Reviewing Third-Line Options for a Patient With mRCC After Progression

Case-Based Roundtable Meetings SpotlightCase-Based Roundtable Meetings Spotlight: March 2022
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During a Targeted Oncology case-based roundtable event, Jad Chahoud, MD, MPH, discussed the case of a patient who progresses while on pembrolizumab plus axitinib, then again while on cabozantinib.

Jad Chahoud, MD, MPH

Jad Chahoud, MD, MPH

Medical Oncologist

Moffitt Cancer Center

Tampa, FL

Targeted OncologyTM: In recent years, how have the National Comprehensive Cancer Network (NCCN) recommendations changed regarding first-line systemic therapy for relapsed or stage IV ccRCC? What is currently recommended?

CHAHOUD: Over the past couple of years, these guidelines have changed significantly at multiple levels. The current guidelines make a greater differentiation between patients with favorable-risk and poor- [risk] or intermediate-risk International Metastatic RCC Database Consortium [IMDC] scores. Our patient falls into the favorable-risk category. In addition to that, 3 approved novel combinations of immunotherapy [IO] plus tyrosine kinase inhibitor [TKI] have been added. These are in addition to the nivolumab [Opdivo] plus ipilimumab [Yervoy] combination [that was approved earlier].1,2

[The first of these 3 novel combinations is] the combination of pembrolizumab [Keytruda] plus axitinib [Inlyta], approved on the basis of the KEYNOTE-426 study [NCT02853331].1,3 The combination of nivolumab plus cabozantinib [Cabometyx] was approved on the basis of CheckMate 9ER [NCT03141177] a bit later.4 Most recently, the combination of pembrolizumab plus lenvatinib [Lenvima] was approved [on the basis of the CLEAR study (NCT02811861)].5 These are all preferred regimens of the NCCN, supported by category 1 data, for favorable-risk patients.1

These 3 combinations are also [listed among] the NCCN recommendations for poor-[risk] and intermediate-risk patients, along with the combination of nivolumab and ipilimumab, all supported by category 1 data. Cabozantinib is also listed as a preferred regimen for patients in this category, probably for patients who cannot tolerate IO due to a history of immune-related disorders or other reasons.

What are the NCCN recommendations for subsequent therapy for ccRCC?

We have a [long] list of options. The preferred regimens for subsequent therapy, supported by category 1 data, are cabozantinib, the combination of lenvatinib plus everolimus—recently added as a preferred regimen—and single-agent nivolumab.

The recommendation of nivolumab was based on some data that do not apply to this patient, and made at a time when frontline IO was nonexistent and our frontline therapy was still sunitinib [Sutent].1 Basically, in this patient, the 2 preferred category 1 options for second-line therapy would be either cabozantinib or the combination of lenvatinib and everolimus.

The pembrolizumab plus lenvatinib combination, listed among “other recommended regimens,” was added later for patients who [have been] on frontline nivolumab or frontline nivolumab plus ipilimumab, had some form of response, and later lost that response. [In that case], if the patient is young, has a very good performance status, and does not have any immune-related toxicity, you want to use a tough IO plus TKI combination.

Another recommended regimen, recently added, is tivozanib [Fotivda], a VEGF receptor [VEGFR] inhibitor.1,6 This was approved [based on] a phase 3, randomized, open-label, multicenter trial [TIVO-3 (NCT02627963)] that compared tivozanib vs sorafenib in patients who had relapsed or refractory RCC and who had received at least 2 or 3 prior systemic therapies.7,8

What data led to the approval of the 3 second-line regimens preferred by the NCCN for ccRCC?

The phase 3 CheckMate 025 study [NCT01668784] compared nivolumab with everolimus.9 The phase 3 METEOR study [NCT01865747] looked at second-line cabozantinib vs everolimus.10 Finally, the phase 2 Study 205 [NCT01136733] looked at lenvatinib plus everolimus vs either lenvatinib or everolimus.11 In these trials, patients were TKI-refractory, and the majority had only had 1 prior line of therapy.

The overall response rates [ORR] are important to look at. For nivolumab, the ORR was 25%; for cabozantinib, 17%; and for lenvatinib plus everolimus, 43%.9-11 The median progression-free survival [PFS] for nivolumab was 4.6 months, and median overall survival [OS] was 25 months [HR, 0.73; 95% CI, 0.57-0.93; P = .002].9 That led to the approval of nivolumab for use in the second line in patients who were TKI refractory.12 For cabozantinib, the median PFS was 7.4 months [HR, 0.51; 95% CI, 0.41-0.62; P < .0001], and the median OS was 21.4 months. A lot of patients had to go through dose reduction with cabozantinib, as we all know.10 [The starting daily dose of] 60 mg is rarely maintained; only around 20% to 30% of patients are able to tolerate cabozantinib at a dose of 60 mg.13 Adverse events [AEs] of grade 3 or grade 4 occurred in 71% of the patients who received 60 mg of cabozantinib [daily].10 Similarly, AEs of grade 3 or grade 4 occurred in 71% of the patients who received lenvatinib and everolimus; many of these patients [had at least] 1 of the 2 drugs reduced or discontinued.11

For the lenvatinib plus everolimus combination, the OS was in the same range [as those observed for nivolumab and for cabozantinib], and the ORR was a bit higher.9-11 These are the data that led to these compounds being the preferred regimens for second-line ccRCC.1

What are some differences among the VEGFR TKIs that are used to treat RCC?

The VEGFR TKIs are heterogeneous drugs with differences in pharmacokinetics, sensitivity, and potency. Tivozanib, a third-generation drug, is specific in a way…similar to that of axitinib, very specifically [targeting] the VEGFRs. That helps with the safety profile, because you don’t have a lot of off-target toxicity from this drug. It’s potent and it has a relatively long half-life.14-22

Please discuss these poll results. Do these answers align with your practice?

Most of us would choose either tivozanib or lenvatinib plus everolimus. I sometimes discuss rechallenging with IO if a patient has had a grade 3 toxicity, but this patient had stable disease and so did not technically respond to the IO plus TKI combination. So, I [wouldn’t] expect them to respond now. Also, this patient had grade 3 pneumonitis. [That worries me]; that could have a major impact on the patient’s life and quality of life. It could subsequently [necessitate] oxygen or an intensive care unit [ICU] admission and could make a patient miserable or shorten his life.

What data are available to guide RCC therapy beyond the second line?

To be honest, we have limited data upon which we can base our choice of third-line therapy.

The data [consist] mainly of retrospective data [and the results of] the TIVO-3 study, a phase 3 trial that looked at advanced ccRCC in 350 patients who had progressed on 2 or 3 prior regimens, including at least 1 VEGFR TKI. The patients were stratified according to their prior regimens: a TKI plus a checkpoint inhibitor, 2 TKIs, or a TKI plus something else. The patients were stratified also according to IMDC prognostic score. Patients were randomly assigned 1:1 to receive either tivozanib or sorafenib.8 At the time of the trial in 2013 and 2014, that was the acceptable [comparator] in the third-line setting according to the FDA.23 Patients were treated until disease progression. The primary end point was PFS.8

The patients were well distributed, and the median age was around 63 years. RCC predominantly [affects men], so 70% of the patients were men. The IMDC risk category of most patients was intermediate or poor [about 60% and 20% of patients, respectively]. It is interesting that 45% of the patients had been treated with 2 VEGFR TKIs, and 27% had been treated with a TKI plus a checkpoint inhibitor. It’s rare to have data [for patients who have been treated previously with a] checkpoint inhibitor plus a TKI. Finally, another 28% of the patients had been treated with a VEGFR TKI plus another therapy.8,24

How did patients do in the TIVO-3 trial in terms of efficacy and safety?

The trial met its PFS end point [median PFS, 5.6 months vs 3.9 months for the experimental and comparator arms, respectively; HR, 0.73; 95% CI, 0.56-0.94; P = .016]. An important landmark is the 1-year PFS, which was achieved by 28% of patients in the experimental arm and by 11% of patients in the comparator arm. Two-year PFS was achieved by 18% vs 5%, respectively. In a patient who is receiving a third-line therapy, having that disease control for a year is important.25-27

It’s important to highlight that the ORR of tivozanib was 23%.8 [In comparison], even in the second line, the ORR with cabozantinib was 17%10;with nivolumab, 25%9; and with lenvatinib plus everolimus, 43%.11 The disease control rate for tivozanib was 82%. The OS end point was not met, but it was trending a bit, getting better with longer follow-up.8 The median [duration of response] DOR was 20.3 months,8 with 71% of patients maintaining a response for 1 year,25-27 which is more than double [the DOR] observed in the sorafenib arm.8 So, this regimen provided [many] patients with some good, durable responses.

The safety profile included hypertension; this occurred in a significantly higher number of patients who received tivozanib than in those who received sorafenib.28 This is to be expected, because tivozanib is specific to VEGFR.6 Around 27% of patients had hypertension of grade 1 or grade 2, and 20% had hypertension of grade 3.28 So, you would have to [start] blood pressure management from the beginning, because you know hypertension is going to affect most of your patients.

The diarrhea, fatigue, palmar-plantar erythrodysesthesia syndrome [PPE], and rashes were much lower than we [would expect] with a TKI, and that’s because of lesser off-target effects. Only 2% of patients treated with tivozanib had grade 3 or grade 4 diarrhea, vs 10% of those treated with sorafenib. Among patients in the experimental arm, fatigue of grade 3 affected 4%, PPE of grade 3 affected 1%, and grade 3 rash affected none.28

The PPE, rash, and nausea and vomiting all affected a smaller percentage of patients in the experimental arm than in the comparator arm.28,29 Also, the exposure to drug was [nearly twice as long] in the experimental arm as in the comparator arm [11.9 months vs 6.7 months, respectively].24,29 Of course, a drug can work only if the patient’s taking it. Finally, dose reduction and dose discontinuation were each required in a smaller percentage of patients in the experimental arm than in those in the comparator arm.24,29 This reflects the greater tolerability of tivozanib than of sorafenib; the longer duration of exposure is important for a third-[line] or fourth-line option.

What is the recommended dose progression for tivozanib?

The starting dose is 1.34 mg, administered orally, over a cycle that consists of 3 weeks on, 1 week off. [If tolerability becomes an issue], medical management of AEs should be attempted before dose interruption or reduction. If necessary, you can reduce the dose to 0.89 mg, administered over a similar cycle—3 weeks on, 1 week off. This drug comes in 1.34-mg and 0.89-mg capsules.6

If a patient treated with a TKI were to develop hypertensive encephalopathy requiring an ICU admission, would you rechallenge that patient with a TKI?

Yes, I would, especially in the case of RCC. If it were a frontline patient, I would probably resume the IO, maximize the benefit from the IO, and then at the time of progression, [rechallenge with the TKI]. Make sure that you’ve taken the time to work closely with the cardiologist to manage the patient’s blood pressure. Make sure that the patient has a [baseline] blood pressure log. [The cardiologist should understand that the patient’s blood pressure] is going to increase by 2 to 4 points, systolic, even when the patient starts in the 110s or 120s, and should have a plan for what to do if [the value] goes to 150 mm Hg.

Whereas, if the patient had [hypertensive encephalopathy] while they were, let’s say, on 2 or 3 blood pressure medications already, then [rechallenging] becomes a bit trickier. I would have a long discussion with the patient about the risks. But if the patient had been on only 1 blood pressure medication, or if the patient hadn’t known that their blood pressure was going up, and now they know and it can be managed, then I would rechallenge. Alternatively, if a patient is doing very well on single-agent IO, you could just try to go as long as you can with the single agent, and you can rechallenge in the future.


1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 4.2022. Accessed February 4, 2022.

2. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed February 7, 2022.

3. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. April 19, 2019. Updated April 22, 2019. Accessed February 7, 2022.

4. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed February 7, 2022.

5. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. August 10, 2021. Updated August 11, 2021. Accessed February 7, 2022.

6. Fotivda. Prescribing information. AVEO Pharmaceuticals; 2021. Accessed February 7, 2022.

7. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. FDA. March 10, 2021. Accessed February 7, 2022.

8. 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

9. 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

10. 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

11. 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. Published correction appears in Lancet Oncol. 2016;17(7):e270. Published correction appears in Lancet Oncol. 2018;19(10):e509.

12. Bristol Myers Squibb receives FDA approval for Opdivo (nivolumab), the only treatment to deliver significant overall survival in advanced renal cell carcinoma vs a standard of care, in patients who have received prior anti-angiogenic therapy. News release. Bristol Myers Squibb. November 23, 2015. Accessed February 15, 2022.

13. Cabometyx. Prescribing information. Exelixis; 2021. Accessed February 7, 2022.

14. 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

15. Bellesoeur A, Carton E, Alexandre J, Goldwasser F, Huillard O. Axitinib in the treatment of renal cell carcinoma: design, development, and place in therapy. Drug Des Devel Ther. 2017;11:2801-2811. doi:10.2147/DDDT.S109640

16. Lacy S, Hsu B, Miles D, Aftab D, Wang R, Nguyen L. Metabolism and disposition of cabozantinib in healthy male volunteers and pharmacologic characterization of its major metabolites. Drug Metab Dispos. 2015;43(8):1190-1207. doi:10.1124/dmd.115.063610

17. Alexandre I, Billemont B, Meric JB, Richard S, Rixe O. Axitinib induces paradoxical erythropoietin synthesis in metastatic renal cell carcinoma. J Clin Oncol. 2009;27(3):472-473; author reply 473-474. doi:10.1200/JCO.2008.20.1087

18. Hepgur M, Sadeghi S, Dorff TB, Quinn DI. Tivozanib in the treatment of renal cell carcinoma. Biologics. 2013;7:139-148. doi:10.2147/BTT.S32958

19. Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D. 2011;11(2):113-126. doi:10.2165/11591240-000000000-00000

20. Albiges L, Salem M, Rini B, Escudier B. Vascular endothelial growth factor–targeted therapies in advanced renal cell carcinoma. Hematol Oncol Clin North Am. 2011;25(4):813-833. doi:10.1016/j.hoc.2011.04.006

21. Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6:18. doi:10.1186/2045-824X-6-18

22. Weitzman SP, Cabanillas ME. The treatment landscape in thyroid cancer: a focus on cabozantinib. Cancer Manag Res. 2015;7:265-278. doi:10.2147/CMAR.S68373

23. Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12(24):7271-7278. doi:10.1158/1078-0432.CCR-06-1249

24. Escudier B, Rini BI, Pal SK, et al. TIVO-3: age-related tolerability outcomes of tivozanib versus sorafenib in metastatic relapsed or refractory renal cell carcinoma, a subgroup analysis of the TIVO-3 clinical trial. J Clin Oncol. 2021;39(suppl 15):e16553. doi:10.1200/JCO.2021.39.15_suppl.e16553

25. 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

26. 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. Paper presented at: American Society of Clinical Oncology 2021 Genitourinary Cancers Symposium; February 11-13, 2021; virtual. Accessed February 7, 2022.

27. 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

28. 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

29. Pal SK, McDermott DF, Escudier B, et al. Temporal characteristics of treatment-emergent adverse events and dose modifications with tivozanib and sorafenib in the phase 3 TIVO-3 study of relapsed or refractory mRCC. J Clin Oncol. 2021;39(suppl 15):4567. doi:10.1200/JCO.2021.39.15_suppl.4567

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