Tolerability Concerns Influence Use of Lenvatinib/Everolimus Vs Tivozanib in RCC


During a Targeted Oncology™ Case-Based Roundtable™ event, Sumanta K. Pal, MD, and participants explored the third-line treatment options for a patient with advanced renal cell carcinoma. This is the second of 2 articles based on this event.


Sumanta K. Pal, MD

Codirector, Kidney Cancer Program

Professor, Department of Medical Oncology & Therapeutics Research

City of Hope

Duarte, CA


  • What is your experience with lenvatinib (Lenvima) plus everolimus (Afinitor)?​
  • How do you approach dosing? ​
  • How long do you patients stay on therapy?​
  • What types of responses have you seen?

SUMANTA PAL, MD: For lenvatinib plus everolimus, could anyone share their experiences with it?

SUTHEE RAPISUWON, MD: [In my experience], nobody who’s on lenvatinib/everolimus can tolerate a full dose. We usually start off a little lower, either 10 mg or 12 mg, and then work our way up or down. The interesting thing…[is that] even if a patient receives 8 mg every other day…it would still induce response to the patient. The first priority is to make sure that they have lenvatinib/everolimus in their system.

PAL: I’ve had the exact same issue as you, in the sense that my patients have had a hard time tolerating lenvatinib/everolimus. My typical preference is to start patients on cabozantinib [Cabometyx] nivolumab [Opdivo] up front; that leaves you with options of lenvatinib/everolimus or tivozanib [Fotivda] in the second-line setting. I tend to favor tivozanib because I can’t get that full dose of lenvatinib/everolimus in for most patients, and I’m not sure what benefit they’re getting If we reduce the dose.

There was…an FDA-mandated study [Study 218 (NCT02714218)] that looked at several dose levels of lenvatinib/everolimus. This was a comparison of lenvatinib at 14 mg vs lenvatinib 18 mg [with 5 mg everolimus in both arms]. What we saw in the study was, which was done as the equivalence study with approximately 300 patients, is that there didn’t seem to be a significant difference in response rate when you use 14 mg vs 18 mg; it was 32% vs 35%, respectively.1 What was striking to me is that for one of the primary end points of the trial, which was treatment-emergent adverse events [AEs], it looked exactly the same. Whether you start with 14 mg or 18 mg, you’re running into 83% of patients who have intolerable grade 2 or grade 3 AEs at 14 mg, vs 80% starting at 18 mg.

Even with that approach of reducing the dose, I don’t know that we’re necessarily mitigating the toxicity, unless we go down to some of the doses that you suggested such as 8 or 10 mg, [like the] hepatocellular carcinoma dosing. It’s hard to know whether or not the patient’s truly deriving benefit, so I’ve always been a little skeptical. Even though it didn’t look as though efficacy based on response in this trial is much different, if you spent a lot of time poring over the Kaplan-Meier curves, it does look like 18 mg confers some advantage. It does seem as though there’s some dose response element here. I fear that if we go down too far on dose, we’re compromising that patient’s outcome, so I’ve tended to swing towards tivozanib, even as my second-line approach in my patients who are getting cabozantinib/nivolumab up front.


  • What toxicities are most concerning to you in this setting? Which do you find most challenging to manage?​

PAL: Toxicity comes to the fore when we’re thinking about second- and third-line therapy. By the time the patient’s burned their bridge with tyrosine kinase inhibitor [TKI] plus immunotherapy upfront, we’re looking to control symptoms, make sure they’re able to tolerate the therapy, and hopefully get a response as well. For the 2 options that we’ve juxtaposed, tivozanib and lenvatinib/everolimus, when it comes to fatigue of grade 3 to 4, it occurred in 4% with tivozanib vs 18% with lenvatinib/everolimus.2,3 For diarrhea, it was 2% [grade 3 or 4] with tivozanib vs 19% with lenvatinib and everolimus. This is probably the toughest AE for me in my practice. I don’t know if this is true for others, [but these are] real differences between these 2 strategies, so I have tended to favor tivozanib as my principal salvage strategy. Dr Aloba, does this reflect your clinical experience with these drugs? Have you seen something akin to [the reported AE rates] in your practice?

MARIA CHONA ALOBA, MD: Yes, this reflects what I see in community practice. The lenvatinib/everolimus combination is very hard to tolerate. Even with dose reduction of the lenvatinib, and lenvatinib alone is very toxic, so the combination is [challenging]. I have not given it after a bad experience with 1 patient.

SWARNA CHANDURI, MD: For me, axitinib [Inlyta] is the first drug. I’m comfortable with that. But lenvatinib, even in other cancers, it’s very difficult to continue with it even after dose reduction.

PAL: Yes, absolutely. It’s interesting to talk to colleagues who specialize in gynecologic malignancies. There, you have limited options beyond lenvatinib-based therapy up front for endometrial cancer, for instance. You might be forced to decrease the dose in order to get patients that drug. In renal cell carcinoma, we were blessed with so many different options that I tend to favor using an alternative in this setting.

CHANDURI: What about the hypertension with [tivozanib]? Blood pressure management is one of the issues [that concern me]. How is it with tivozanib?

PAL: It is an issue that is cited. The rate of grade 3/4 hypertension is 21%.2 It’s not so dissimilar from the [other TKIs, such as] 16% with cabozantinib.4 I personally think it’s manageable, having used the drug for quite some time now. I try to get those patients checking their blood pressure logs daily especially the first month or 2, when these AEs manifest. I’ll try to make sure that we have them reporting back any blood pressure in excess of the norm, then my nurse practitioner will usually try to give them some feedback in terms of antihypertensives along the way. I would definitely encourage your patients to keep close tabs on blood pressure, but I would say it is largely manageable.


1. 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

2. 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

3. 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

4. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016

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