Roundtable Discussion: Choueiri Leads Debate on Second-line Therapy in Patients with RCC

Toni K. Choueiri, MD

During a virtual Targeted Oncology Case-Based Roundtable event, Toni K. Choueiri, MD, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, coleader, Kidney Cancer Program, Dana-Farber/Harvard Cancer Center, Jerome and Nancy Kohlberg chair and professor of Medicine at Harvard Medical School lead a debate with a group of peers on second-line therapy options for patients with renal cell carcinoma (RCC).

TONI K. CHOUEIRI, MD: What factors would you take into consideration for second-line therapy if a tumor progressed on cabozantinib [Cabometyx] plus nivolumab [Opdivo]?

CHRISTIAN A. THOMAS, MD: PD-L1 status. The genomic profile is something that I always look at or try always to look at if I can. Now that we’re talking progression, what I’ve been able to do is sometimes switch tyrosine kinase inhibitors [TKIs] on patients. You are asking what the preferred second-line regimen would be, so that would be a switch regimen with TKI, probably—so lenvatinib [Lenvima], for instance, and everolimus [Afinitor].

ILYA BLOKH, MD: I typically use axitinib-pembrolizumab [Inlyta-Keytruda] up front, and then I’ll give cabozantinib as second line. But if you’re using cabozantinib front line…a TKI and...a single new drug, perhaps another alternative could be ipilimumab [Yervoy]/nivolumab, where now you’re giving [a new] immune attack. I was wondering what you thought of that?

CHOUEIRI: That’s a good question. There’s a study, FRACTION-RCC [NCT02996110], we presented at the American Society of Clinical Oncology 2020 meeting, which was a very interesting study. We used nivolumab and [it had] 2 tracks: [either patients who had] no immuno-oncology [IO] experience…or patients whose tumor had progressed on prior IO, so track 1 and track 2. For each track, they have nivolumab as the backbone and they add the assets they want to explore in RCC. We had an IDO inhibitor; we had ipilimumab [and] many more. We presented the data of track 2, so patients with IO experience of pembrolizumab-axitinib or cabozantinib- nivolumab received nivolumab-ipilimumab. The response rate was 15%.¹

If you progressed on prior IO, [you can’t] expect the nivolumab-ipilimumab response to be the same as in a completely untreated patient, which is 42%. So, it was 15%. You could argue that these are very good durable responses and it’s worth it, but you could also argue that maybe you did not need the nivolumab and that it was [due to] ipilimumab single agent, which we have no recent data for. The last data are from over 10 years ago, from a study from the National Cancer Institute with high doses of ipilimumab.²

ANAMIKA KATOCH, MD: If you’ve already used cabozantinib up front and also immunotherapy, then I think the one option would be the nivolumab-ipilimumab. It is reasonable, but that’s a tough situation [after cabozantinib-nivolumab].

PETER T. GEORGES, MD: How about something like the lenvatinib and everolimus combination?

M. SHEILA DONNELLY, MD: I have a question about a patient. She had indolent metastatic RCC where she originally presented with bone metastases and had a nephrectomy at the same time. She did well years ago, got other drugs such as pazopanib [Votrient]. Ultimately, there was slow progression—and this is over many years—she got nivolumab and stopped it because of arthritis. Now she has progressive disease…and, I might add, she also probably has some central nervous system disease. Would you go\ back to a combination? Will you ever go back to a combination of pembrolizumab-axitinib or nivolumab-ipilimumab in someone [like this]? She’s been off nivolumab for probably 2 years and I certainly want to offer her something.

CHOUEIRI: We have published [data] in RCC and bladder cancer about rechallenging in patients that have immune-related adverse events [irAEs]. Yes, you can have these irAEs again, and sometimes worse, but there are patients that respond and don’t have the irAEs again. So absolutely, yes, [I would rechallenge this patient].

DONNELLY: Would you use a combination?

CHOUEIRI: I don’t know. If she responded to a single agent and had an irAE, I would use just a single agent because I can assure you that with the combination, the risk of an irAE is probably higher.

The majority, especially [for after] cabozantinib- nivolumab, suggested lenvatinib-everolimus…. National Comprehensive Cancer Network [NCCN] guidelines [have] cabozantinib-nivolumab in category 1 because of the phase 3 trial and nivolumab-ipilimumab [beneath that] because it has phase 2 data.

The data, when you look at the NCCN guidelines in the second line, [mostly] don’t apply because all the trials were done in IO-na.ve patients. Axitinib versus sorafenib [Nexavar], nivolumab versus everolimus, cabozantinib versus everolimus, and lenvatinib-everolimus versus lenvatinib versus everolimus were all in patients whose tumors progressed on prior TKI. A small number of patients received prior IO, like in the METEOR study [NCT01865747], but most of them did not. So a lot of [those data] do not apply.

CHOUEIRI: What’s your experience with lenvatinib/everolimus in terms of depth and duration of response overall and toxicity?

THOMAS: None of the TKIs are super easy. There’s a lot of dialing back the lenvatinib dose, there’s a lot of skipping everolimus or dialing that back, too. I have a patient right now with disease in the spine where [I’ve taken] everolimus down to 1.25 mg. This patient cannot tolerate the 2.5-mg dose. So it can be a challenge sometimes. I see reliable response rates with [this combination]. A third of the patients [I see], maybe more than that in the secondline settings, [do not do] badly. The duration is variable; I couldn’t tell you an average of [it]. That’s a combination where, when you see people respond to it, sometimes you do get [a good duration]. So I would say half the patients that respond have a response that lasts a year or more.

NANCY E. KADDIS, MD, MPH: I’ve only used it one time, actually. I agree that I had to dose reduce; it was fairly toxic.

CHOUEIRI: There is a press release of lenvatinib-everolimus because it’s one of the arms of the CLEAR study [NCT02811861], which was lenvatinib-everolimus or lenvatinib-pembrolizumab versus sunitinib [Sutent].3 Lenvatini-beverolimus beat sunitinib for progression-free survival [PFS], according to this press release.

GEORGES: I have not used lenvatinib-everolimus much. I usually start with the combination IOs and then go to TKI [when] patients receive therapy beyond the second line.

CHOUEIRI: A small, randomized phase 2 trial [NCT01136733] led to the approval of lenvatinib and everolimus.^4,5 It’s called the [E7080-G000-]205 study, which was lenvatinib-everolimus versus lenvatinib versus everolimus. PFS was the primary end point. Lenvatinib was 18 mg and everolimus was 5 mg, in combination [vs 24 mg and 10 mg, respectively, as monotherapy].

This combination was not used at full-dose everolimus or full-dose lenvatinib. In the study where lenvatinib was a control arm here, the dose of lenvatinib was higher. One thing to remember also is to get, at baseline and on therapy, cholesterol and blood sugar [levels of patients]. There’s a lot of metabolic perturbation due to everolimus. [Diarrhea was the most common grade 3/4 AE with the combination.]

CHOUEIRI: This is not so specific to lenvatinib-everolimus as much as a TKI discussion….We’re all now getting more comfortable with [using a] TKI. I don’t think there’s a lot of physicians that have experience [with this combination]; they will hold and dose reduce, thinking that the patient just started and the diarrhea may not become grade 2 or 3, and that’s OK. In my experience with grade 1, I usually add antidiarrheal prophylaxis and find that many patients are able to continue the full dose, but certainly not every patient.

_REFERENCES

_{1. Choueiri TK, Kluger HM, George S, et al. FRACTION-RCC: innovative, high throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell carcinoma (aRCC). J Clin Oncol. 2020;38(suppl 15):5007. doi:10.1200/JCO.2020.38.15_suppl.5007}

_{2. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828-833. doi:10.1097/CJI.0b013e3181eec14c}

_{3. Lenvima plus Keytruda demonstrated statistically significant improvement in progression-free survival, overall survival and objective response rate versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma. News release. Eisai Co, Ltd. November 10, 2020. Accessed February 26, 2021. https://bit.ly/2ZUxcP2}

_{4. Lenvatinib in combination with everolimus. FDA. Updated May 16, 2016. Accessed February 26, 2021. https://bit.ly/3uyS9Nj}

_{5. 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}