Advances in Subsequent Therapies Shake Up Sequencing of ccRCC Treatment

Peers & Perspectives in OncologyApril II, 2024
Pages: 48

With the approval of belzutifan and other newer data for treating patients with recurrent renal cell carcinoma, the state of subsequent therapies is advancing beyond the reuse of frontline options with impacts on duration of response and quality of life.

Image by Kelly Carmack/MJH Life Sciences using AI

Image by Kelly Carmack/MJH Life Sciences using AI

The introduction of combination therapies for advanced clear cell renal cell carcinoma (ccRCC) has brought the question of sequencing later-line therapies into focus. With patients receiving efficacious treatments with varying degrees of toxicity in the front line, clinicians have a variety of options but limited data to use for patients with recurrent disease going into the second, third, and later lines of therapy.

Not all available later-line options were investigated in a modern patient population who have received prior immunotherapy (IO) and a tyrosine kinase inhibitor (TKI) in the first or second lines. Newer agents have been introduced as subsequent therapy based on more recent trial findings, namely, tivozanib (Fotivda) and belzutifan (Welireg), the latter of which was approved in December 2023 in this setting.1 However, besides these options, sequencing therapies may come down to which older therapies have not been used before.

“The NCCN [National Comprehensive Cancer Network] guidelines in RCC are challenging because they have listed all the available drugs that have been tested in different settings over the years and there’s not a lot of guidance in terms of what to select and how to select,” Matthew T. Campbell, MD, MS, said in a Case-Based Roundtable® event he comoderated with Nizar M. Tannir, MD, FACP. Campbell is an associate professor and associate medical director at The University of Texas MD Anderson Cancer Center in Houston.

Sequencing Depends on Prior Options

Three IO/TKI regimens plus the IO/IO regimen of nivolumab (Opdivo) plus ipilimumab (Yervoy) have category 1 status from the NCCN in the front line for patients with intermediate- or poor-risk disease, with the 3 IO/TKI regimens having category 1 status for favorable-risk disease as well.2 For patients who experience disease progression, the next regimen can depend heavily on what was used in the front line. Switching to a different TKI is an option unless the patient has significant toxicities, whereas giving additional IO has limited efficacy.

Tannir, a professor at The University of Texas MD Anderson Cancer Center, said that because he prefers giving nivolumab plus ipilimumab in the front line, he will often give axitinib (Inlyta) in the second line. However, in those who use axitinib with pembrolizumab (Keytruda) first, a common second option mentioned by other participants was single-agent cabozantinib (Cabometyx). Nivolumab plus cabozantinib may be preferred over other IO/TKI regimens in the first line, particularly in certain cases such as patients with bone metastases, so axitinib could be used as a second-line TKI. Lenvatinib (Lenvima) can also be used in combination with the mTOR inhibitor everolimus (Afinitor) in subsequent lines. Patients who experienced progression after receiving frontline lenvatinib plus pembrolizumab would not receive lenvatinib in later lines.

Tivozanib was investigated in the phase 3 TIVO-3 trial (NCT02627963) as third- or fourth-line treatment, leading to an indication for patients who received 2 prior systemic therapies, including a VEGF-TKI. Only 27% of patients received both prior immune checkpoint inhibitor and VEGF-TKI in this trial.3 In the more recent LITESPARK-005 trial (NCT04195750) of belzutifan, patients must have received prior VEGF-TKI and IO, leading to approval in the second line or later.4 Tivozanib was compared to sorafenib (Nexavar), whereas belzutifan was compared to everolimus. “When you have all these agents vs either sorafenib or everolimus and they haven’t been compared head to head, you do not know which one is better than the other,” Tannir pointed out.

Goals of Third-Line Therapy

The question of sequencing is most pertinent to the third-line setting, where multiple effective agents have been exhausted and patients may have worse performance status but many patients can still have clinical benefit from treatment. Many patient-specific factors determine the goals of treatment and which treatment is chosen for each individual.

Sumit Gaur, MD, of Texas Tech Physicians of El Paso, said in Tannir’s event that he looks at performance status and age first. If the patient is younger and fit, he would use lenvatinib plus everolimus, but he thinks older patients don’t tolerate it as well.

In a second virtual event moderated by Yasser M. Ged, MBBS, he noted that some patients have indolent, slowly growing disease going into the third line whereas others have rapidly progressing disease. Ged, codirector of the Kidney Cancer Research Program and assistant professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland, said the time to response of belzutifan was approximately 4 months in findings from LITESPARK-005, leading to the Kaplan-Meier curves for progression or death not separating from everolimus until 6 months, though the progression-free survival end point was met.4 According to Ged, this slower time to response would lead him to use tivozanib in cases of rapid progression but to prefer belzutifan in patients with slower-growing disease.

Participants agreed that a durable response was an important goal in the third line. They pointed to the favorable durations of response of 19.5 months with belzutifan and 20.3 months with tivozanib.3,4 The duration of response of lenvatinib plus everolimus after prior TKI was 13 months.5 The overall response rate was 23% for tivozanib vs 11% with sorafenib in findings from TIVO-3 and 21.9% for belzutifan vs 3.5% for everolimus in findings from LITESPARK-005.3,4

Tivozanib had a median PFS of 5.6 months vs 3.9 months with sorafenib (HR, 0.73), and belzutifan showed a median PFS of 5.6 months vs 5.6 months with everolimus (HR, 0.74; 95% CI, 0.63-0.88).3,4 Although overall survival (OS) is seen as an important consideration, the later-line therapies have not shown a clear OS benefit with current follow-up. Ged acknowledged that OS is a difficult end point to achieve in the multiple refractory setting.

The treatment burden of prior therapies could also influence choice of therapy. If a patient had TKI-related adverse events (AEs) in prior lines, this could indicate that they should not receive lenvatinib or tivozanib in the third line.

“This is fair to say that if a patient has already received 2 TKIs in the first line and second line and they are running into complications that are still ongoing with nephrotic-range proteinuria and hypertension…you want to avoid the TKI there and go with belzutifan,” Tannir observed. He added that he has many patients without hypertension and proteinuria with prior TKI therapy, and tivozanib would be a reasonable option in that case.

Impact of Belzutifan's Approval

The LITESPARK-005 trial randomly assigned 746 patients who had experienced progression following both a PD-1/ PD-L1 inhibitor and a VEGF-TKI to receive either belzutifan or everolimus.4 The objective response rate was 22.7%, including a 2.7% complete response rate, and 39.3% of patients had stable disease. At median follow-up of 25.7 months, the median OS was 21.4 months vs 18.1 months with everolimus, with an HR of 0.88 not reaching statistical significance for this coprimary end point (95% CI, 0.73-1.07; P = .09941). In terms of quality of life, median time to deterioration for Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index–Disease Related Symptoms favored belzutifan (not reached vs 12.0 months with everolimus; HR, 0.53; 95% CI, 0.41-0.69; nominal P < .0001).

As a first-in-class oral HIF2α inhibitor, belzutifan appealed to many of the participant oncologists as a distinct mechanism of action from TKIs. In Ged’s group, Daya S. Sharma, MD, of Greater Washington Oncology Associates in Silver Spring, Maryland, suggested that belzutifan could be a better option than a TKI in the third line because of the different mechanism of action.

“That’s what we’re mostly looking for,” Kevin Chen, MD, of MedStar Health in Maryland, said. “[We’re] hoping that a different mechanism of action will give us a longer duration of response rather than the usual 7 or 8 months on the TKI [before] they [have] to switch to a different one.” Chen said he typically uses cabozantinib in the second line followed by another TKI in the third, but he recently prescribed belzutifan to a patient for the first time.

When evaluating the study findings, Ged cautioned that belzutifan had a high rate of primary progressive disease of 33.7% vs 22% with everolimus.4 In comparison, tivozanib had a 22% primary progressive disease rate and 18% for those who received prior IO and TKI.3 “Until we get the biomarker that could guide us [to] which patients fall within the 33% who have primary disease progression as the best response, we just have to rely on clinical judgment,” he said, citing those with rapidly growing liver metastases or risk of visceral crisis as patients for whom he might choose a TKI-based regimen instead.

Safety and Tolerability Profiles

Each possible therapy option comes with its own toxicities that must be considered, particularly in the setting of relapsed/refractory disease. Because of patients’ declining performance status, some participants expressed their preference for a single agent vs a combination regimen such as lenvatinib/everolimus in the recurrent setting. Additionally, lenvatinib often requires dose reductions from the starting dose of 18 mg daily due to AEs including hypertension, fatigue, and diarrhea. The phase 2 Study 218 (NCT03173560) randomly assigned patients to start at 5 mg everolimus plus either 18 mg or 14 mg lenvatinib daily. Results from the study found that the overall response rate for the lower dose did not show noninferiority and that other efficacy end points were numerically higher with the higher dose, discouraging a lower starting dose.6 In findings from the HOPE 205 study (NCT01136733) of lenvatinib plus everolimus vs everolimus alone, the rate of grade 3 or 4 AEs was 70% vs 50%, respectively.5

Tivozanib showed a manageable safety profile in findings from TIVO-3, with a 67% rate of grade 3 or 4 toxicity compared with 72% with sorafenib.3 Grade 3 or 4 AEs included rates of 21.4% hypertension, 5% asthenia, 4% fatigue, 4% decreased appetite, and 2% diarrhea.

In Tannir’s event, Swetha Yadav, MD, of Memorial Hermann in Pasadena, Texas, said she had used tivozanib and observed hypertension, diarrhea, and fatigue that led to dose reductions. Additionally, she started treating 1 patient with belzutifan and saw significant anemia.

The most common AEs of any grade in patients who received belzutifan were anemia in 82.8%, fatigue in 31.5%, nausea in 18%, peripheral edema in 16.1%, dyspnea in 15.1%, and hypoxia in 14.5%.4 According to Ged, belzutifan leads to inhibition of erythropoietin, which is responsible for fatigue, hypoxia, and anemia. In Tannir’s event, Gaur commented that in his experience with belzutifan, the anemia responds well to erythropoietin-stimulating agent (ESA).

A post hoc analysis of the phase 2 LITESPARK-004 trial (NCT03401788) in patients with Von Hippel–Lindau disease– associated RCC, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas showed ESA was used in 14 of 61 patients (23%) with belzutifan and did not adversely affect overall drug exposure or efficacy.7 In findings from LITESPARK-005, 22% of patients with anemia received transfusions, 20% received ESAs, and 12% received both.8

Trends in Sequencing

Because first-line therapy shapes the available options for second-and later-line therapy, the sequencing of the second line will inevitably vary. The NCCN guidelines list no preferred regimen for subsequent lines.2 Various agents are approved based on older data predating the use of frontline immunotherapy, but their use is growing less common. For instance, Tannir discussed that although high-dose interleukin-2 has a category 2B recommendation, it is not used in subsequent lines because of its toxicity.

However, TIVO-3 and LITESPARK-005 findings show that trials of subsequent therapies are catching up to the modern frontline treatment paradigm. Real-world evidence is also developing over time; Tannir brought up a recent retrospective study to which he and Campbell contributed, of 26 real-world patients treated with tivozanib after a median of 4 prior lines of therapy, leading to a modest clinical benefit of 23.3% in a heavily pretreated patient population.9 He said this showed that tivozanib is effective after prior TKIs and IO including cabozantinib and lenvatinib, which were not used at the time of TIVO-3 enrollment.

Participants in the events expressed that if they were to use tivozanib or belzutifan in the third line, they could use the other after progression provided the patient could tolerate it. Five of the patients in this retrospective study received belzutifan after tivozanib.9

Real-world experience with these regimens in patients previously treated with IO/IO and IO/TKI regimens is developing. As there may be no definitive sequencing algorithm in this setting for the time being, patient goals, performance status, and comorbidities will guide the selection of second, third, and later lines of therapy in metastatic ccRCC.


1. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed March 21, 2024.

2. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 3.2024. Accessed March 21, 2024.

3. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1

4. Albiges L, Rini BI, Peltola K, et al. Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): randomized open-label phase III LITESPARK-005 study. Ann Oncol. 2023;34(suppl 2):S1329-S1330. doi:10.1016/j.annonc.2023.10.090

5. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9

6. Pal SK, Puente J, Heng DYC, et al. Assessing the safety and efficacy of two starting doses of lenvatinib plus everolimus in patients with renal cell carcinoma: a randomized phase 2 trial. Eur Urol. 2022;82(3):283-292. doi:10.1016/j.eururo.2021.12.024

7. Maughan BL, Srinivasan R, Iliopoulos O, et al. Effect of erythropoietin-stimulating agent use on belzutifan antitumor activity in patients with VHL disease– associated renal cell carcinoma: post hoc analysis of the LITESPARK-004 study. J Clin Oncol. 2024;42(suppl 4):3. doi:10.1200/JCO.2024.42.4_suppl.3

8. Welireg. Prescribing information. Merck & Co Inc; 2024. Accessed March 21, 2024.

9. Johns AC, Campbell MT, Gao M, et al. Efficacy, safety, and tolerability of tivozanib in heavily pretreated patients with advanced clear cell renal cell carcinoma. Oncologist. Published online March 13, 2024. doi:10.1093/oncolo/oyae037

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