters using the tools we [utilized during the study], including physical, emotional, role, and functional parameters. There was inconsistency, as is often the case with these QOL tools, because they are not designed specifically for adjuvant belzutifan or adjuvant pembrolizumab.

It is fair to summarize the following. First, the [QOL] tools we are using are not perfect. There are also limitations related to follow-up, and patients often stop looking at QOL after AEs occur. There is room for improvement in the assessment of QOL in this setting. Second, we know the study was positive, with a clinically meaningful delay in disease recurrence associated with the addition of belzutifan. The toxicity was in line with expectations. AEs may be more frequent, particularly hypoxia and anemia, and although we can see higher rates of those toxicities, they do not appear to have a major impact on QOL, particularly longer-term QOL once the drugs have stopped. In the metastatic setting, this [distinction] is important because patients continue on therapy indefinitely, so QOL can remain affected while they continue the drugs. In the adjuvant setting, we are hoping to cure patients, so short-term, reversible toxicity, in my opinion, is worthwhile [for the] long-term benefit, whereas long-term, permanent toxicity is a more complex issue.

How do the LITESPARK-022 PRO findings complement safety data for adjuvant belzutifan plus pembrolizumab?

When we summarize the PRO data, we see what we would expect: imperfect results and trends toward a correlation between some AEs and QOL, [without] hitting clinically meaningful levels. From my perspective, this reinforces the issue of the relatively modest AE profile associated with adding belzutifan and the transient nature of that [additional] toxicity. [These data] support the package of adding belzutifan being associated with a reduction in the risk of the cancer coming back without having a major impact on patients’ QOL, particularly in the longer term.

Are there subgroups of patients with resected RCC who may be less suitable for adjuvant belzutifan plus pembrolizumab?

The choice of whether patients want adjuvant therapy in this setting is a black-and-white one. We have only tested pembrolizumab [monotherapy] and the combination [of belzutifan and pembrolizumab] in this higher-risk group, therefore, I would not give it off-label to patients with non–clear cell [disease] or those with lower-risk [disease].

There are also patients at higher risk of other problems. They may have other comorbidities, a shorter life expectancy, or lower tolerability. They may have a contraindication to immuno-therapy, such as existing autoimmune disease. There are also patients who choose not to have adjuvant therapy, even when we approach them with the data.

When I speak to friends and colleagues about [treatment approaches in the adjuvant setting], approximately half and two-thirds of patients are taking up adjuvant therapy. I discuss it with all my [eligible] patients. My take is that if a patient is going. to choose to have adjuvant therapy, knowing that belzutifan adds modest toxicity that is reversible during the treatment period, why not give the most active drugs we have? That does not mean everyone needs it.

If patients have cardiovascular issues or do not want the risk of hypoxia, that discussion should take place. However, if we are going to [use adjuvant therapy], let’s do it with the best drugs we have, in the understanding that in my practice, probably 40% of eligible patients choose not to have adjuvant therapy.

How is adjuvant belzutifan plus pembrolizumab changing RCC management, and what questions remain?

The addition of belzutifan to pembrolizumab as a standard of care is an important step toward improving outcomes in [RCC]. We need more accurate techniques to identify those patients [at higher risk of recurrence]. We are talking about circulating tumor DNA as potential ways to identify higher-risk patients, because patient selection is important.

There is [the issue of] overtreatment. If the cancer is not coming back in [subset of] patients, they are cured with surgery alone. By definition, we are overtreating those patients. That is an important step for the future.

The final OS results for [adjuvant] belzutifan plus pembrolizumab are also important. Ultimately, we want patients to live longer, particularly if treatment is associated with AEs. OS and patient selection are two key components.

Where we stand now, we have a regimen associated with better outcomes, particularly DFS, with OS trending in the right direction. It is a standard of care in this setting for patients who choose to have adjuvant therapy.

References

1. Powles TB, Choueiri TK, Karam JA, et al. Pembrolizumab plus belzutifan versus pembrolizumab plus placebo as adjuvant therapy for renal cell carcinoma: patient-reported outcomes in LITESPARK-022. Presented at: 2026 Kidney Cancer Research Summit; July 23-24, 2026; Boston, MA. Abstract 1.
2. FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. June 12, 2026. Accessed November 11, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma
3. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695