During a Targeted Oncology™ Case-Based Roundtable™ event, Matthew Campbell, MD, MS, discussed guidelines and available therapies for a patient who requires second-line treatment and beyond for metastatic renal cell carcinoma.
Targeted Oncology: What systemic regimens are recommended by the National Comprehensive Cancer Network (NCCN) Guidelines for the subsequent treatment of ccRCC in a patient such as this one?
CAMPBELL: There’s not a lot of guidance. This patient has already had an immune checkpoint [inhibitor] and has already had cabozantinib. There are some category 1 regimens listed among “other recommended regimens” and among the regimens that are “useful in certain circumstances.” In terms of recent updates, tivozanib [Fotivda] was changed to a category 1 recommendation. The combination of lenvatinib [Lenvima] plus everolimus [Afinitor] remains listed as a category 2A regimen based on the small phase 2 study that led to its approval,1 and belzutifan [Welireg] has been added as a category 2B regimen based on a relatively small phase 1b study in sporadic [ccRCC].2,3
Which studies produced the data that support the NCCN Guidelines recommendations for second-line therapy?
The CheckMate 025 study [NCT01668784] was a trial of nivolumab [Opdivo] vs everolimus. The patients in that trial had to have failed treatment with a tyrosine kinase inhibitor [TKI], and this was the first trial that brought immune checkpoint [inhibitor] therapy to the treatment of RCC in the second line. There was a lower objective response rate [ORR]4 compared with what we see in frontline settings with nivolumab plus ipilimumab [Yervoy].5 Even the frontline pembrolizumab study [KEYNOTE-427; NCT02853344] showed a little higher ORR than [second-line nivolumab] in ccRCC.6 The CheckMate 025 study was the first study that improved overall survival [OS] in metastatic ccRCC. That was shortly followed by the study of cabozantinib vs everolimus in the METEOR study [NCT01865747], again in patients with TKI-refractory disease.7 [Cabozantinib] was the only TKI to date that has been proven to improve OS in the TKI-failed setting, which differentiates it from its peers. The study [NCT01136733] of lenvatinib plus everolimus vs lenvatinib or everolimus [monotherapy] was a smaller phase 2 study, with 50 patients per arm. The median progression-free survival [PFS] in the lenvatinib plus everolimus arm, per the investigators, was 14.6 months [HR, 0.40; 95% CI, 0.24-0.68; P = .0005 vs everolimus]. On independent review, it was 12.5 months. Lenvatinib, on independent review, [produced a median PFS of] 9 months, and therefore performed well as a single agent, though the approval was for the combination.1,8 Many patients on both cabozantinib and on lenvatinib plus everolimus did require dose reductions, and there is a risk of having to discontinue because of toxicity.7,8
How specific is the targeting of the VEGFR pathway by the various available TKI regimens?
Among the different targeted therapies in mRCC, different TKIs have different targets. [Although] they all uniformly target the VEGFR pathway, some are more targeted to the VEGFR pathway than others. Tivozanib has very low half-maximal inhibitory concentrations for VEGFR-1, -2, and -3. It also has some activity toward PDGFR-β and c-kit and [no real activity] in terms of FGFR targeting. When we think about cabozantinib, we’re targeting c-Met and AXL. With lenvatinib, we’re also targeting PDGFR-β and FGFR. And [from] the older generation, axitinib has very similar properties to those of tivozanib and is very active against the VEGFR-1, -2, and -3 receptors.9
Q:What data supported the FDA approval of tivozanib?
The data from the TIVO-3 study [NCT02627963] led to the approval of tivozanib.10 In this study, patients had to have clear cell histology, they had to have failed 2 or 3 prior regimens, and they had to have received at least 1 previous VEGFR-targeting TKI. They had to have good performance status to enroll. They were stratified based on what regimens they had received: [a PD-1 inhibitor] plus a TKI, 2 TKIs, or a TKI plus another therapy. They were also stratified based on the IMDC [International Metastatic RCC Database Consortium] prognostic score ( favorable, intermediate, or poor). They were [randomly assigned] to receive either tivozanib or sorafenib [Nexavar], and then patients were treated until progression or unacceptable toxicity.11 Notice that the dosing [1.5 mg]11 was slightly different from the approved dose [1.34 mg as a starting dose]10; tivozanib was given according to a cycle of 3 weeks on, 1 week off.11
Why was sorafenib chosen as the comparator in the TIVO-3 study?
It’s been a standard late-line comparator. I think that the [other potential] choice was everolimus, which is common, which has been [inferior in efficacy] numerous times vs an older-generation TKI. Sorafenib was their choice.
What were the results of the TIVO-3 study? The baseline characteristics were reasonably well matched with respect to age, [though the patients were] a little bit younger than the standard population with mRCC, which tends to be in their late 60s. The patients were reasonably [balanced] in terms of region [and] performance status…[and] with respect to prior therapies. The time from initial diagnosis, on average, was more than 4 years, which tells you that most of these patients had had a cytoreductive nephrectomy and then later relapsed.12
The PFS was assessed by a blinded radiologic review. There was an improved HR of 0.73 [95% CI, 0.56-0.94], which met statistical significance [P = .016], with a median PFS improvement of 5.6 months vs 3.9 months for tivozanib vs sorafenib, respectively. As you would anticipate, the majority of patients had progressed at 1 year, but there were patients who continued to do well 2 years out [18% in the experimental arm].13,14
When PFS was assessed at 3 and 4 years, there was continued separation [of the Kaplan-Meier curves]. More patients lasted longer in the tivozanib arm as compared with those in the sorafenib arm, where all patients had failed by year 4 [7.3% vs 0%, respectively].15
For patients who had received prior immune checkpoint therapy, the median PFS in the tivozanib arm was 7.3 months vs 5.1 months with sorafenib [HR, 0.55; 95% CI, 0.32-0.94; P = .028]. So sorafenib got a little [boost] too.16 For patients [receiving tivozanib] who had received 2 prior TKIs, the 12-month PFS [rate] was numerically about the same as [the rate] for patients who had received any previous immunotherapy or no previous immunotherapy, and [the regimen] continues to perform well, and actually [there was] a bigger [numerical] difference between [those who had 2 prior TKIs] and the ones that received immunotherapy [vs those who received no prior immunotherapy].
The ORR in the tivozanib arm was 23%—again, this is in the third line in previously TKI-exposed patients—vs 11% in the sorafenib arm. The disease control rate was 82%; that’s numerically higher than what was observed with sorafenib [69%]. For the patients who responded, the median duration of response was 20 months vs 9 months for the respective arms. Again, [responders were] a relatively small number of patients.12
Regarding OS, the authors point out that [these data are] continuing to mature. At the time of follow-up, now close to 2 years, there is still no difference in OS.17
What are some practical considerations surrounding the use of tivozanib?
You need to make sure that you’re managing TKI-associated adverse events, including nausea, diarrhea, and vomiting. The starting dose is a 1.34-mg capsule, [once daily,] 21 days on, 7 days off. The first dose reduction is down to 0.89 mg, again, 21 days on, 7 days off. You can administer it with or without food, and they suggest making dose modifications rather than changing the cycle.10
What were some key results of the phase 2 study that compared 2 starting doses of lenvatinib plus everolimus (NCT03173560)?
This study looked at 2 starting doses: either 14 mg of lenvatinib plus 5 mg of everolimus or 18 mg of lenvatinib plus 5 mg of everolimus. The ORRs [of both arms] were very close [32% vs 35% for the lower-dose and higher-dose arms, respectively]. However, the PFS was numerically greater [in the higher-dose arm than the lower-dose arm (14.7 months vs 11.1 months, respectively)]. The investigators felt the toxicity was similar [between the arms].18
What are the most concerning toxicities of these agents?
The rates of high blood pressure [and] fatigue are numerically highest with cabozantinib and with lenvatinib plus everolimus, with a grade 3/4 fatigue toxicity of [13%] for tivozanib. Hand-foot syndrome of all grades was more common with cabozantinib, sorafenib, and lenvatinib plus everolimus. Among patients treated with tivozanib, diarrhea of all grades and of grade 3/4 affected [43%] and 2% of patients, respectively.10,19-21
1. Lenvatinib in combination with everolimus. FDA. May 13, 2016. Updated May 16, 2016. Accessed April 14, 2023. https://bit.ly/3LS4J3T
2. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. August 13, 2021. Updated February 1, 2022. Accessed April 13, 2023. https://bit.ly/3LYGcu0
3. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 4.2023. Accessed April 13, 2023. https://bit.ly/2TAx1m3
4. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665
5. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126
6. McDermott DF, Lee JL, Bjarnason GA, et al. Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced clear cell renal cell carcinoma. J Clin Oncol. 2021;39(9):1020-1028. doi:10.1200/JCO.20.02363
7. Choueiri TK, Escudier B, Powles T, et al; METEOR Investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927. doi:10.1016/S1470-2045(16)30107-3
8. 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
9. Fogli S, Porta C, Del Re M, et al. Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs. Cancer Treat Rev. 2020;84:101966. doi:10.1016/j.ctrv.2020.101966
10. Fotivda. Prescribing information. AVEO Pharmaceuticals; 2021. Accessed April 13, 2023. https://bit.ly/3LWkSoP
11. 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
12. Verzoni E, Escudier B, Hutson TE, et al. TIVO-3: durability of response and updated overall survival of tivozanib versus sorafenib in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021;39(suppl 15):4546. doi:10.1200/JCO.2021.39.15_suppl.4546
13. Pal SK, Escudier BJ, Atkins MB, et al. Final overall survival results from a phase 3 study to compare tivozanib to sorafenib as third- or fourth-line therapy in subjects with metastatic renal cell carcinoma. Eur Urol. 2020;78(6):783-785. doi:10.1016/j.eururo.2020.08.007
14. Rini BI, Pal SK, Escudier B, et al. TIVO-3: Tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib. J Clin Oncol. 2021;39(suppl 6):278. doi:10.1200/JCO.2021.39.6_suppl.278
15. Atkins MB, Verzoni E, Escudier B, et al. Long-term PFS from TIVO-3: tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC. J Clin Oncol. 2022;40(suppl 6):362. doi:10.1200/JCO.2022.40.6_suppl.362
16. Rini BI, Pal SK, Escudier B, et al. TIVO-3: a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). J Clin Oncol. 2019; 37(suppl 7S):541. doi:10.1200/JCO.2019.37.7_suppl.541
17. Rini BI, Pal SK, Escudier B, et al. Maturation of overall survival (OS) in TIVO-3 with long-term follow-up. J Clin Oncol. 2022;40(suppl 16):4557. doi:10.1200/JCO.2022.40.16_suppl.4557
18. 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
19. Cabometyx. Prescribing information. Exelixis; 2021. Accessed April 14, 2023. https://bit.ly/44Qkhh0
20. Inlyta. Prescribing information. Pfizer; 2022. Accessed April 14, 2023. https://bit.ly/3BhwLAR
21. Lenvima. Prescribing information. Eisai; 2022. Accessed April 14, 2022. https://bit.ly/3MlisSk