Hammers Discusses Ease of TKI/IO Management for ccRCC

CASE SUMMARY:

A 59-year-old African American woman with a left renal mass underwent left radical nephrectomy in December 2019, revealing clear cell renal cell carcinoma (ccRCC). Nine months later, she developed nodules in both lungs, with mediastinal (35 × 38 mm) and retroperitoneal lymph nodes. A lung biopsy confirmed stage IV RCC with clear cell histology.

She had a Karnofsky performance status of 90%. Her hemoglobin level was 11.1 g/dL and her corrected calcium, neutrophils, and platelets were within normal limits. The patient is scheduled to begin pembrolizumab (Keytruda) at 200 mg every 3 weeks plus lenvatinib (Lenvima) at 20 mg daily.

DISCUSSION QUESTION

What are the recommendations of the National Comprehensive Cancer Network guidelines for the first-line systemic treatment of ccRCC in the setting of relapsed or stage IV disease?

HAMMERS: For poor- and intermediate-risk disease, all of the preferred regimens have category 1 evidence except for cabozantinib [Cabometyx]. The preferred regimens, if patients don’t have a contraindi cation for immune checkpoint inhibition [ICI], would be either dual ICI with nivolumab [Opdivo] plus ipilimumab [Yervoy], which…lacks the tyrosine kinase inhibitor [TKI], as well as all 3 FDA-approved PD-1–inhibitor plus TKI combinations; axitinib [Inlyta]…cabozantinib, and lenvatinib.

We use, much less commonly, axitinib plus avelumab [Bavencio] because of the lack of overall survival benefit. We don’t use sunitinib [Sutent] and pazopanib [Votrient] in the first line anymore.¹

DISCUSSION QUESTIONS

• How often do you consider each of the preferred, category 1, ICI-based regimens as first-line therapy for your patients with poor- or intermediate-risk metastatic ccRCC?

• In general, how often are you using dual ICI therapy vs immunotherapy [IO] plus TKI as first-line therapy for advanced or metastatic RCC that is intermediate or poor risk?

HAMMERS: How do you choose between the different regimens, let’s say dual ICI vs IO-TKI, or even among IO-TKIs, if you’re living on that side, therapeutically? How do you choose between axitinib plus pembro lizumab or lenvatinib plus pembrolizumab, for example?

REDDY: It’s a matter of comfort. [Axitinib plus pembrolizumab] was the regimen I have been using all along…. That was the first one that got approved for the metastatic setting.

CHALLAGALLA: I agree with that, but I saw a patient from [University of Texas] Southwestern [Medical Center] today with bone metastases and hypercalcemia. I’m going with lenvatinib and pembrolizumab. With the bone metastases and the hypercalcemia, I thought lenvatinib and pembrolizumab had a better response rate, and with bone metastases, it’s a prognostic feature. Otherwise, my goto regimen is axitinib and pembrolizumab because I reserve lenvatinib [plus] everolimus [Afinitor], or cabozantinib, for the second or third line.

HAMMERS: Very good. So you differentiate between different regimens; you can individualize.

CHALLAGALLA: Correct.

JOHNSON: I’ve been using pembrolizumab plus axitinib, and it’s been pretty well tolerated, so I’ve stuck with that one. If a patient needs a quicker response, I would be more inclined to go with the VEGF-TKI.

AGARWAL: Same here. I also go with pembrolizumab plus axitinib most of the time.

HAMMERS: What do you like about this regimen? Is it just because you are used to it? Or do you differentiate depending on [various factors]? Why would you choose one TKI over another TKI?

AGARWAL: Like Dr Challagalla said, we have to look for the second- and third-line thing. I’m using cabozantinib mostly in the second line, and I don’t want to exhaust [my options]. I have a lot more experience with pembrolizumab plus axitinib, and it’s easy to get it approved. It’s on our pathway, too.

HAMMERS: Is anybody here using dual ICI, or are most of you are using IO-TKIs?

KAPPOR: I’ve used dual IO therapy several times in patients who have good performance status but have poor or intermediate risk. I’ve used it several times by now and with good results.

AGARWAL: Yes. I also have used dual IO. In fact, I have a patient who’s been on nivolumab for almost 3 years, and I don’t know when to stop because he’s in complete remission. I want to stop it, and this patient doesn’t want to stop it. He’s feeling great. He keeps coming every month…. I just did a PET scan last month, and he’s in complete remission.

CHALLAGALLA: I hear that. I’ve used ipilimumab plus nivolumab in poor-risk patients. Usually at the 2-year mark, I extrapolate [from] the melanoma data.² I don’t know if I’m right or wrong, but most patients don’t want to stop; some patients do. At the 2-year mark, I have a conversation [with them].

HAMMERS: That’s something I do very similarly. At the 2-year mark, I have a conversation, especially if there’s a very deep response. But you’re right, some patients don’t want to stop it. What about the quality of life with dual ICI vs PD-1 inhibitor plus TKI?

CHALLAGALLA: I think if the patient is not having any immune-mediated complications, their quality of life is better, because cabozantinib, lenvatinib, and axitinib have their own adverse events [AEs]: fatigue, diarrhea, skin-related issues, etc. But you could have catastrophic colitis or pneumonitis with IO, or they could sail through without a problem. [Some patients] don’t want to stop.

DISCUSSION QUESTIONS

• Do you have experience with pembrolizumab plus lenvatinib in RCC?

• At what dosage do you most commonly initiate lenvatinib?

HAMMERS: Who among you has used lenvatinib plus pembrolizumab? For lenvatinib plus pembrolizumab or axitinib plus pembrolizumab, do you stay with the initial 3-week dosing or go directly to every 6 weeks? How do you dose the pembrolizumab?

REDDY: I do 200 mg every 3 weeks.

JOHNSON: I start them [on] the 3-week dosing, and then when I see that they are tolerating it pretty well, I switch to the 6-week dosing.

CHALLAGALLA: I agree with that. I usually start at 3 weeks, but if they’re traveling an hour and a half [to get here], after the initial response, I switch them over [to every 6 weeks].

AGARWAL: I switch all of my patients to every 6 weeks because I’m so busy in my office. We don’t have enough [infusion] chairs [and] we don’t have enough infusion nurses. There’s always a struggle, so I switch everyone to every 6 weeks for as long as I can.

HAMMERS: Do you keep the follow-up at 6 weeks then, or do you have an intermittent visit after 3 weeks to keep an eye on them initially?

AGARWAL: No, my nurse practitioner sees the patient every 6 weeks.

HAMMERS: I have a similar pattern; I tend to see patients initially roughly every 3 weeks. We often do the infusion every 3 weeks. I understand about the [use of] every-6-weeks infusion for chair time, etc. Personally, I keep a close eye on patients for the first 6 months or so. Most autoimmune AEs will happen in the first 6 months; after that, it typically becomes a cakewalk [with respect to] the IO component. Those of you who have used lenvatinib, did you start at the full dose of 20 mg or do you use a lower dose?

LAZO: I’ve been seeing a lot of patients lately with problems with blood pressure. I start at the full dose because that’s the guideline,3 but then you have to cut down the dose very quickly, because I’ve seen a lot of blood pressure issues.

HAMMERS: Yes. [High] blood pressure is clearly one of the early AEs. I have some luxury in terms of having cardiologists who have focused their academic careers on patients with cancer. If a patient has even a slightly elevated blood pressure, I send them right to these cardiologists and then try to get it optimally controlled before they even start lenvatinib. Does anyone else want to share any other AEs that you experience with lenvatinib at this high dose early on?... In general, how would you rate the tolerability besides the blood pressure? Dr Lazo, since you had a patient with [high] blood pressure, are there any other AEs that you are worried about?

LAZO: The main thing I have seen is the blood pressure issues. I have a couple of patients for whom the blood pressure has not been an issue, but most of them have blood pressure issues. Otherwise, I haven’t seen many problems with lenvatinib.

CHALLAGALLA: [I observed] fatigue. I’ve never been able to give the full dose. [Lenvatinib is] better with RCC than with hepatocellular carcinoma, but it’s a different population. I could never give 20 mg; 18 mg is a stretch.

HAMMERS: Do you typically start patients at 18 mg? CHALLAGALLA: Well, for the patient that I just saw…I’m starting him on 18 mg. He’s 78 years of age.

AGARWAL: [I would] start him at 14 mg.

CHALLAGALLA: I know, [but] his daughter said, ‘20 mg, Dr Challagalla,’ and I said, ‘No, it’s not going to be 20 mg.’ I wanted 14 mg, so we got a middle ground.

HAMMERS: I use 20 mg a lot. I start everybody at 20 mg.

CHALLAGALLA: [Would you do that] at any age [or] any performance status?

HAMMERS: Yes, to be honest with you. My last patient was on a clinical trial with lenvatinib plus pembrolizumab as a backbone, and she was in her 80s.

CHALLAGALLA: The problem with clinical trials is that they’re very well selected. Those patients have a great performance status.

HAMMERS: Yes, [it’s true that] she’s doing well for being in her 80s, but she is [still over] 80 years of age.

AGARWAL: In [the CLEAR trial; NCT02811861], what was the actual delivered dose? Because there must have been a lot of dose reductions.

HAMMERS: Yes, approximately 70% of the patients had a dose reduction [From the Data⁴]. Sometimes I use intermittent dosing, which works quite well. Remember, the half-life is only 24 hours.² It’s not like cabozantinib, the half-life of which is 5 to 7 days.⁵

And some of these patients can do well with 5 days on, 2 days off, for example, so it’s not uncommon to use something like that. But at the end of the day, you do what you feel comfortable with. We do know that drug exposure is important. There’s a difference between starting patients at 20 mg and 14 mg; there’s a drop in efficacy, not surprisingly.

DISCUSSION QUESTIONS

• How do you counsel patients before and at initiation of an ICITKI regimen? Are there any differences in your approach for each of the 3 approved regimens?

• What steps can be taken to optimize efficacy and safety?

HAMMERS: How do you approach counseling with an IO-TKI combination? What do you think, from your perspective, is important to [do to] optimize efficacy and safety? Do you do a lot of teaching yourself? Do you have a physician assistant or nurse practitioner? What are some of the things that you have found in your practice to be helpful in approaching these patients?

CHALLAGALLA: We have nurse practitioners who do the education, so the burden is on them. But the subsequent visits are with us, so we have to analyze what their quality of life is and how they’re tolerating the therapy and make the appropriate dose reductions. I always have to dose-reduce [lenvatinib].

HAMMERS: Yes. I don’t think everybody can stay at 20 mg for a year, but I think we can push it. All I’m saying is that everybody has a different style. I think 14 mg is a good dose; 10 mg is probably too low for a number of patients. But nonetheless, there are some patients who do well with 10 mg so it’s difficult to predict who needs what. It’s all about individualizing.

CHALLAGALLA: Is there a dose-response curve that [shows that] we have to hit 20 mg…?

HAMMERS: There was a study where they had patients start [lenvatinib] at [18] mg vs 14 mg and there was a clear difference in the progression-free survival [PFS] curve.⁶ There is a dose response with these agents. Even when the question was if you should give sunitinib [Sutent] at 50 mg for 4 weeks on, 2 weeks off vs 37.5 mg continuously, [the data were] clearly in favor of 50 mg given discontinuously.⁷ If you look at Canada…there’s a group in Toronto that is focused on individualizing these [regimens], and they go into [different] schema, but they’re effective with their management. They achieve PFS values that are unbelievable, and they often have this approach where they tend to [use] higher doses but with more dose interruptions, and that tends to work well.⁸ That’s a pattern that I learned from them, to stick with higher doses and give breaks, rather than doing a continuous dose reduction. There will be some patients for whom it’s just going to be a problem to stay at 20 mg, even early on, and you have to dose reduce. At the end of the day, it’s [about] safety and comfort with your medication, but there’s a clear dose-efficacy relationship.

CHALLAGALLA: We’re going to be seeing another patient who has never seen a medical oncologist and who was diagnosed with ccRCC in 2006. She had a pancreatic mass in 2020 and was diagnosed with ccRCC metastatic to the pancreas [but] nowhere else. [UT Southwestern Medical Center’s] radiation oncologists and immunoradiotherapy [physicians] have been working on her. She’s 88 years of age and appears to have indolent disease.

As far as I know, she’s never had any other scans except for CT of the abdomen at UT Southwestern and her local hospital, which is an hour away from us, and she is going to come for her first visit with a medical oncologist. My [inclination] is, if she does not have any other disease, to sit tight, because this seems like very indolent disease: 2006 to 2020, pancreatic mass, and she got stereotactic body radiotherapy, then subsequently the interventional radiologist did embolization, and it’s just there. Nobody did a CT scan of the chest. I’m probably going to do that and look at the bones, etc, and if there’s no other disease, I’m going to say to [observe only].

HAMMERS: This is good-risk disease and, especially if it is affecting the pancreas solely, typically those patients do well in the long term with focal therapy. They went from pancreatectomies to stereotactic body radiotherapy and interventional therapy. Those patients can do well. If it’s just sitting there and nothing is happening, I wouldn’t do anything.

AGARWAL: I would try [dual] IO therapy.

CHALLAGALLA: I’m not so sure. She’s 88 years of age. I don’t want to give her problems.

HAMMERS: Yes, if nothing is changing, I wouldn’t recommend it. I’m a big fan of IO-IO, obviously, but pancreatic metastases are less likely to be immunogenic, so they tend to be more driven by the VEGF pathway. I’ve seen a few patients respond with pancreatic metastases, but it’s not the most common scenario. I think they typically are uniquely VEGF sensitive, and if you look at the tumors, and UT Southwestern has done some studies [on this], they are typically well-differentiated tumors, often very indolent.⁹

REFERENCES
1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1. 2024. Accessed August 3, 2023. https://tinyurl.com/3f4zyez9
2. Ksienski D, Truong PT, Wai ES, et al. Survival outcomes following discontinuation of
ipilimumab and nivolumab for advanced melanoma in a population-based
cohort. Clin Oncol (R Coll Radiol). 2021;33(12):e561-e569. doi:10.1016/j.clon.2021.06.009
3. Lenvima. Prescribing information. Eisai; 2022. Accessed August 3, 2023.
https://tinyurl.com/bdz5z5fs
4. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus
pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med.
2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
5. Cabometyx. Prescribing information. Exelixis; 2022. Accessed August 3, 2023.
https://tinyurl.com/yup3n2bv
6. Pal SK, Puente J, Heng DYC, et al. Phase II trial of lenvatinib (LEN) at two
starting doses + everolimus (EVE) in patients (pts) with renal cell carcinoma
(RCC): Results by independent imaging review (IIR) and prior immune
checkpoint inhibition (ICI). J Clin Oncol. 2021;39(suppl_6):307.
doi:10.1200/JCO.2021.39.6_suppl.307
7. Motzer RJ, Hutson TE, Olsen MR, et al. Randomized phase II trial of sunitinib on an
intermittent versus continuous dosing schedule as first-line therapy for advanced
renal cell carcinoma. J Clin Oncol. 2012;30(12):1371-1377.
doi:10.1200/JCO.2011.36.4133
8. Bjarnason GA, Knox JJ, Kollmannsberger CK, et al. The efficacy and safety of sunitinib given on an individualized schedule as first-line therapy for metastatic renal cell carcinoma: A phase 2 clinical trial. Eur J Cancer 2019;108:69-77.
doi:10.1016/j.ejca.2018.12.006
9. Singla N, Xie Z, Zhang Z, et al. Pancreatic tropism of metastatic renal cell
carcinoma. JCI Insight. 2020;5(7):e134564. doi:10.1172/jci.insight.134564