Pal Discusses Efficacy and Tolerability of Third-line RCC Therapy Options

Peers & Perspectives in OncologyJune 2023
Volume 1
Issue 1
Pages: 23

During a Targeted Oncology™ Case-Based Roundtable™ event, Sumanta Kumar Pal, MD, and participants discussed next-line therapy for a patient with advanced clear cell renal cell carcinoma who progressed on axitinib/pembrolizumab and single-agent cabozantinib.

Sumanta Pal

Sumanta Kumar Pal, MD (MODERATOR)

Professor, Department of Medical Oncology and Therapeutics Research Codirector, Kidney Cancer Program

City of Hope

Duarte, CA


Robert D. Yoo, DO

Elisa Bomgaars, MD

Roopesh K. Kantala, MD

Carlos Arce-Lara, MD

Holavanahalli S. Keshava-Prasad, MD

Jaspreet Chahal, MD

Pranshu Bansal, MD

Akshay Amaraneni, MD

Stephen B. Goldfarb, DO

Darshil Shah, MD

Christopher Chen, MD

Benjamin L . Maughan, MD, PharmD

EVENT REGION Arizona and Nevada


A man aged 54 years with a history of metastatic renal cell carcinoma (mRCC) had undergone a left nephrectomy and adrenalectomy. He had clear cell RCC and metastases in his adrenal gland. Four years later, the patient had a recurrence of cancer, and a biopsy showed lung nodules consistent with clear cell RCC. In retrospect, it had been present on scans for at least 2 years prior to biopsy.

The patient was observed based on the low volume and indolence of the disease and the patient’s preference. Eighteen months later, reexamination showed continued indolent growth on scans, with an increased total tumor burden and a new paratracheal lymph node (2.0 × 1.5 cm). A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta).

At patient follow-up, the disease was stable. Adverse events reported were moderate diarrhea, well controlled with antidiarrheal medication, and mild fatigue. After cycle 6, the patient developed fatigue, mild shortness of breath, and mild cough without chest pain. The pulse oximeter reading was 93% at rest. He had no fever and no recent sick contact, and his influenza vaccination was up-to-date. Infectious work-up was negative.

After approximately 18 weeks, a chest CT confirmed grade 3 pneumonitis. Pembrolizumab treatment was held, and intravenous steroids were administered. Pembrolizumab was discontinued, and the patient continued axitinib.

Fourteen months after initiation of systemic therapy, the patient reported increasing back pain, mild nausea, weight loss, and new onset of persistent rib pain. Imaging confirmed disease progression:

  • The paratracheal lymph node was now 2.5 × 2.8 cm.
  • There were new mediastinal and hilar nodal involvement, retroperitoneal lymph nodes, and lytic lesions.
  • ECOG performance status: 1

Cabozantinib (Cabometyx) 60 mg/d was initiated, but 4 months later, disease progression was documented. The patient would like to continue active therapy.


  • What are the goals of therapy going into the third line?
  • What factors influence your third-line regimen selection for a patient like this?

PAL: What are your goals of therapy when you get to the third-line setting? Dr Yoo, you…are at a brain metastasis clinic [Barrow Neurological Institute, Phoenix, Arizona], and I am sure a lot of patients who are in the third and fourth lines come to you. What are you generally discussing with patients at that juncture?

YOO: For a patient who progresses after previous [immunotherapy (IO)] and the different tyrosine kinase inhibitors [TKIs], for the third line I usually look for the most tolerable regimen. If there is a survival benefit, of course, and category 1 recommendations, newly updated, those are some of the things I [investigate]. Since the FDA approved tivozanib [Fotivda],1 I have been using that, but it didn’t have a category 1 recommendation. But now, with the category 1 recommendation, I feel more compelled to use that.2

PAL: That’s great. Dr Bomgaars, what are you starting to think about in the third-line setting as opposed to the first or second line?

BOMGAARS: The main [factor] would be tolerability because the patients are probably more beaten down and they have more disease burden. Also, prior response.

PAL: Excellent. That makes a lot of sense, looking at disease burden in addition to clinical factors. Dr Kantala, what factors do you find to be the most relevant?

KANTALA: At this stage, it is tolerability and impact on the patient’s performance status. The impact on the patient’s preferences plays a major role.

PAL: I agree with all of you. At this point, tolerability and quality of life…come to the fore.


  • A shared decision was made to initiate tivozanib.

PAL: What has your experience with tivozanib been like?

YOO: The initial problem was getting the insurance approved because it was a new FDA approval, and a lot of commercial insurances had not updated their guidelines. In terms of tolerability, there was a little bit of rash and diarrhea, but after dose reduction, I had a couple of patients tolerating it well.

ARCE-LARA: I just started the first patient a month ago. So far, it’s going well. No surprises in toxicity. I know about the dose reduction and what to anticipate. The patient has an excellent performance status, so I think that has something to do with it.

KESHAVA-PRASAD: Yes, I have one patient who is on it. He is in his 60s and he has gone through 3 or 4 lines of therapy, and he also had metastasectomy. He had an inguinal lymph node with RCC, and not surprisingly, he had pancreatic metastasis from RCC. It was biopsy proven. So, he was on various lines of therapy, and the last one was axitinib. But he did not tolerate it very well, so we had to reduce the dose because of diarrhea. Finally, I put him on tivozanib. He has been on it for approximately a year now, and he is doing well. I have a second patient who will be starting shortly. She has also gone through IO and other TKIs before.

CHAHAL: I haven’t had the chance to use it yet.

PAL: How about lenvatinib [Lenvima] and everolimus [Afinitor]—have you used that regimen in some of your salvage patients?

CHAHAL: I haven’t used that combination, although I did select it in this [poll]. For this patient, we are discussing, who had [received] pembrolizumab plus axitinib and then cabozantinib, I was thinking of a different line of treatment, a different mechanism of action, and something oral as well, that they would tolerate. But I guess I would be in between. If you go with tivozanib, you are looking at a single-drug regimen, which is more tolerable than the 2-drug regimen. I don’t know how the 2 regimens compare with each other in further-line treatment for mRCC, but I would be interested to learn more about that.

PAL: My candid take is that I still don’t think we have good level 1 evidence for lenvatinib plus everolimus in the salvage setting, because everything that we have is randomized phase 2 evidence. I somewhat agree that the tolerability for tivozanib seems reasonable. I’ve had a harder time maintaining the dose with lenvatinib and everolimus. But your insights are very well taken.


  • What factors would influence your decision to use tivozanib?

PAL: We can use this as an opportunity to get opinions on what you think of these data.

BANSAL: It’s interesting. I wasn’t aware of the separation of the [Kaplan-Meier] curves and the HRs improving over time [From the Data3,4]. So [it is] definitely feasible. My limited experience with mRCC in the third line is [that patients have] very poor performance status, significant tumor burden, [and] poor tolerability in general. If there are patients who can take a drug for 3 years, that’s [great, but] not what I have experienced.

From the data: TIVO-3 PFS

PAL: Yes, [the data are] interesting,3,4 [including] those durable responses.5 Dr Amaraneni, I know you primarily see patients with hematological cancer, but do you have any general takeaways from [these data]?

AMARANENI: It seems like if you can get those patients through the first few days to weeks of taking this medication, there is a benefit that [is] worth the trade-off, especially for some of these patients who don’t have a lot of options left at that point.

PAL: Yes, it makes sense. There is a lot of redundancy in this setting. [We can also] think about the mechanism of action. Even though this is a very specific and potent TKI, some of the data that are coming out of this study suggest that tivozanib works in the setting of [patients who have received] prior therapy with agents like axitinib, like in our case scenario.4,6,7 Even though the mechanism seems to be duplicative, there still seems to be activity.

GOLDFARB: This gives us a good option for third-line therapy. I would use cabozantinib and lenvatinib for lines 1 and 2, and this gives me a third line, so this is very helpful.


  • What has been your experience with lenvatinib plus everolimus? If you have not used it, please share your perceptions of this combination.
    • If you have used it for advanced or metastatic RCC, In what line(s) of therapy?
    • What is your typical approach toward dosing?
    • What is the average duration of therapy, in your experience?
    • What types of responses have you seen?
  • What do we know about the efficacy of lenvatinib at reduced doses?

PAL: Dr Shah, have you used lenvatinib plus everolimus in your practice for patients in the salvage setting?

SHAH: No, not yet. I have used lenvatinib in other indications, but I have not used this particular combination.

PAL: What has your experience with lenvatinib been?

SHAH: Usually I start with a lower dose and try to ramp up, but I have had issues with hypertension [and] some hand-foot toxicities. I have used it in uterine cancer, so I had bleeding issues as well. But I haven’t used it in the RCC setting.

PAL: That experience is helpful. Many times, I’ve leaned on experience from thyroid or uterine cancer or hepatocellular carcinoma. The dosing is tricky. You start at 18 mg, not 20 mg like in uterine cancer, and not at the lower dose like in hepatocellular carcinoma. This is combined with everolimus 5 mg/d.8

You can perhaps use a lower dose. We did an FDA-mandated study looking at lenvatinib at 14 mg vs lenvatinib at 18 mg. This was a noninferiority study and it was larger than the study that led to the approval of lenvatinib plus everolimus.9 It seemed as though, from the standpoint of response, 32% with lenvatinib at 14 mg and 35% for lenvatinib at 18 mg [odds ratio, 0.88; 95% CI, 0.59-1.32; P = .3]), the lower dose was not noninferior to the higher dose.10 So we couldn’t suggest that this was a good modality.

If you look at our data vs what we see for tivozanib, for cabozantinib, for axitinib, and for sorafenib [Nexavar], it looks as though the rates of fatigue, hand-foot syndrome, and diarrhea are a bit more challenging [with lenvatinib plus everolimus], especially when it comes to grade 3 toxicities. Dr Chen, do [these results] mirror the experiences that you’ve had, in terms of toxicity?

CHEN: I have had a tough time with drugs like sorafenib. When I combine lenvatinib with everolimus, my patients who were on axitinib tend to tolerate it better. But I tend to use axitinib up front, so the patients are in their best state with respect to performance status when I use axitinib plus pembrolizumab. Sorafenib is a rough drug to use, no matter what setting I have used it in. I usually start it at a lower dose too. With lenvatinib plus everolimus, I find the gastrointestinal issues to be the biggest. Everolimus tends to have some oral issues as well, even at the lower doses. Maybe it’s because these patients are a little beat up by the time I use [this combination]; I tend to use that combination in the third-line setting.

PAL: Dr Goldfarb, how does that compare with yourexperience? Is that on par with what you’ve seen?

GOLDFARB: Yes, I would say so.


  • How do you prevent, monitor, mitigate, and manage TKI-associated toxicities?
  • Please share your perspectives on the tolerability of tivozanib vs lenvatinib plus everolimus or other options you would strongly consider as third-line therapy for a patient like this.
  • How do you decide which drug to modify when using a combination regimen?

PAL: How do you tend to manage these TKI-associated toxicities? Dr Kantala, has anything been particularly problematic? Has anything been useful in your practice for managing TKI-related toxicity?

KANTALA: I think patient education plays a very important role, especially with fatigue, diarrhea, and [toxicities] like that, because they can be debilitating. Patient education, monitoring, and lowering the dose when needed are some of [my] strategies.

PAL: Dose reduction is key, and one of the benefits with lenvatinib plus everolimus is that it comes as 10-mg and 4-mg tablets, so it is easy for patients to switch up the formulation. I wish that were true for most of the other agents. But we must make sure that patients are able to access [their oncology care provider] quickly; managing dose reductions promptly is essential.


  • Thinking beyond the patient case, please discuss your preferred subsequent-line sequencing strategy after first-line axitinib plus pembrolizumab.

PAL: Dr Maughan, let’s say you start a patient on axitinib and pembrolizumab. Can you walk us through how you might envision second- and third-line therapy, using some of the choices in the National Comprehensive Cancer Network guidelines?2

MAUGHAN: If I am starting with a TKI-IO therapy, axitinib plus pembrolizumab, for instance, usually patients are still at a place where they can tolerate a lot more adverse events from their second-line therapy. I tend to have more toxicity management issues with either cabozantinib- or lenvatinib-based treatments.

I will usually pick one of those as the second-line therapy, in part because, compared with some older treatments, like sorafenib or sunitinib [Sutent], they seem to be more effective. So I will usually prioritize one of those in the second-line setting. For me, it is often cabozantinib, because I tend to use other treatments besides cabozantinib in the first-line setting.

When it comes to the third line, that’s when many patients start having more tolerability issues. Occasionally I will have a patient who is still doing well and hasn’t had too many problems with their TKI treatment, so I will switch to the alternative agent in the third-line setting. If I used cabozantinib in the second line, I will use lenvatinib plus everolimus in the third line, or vice versa. But for most patients, I use tivozanib. I used to use axitinib in the third line. Those two tend to be well tolerated. That’s usually how I think about sequencing them.

PAL: I like that strategy. If I had started the patient on axitinib plus pembrolizumab, [the sequence of] cabozantinib and then tivozanib makes a lot of sense.


  • Thinking beyond the patient case, please discuss your preferred subsequent-line sequencing strategy after first-line ipilimumab [Yervoy] plus nivolumab [Opdivo].

PAL: This scenario comes up often. We see lots of patients with intermediate- and poor-risk disease, and they will start on ipilimumab plus nivolumab. In that setting, cabozantinib tends to be my mainstay in the second line, and then I will give consideration to tivozanib in the third-line setting.

SHAH: If a patient has progressed on a single IO [plus TKI], what are the data to support using a different IO? Let’s say they progress on axitinib and pembrolizumab. What is the response that would be [expected] with single-agent nivolumab after that or with ipilimumab plus nivolumab?

PAL: There are no data, as it stands right now, for single-agent IO after prior IO. There are data for salvage ipilimumab plus nivolumab. What’s interesting is that [first-line] ipilimumab plus nivolumab has a response rate of 42%. In the salvage setting, it is between 5% and 10%, across 3 small studies.11 The yield from ipilimumab plus nivolumab is actually very low. You are better off with a TKI in that salvage setting. With ipilimumab plus nivolumab, if you give it in the second, third, or fourth line, you are still getting the same aggressive toxicity profile.

I just finished a study called CONTACT-03 [NCT04338269]. This study took patients who had gotten either ipilimumab plus nivolumab or axitinib plus pembrolizumab, and it [randomly assigned] them to get cabozantinib or cabozantinib plus atezolizumab [Tecentriq]. If that study is positive, then there may be some rationale for continuing IO beyond the front line. But until those results come out, I probably wouldn’t do any second-line IO.

GOLDFARB: Is there any evidence [showing that] using lenvatinib alone in the second line is effective?

PAL: In the randomized phase 2 trial that led to the approval of lenvatinib plus everolimus in the second-line setting,9 there was 1 arm of lenvatinib monotherapy at [24 mg], and that [dose] performed substantially inferiorly to the combination. The [progression-free survival was 7.4 months vs 14.6] months with the combination.12 So there are not a lot of good supportive data for single-agent lenvatinib, and it hasn’t garnered approval.


1. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. FDA. March 10, 2021. Accessed March 27, 2023.

2. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 4.2023. Accessed March 24, 2023.

3. 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

4. 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

5. 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

6. 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). Poster presented at: 2019 Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Abstract 541. Accessed March 26, 2023.

7. 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

8. Lenvima. Prescribing information. Eisai; 2022. Accessed March 26, 2023.

9. Lenvatinib in combination with everolimus. FDA. Updated May 16, 2016. Accessed March 26, 2023.

10. 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

11. Yang Y, Mori SV, Li M, et al. Salvage nivolumab and ipilimumab after prior anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma: a meta-analysis. Cancer Med. 2022;11(7):1669-1677. doi:10.1002/cam4.4587

12. 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

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