The Field of Recurrent RCC Regimens Continues to Grow


During a Case-Based Roundtable® event, Sumanta Kumar Pal, MD, discussed regimens for recurrent metastatic clear cell renal cell carcinoma including lenvatinib plus everolimus, belzutifan, and investigational cell therapy and bispecific agents in the second article of a 2-part series.

Sumanta Kumar Pal, MD

Sumanta Kumar Pal, MD

Codirector, Kidney Cancer Program

Chair, Kidney and Bladder Cancer Disease Team

Professor, Department of Medical Oncology & Therapeutics Research

City of Hope

Duarte, CA

TARGETED ONCOLOGY: What evidence supports the use of the combination of lenvatinib (Lenvima) and everolimus (Afinitor) in patients with previously treated advanced clear cell renal cell carcinoma (RCC)?

SUMANTA KUMAR PAL, MD: The initial study [HOPE 205 (NCT01136733)] that led to the approval of lenvatinib and everolimus…randomly assigned patients to either lenvatinib alone, lenvatinib with everolimus, or everolimus by itself. Not surprisingly, lenvatinib with everolimus [was superior to] everolimus therapy.1 There’s a trend towards overall survival benefit. But I would highlight…that this is a randomized phase 2 study, so it’s 50 patients per arm. It’s always been challenging to figure out how this weighs in the context of the existing datasets that we have in the refractory setting. The majority of patients in this trial had just [received] 1 prior tyrosine kinase inhibitor, so it’s not necessarily the type of dataset that reflects the contemporary population.

What did Study 218 (NCT03173560) show concerning the optimal dose level of lenvatinib in combination with everolimus in RCC?

This is a study that I ran which looks at 2 dose levels of lenvatinib with everolimus. We looked at lenvatinib at 18 mg or 14 mg with everolimus at 5 mg. The end point of the study was to see if the tolerability was similar between these 2 strategies. This was an FDA-mandated study. What stands out to me is that [although] this study wasn’t powered to look at differences in progression-free survival [PFS], the study is 6 times the size of the [experimental arm of] the original trial that led to the approval of lenvatinib and everolimus. Here we had [over] 300 patients treated with lenvatinib and everolimus. It looks as though those patients who started with a higher dose level of lenvatinib at 18 mg fared a bit better with respect to PFS than those that started at 14 mg [median PFS of 14.7 months vs 11.1 months, respectively].2 The other big surprise to me is that patients didn’t seem to have massive distinctions in toxicity. If I were to summarize it, in terms of treatment-related adverse events that we saw as a consequence of lenvatinib are not different if you start at 14 mg vs 18 mg [any-grade, 95% vs 96%, respectively; grade 3 or 4, 72% vs 77%, respectively]. I often hear from my colleagues, “Perhaps we’ll start at 10 mg or 12 mg.” Maybe that leans on data from hepatocellular carcinoma, but I think it’s a little risky, because you may not necessarily be getting the same clinical efficacy that you’re hoping for, and based on these data, you may not be mitigating much of the toxicity that you see with it either.

What is the significance of the approval of belzutifan (Welireg) in this setting?

Belzutifan blocks hypoxia inducible factor [HIF-2α], which is essentially a transcription factor for VEGF. If you block hypoxia inducible factor, you’re not going to get VEGF production. That shuts down the signaling cascade from a different mechanism. Belzutifan [had FDA] approval for Von Hippel-Lindau syndrome, where patients get hemangiomas and RCC on occasion. [The phase 3 Litespark-005 trial (NCT04195750)] is not a study that focused exclusively on that VHL germline mutation population but took all patients with clear cell RCC who had received at least 1 prior therapy. Patients had to have 1 to 3 prior treatments. This is a trial that looked at patients a bit earlier than what we saw in the context of tivozanib [Fotivda] and randomly assigned them to belzutifan or everolimus.

Numerically, there’s no difference in terms of PFS [median, 5.6 months for belzutifan vs 5.6 months for everolimus], but there is a significant benefit, nonetheless, with an HR of 0.75 [95% CI, 0.63-0.90; P < .001], but there is some crossover in the [Kaplan-Meier] curve.3 If you look early on, patients fare a little bit better with everolimus and then the curve for belzutifan crosses over. This underscores a very important point with this drug, which is that you may get benefit from it, but it takes a longer time to elicit that benefit. When you think about a patient…whose disease is progressing with multiple new metastases, maybe with symptomatic metastases, and it’s causing compromise of functional status, bear in mind that belzutifan takes time to work.

[In terms of] response rate, we’re seeing similar data to what we saw for tivozanib. The objective response rate is 22%, albeit in a slightly less heavily pretreated population. But what’s very important to bear in mind is that with [tivozanib], you see about 20% of patients with primary progression… here you have 35% of patients with primary progression, so more patients are going to progress right through therapy with belzutifan.3,4 That lends itself to the time that it takes the drug to act, and it may just be a little too slow in this therapeutic setting.

Belzutifan does offer benefit when it comes to toxicity. There are a couple of toxicity elements that stand out; patients had more anemia [and] hypoxia with belzutifan. Otherwise, it’s a pretty well-tolerated agent on the whole. I still tend to utilize tivozanib in that refractory setting because of the time to action with the drug and the rates of primary progressive disease.

What data are there on using immunotherapy (IO) in patients who received it in the frontline setting?

CONTACT-03 [NCT04338269] looked at the principle of using IO after IO. To date, the only data that we have, [which] you can argue isn’t a perfect trial, is this phase 3 trial looking at cabozantinib [Cabometyx] vs cabozantinib plus atezolizumab [Tecentriq]. This was done in a very contemporary population. These are patients who have [received] in many cases nivolumab [Opdivo] plus ipilimumab [Yervoy] or axitinib [Inlyta] plus pembrolizumab [Keytruda] upfront, and we saw no benefit in terms of PFS [HR, 1.03; 95% CI, 0.83-1.23; P = .78].5 We tried to tease apart any potential subgroups [such as] patients with sarcomatoid disease and patients with responses to prior IO, [but] nobody seemed to derive benefit from the addition of IO in the second- or third-line setting. I generally wouldn’t recommend continuing IO.

There’s going to be another important study that’s tivozanib-based called TiNivo-2 [NCT04987203], which we hope is going to report out at some point in the near future. That utilizes a very similar design with tivozanib and nivolumab so we’ll see if that follows this trend, but for the moment, I wouldn’t advocate for any further IO.

What other investigational agents are being investigated in patients with recurrent advanced RCC?

We’re doing a lot of work with CAR [chimeric antigen receptor] T-cell therapies. [CTX130] is a CD70-directed CAR T-cell therapy for RCC. What was unique about this compound is that this is something that a solid tumor oncologist could manage [in terms of toxicity]. The rates of cytokine release syndrome were modest.6 We didn’t see [high rates] fevers or neurologic change, etc. Patients did quite well. We had 1 [patient] who had a complete response for a total of 3 years. Most patients on this study didn’t respond, so we are now developing the next generation of this construct called CTX131, and that study [NCT05795595] is enrolling…right now.

I also wanted to highlight that bispecifics, which are gaining traction in hematologic malignancies, are another element that we’re looking at in RCC. [One example is] a bispecific T-cell engager [XmAb819] that focuses on a target called ENPP3, which is very heavily expressed in RCC.7

1. 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
2. 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
3. Albiges L, Rini BI, Peltola K, et al. Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): randomized open-label phase III LITESPARK-005 study. Ann Oncol. 2023;34(suppl 2):S1329-S1330. doi:10.1016/j.annonc.2023.10.090
4. Verzoni E, Escudier B, Hutson TE, et al. TIVO-3: Durability of response and updated overall survival of tivozanib vs sorafenib in metastatic renal cell carcinoma (mRCC). Presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021; virtual. Abstract 4546.
5. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4
6. Pal SK, Tran B, Haanen JBAG, et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. Published online April 5, 2024. doi:10.1158/2159-8290.CD-24-0102
7. Pal SK, Masouel P, Yalamanchili S, et al. A phase 1, multiple-dose study to evaluate the tolerability and safety of XmAb819 in patients with relapsed or refractory clear cell renal cell carcinoma. Presented at the Society for Immunotherapy of Cancer Annual Meeting; November 8-12, 2022; Boston, MA and virtual.
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