Selecting Checkpoint Inhibitor–Based Regimens in Clear Cell RCC Requires Several Considerations

The use of immune checkpoint inhibitor (ICI)–based regimens may evolve beyond the standard doublet therapies to include drugs with other mechanisms of action beyond ICIs and TKIs in clear cell renal cell carcinoma (RCC), according to Yousef Zakharia, MD. Long-term subgroup data from the phase 3 CheckMate-214 study (NCT02231749) and emerging data on triplet therapies from the phase 3 COSMIC-313 trial (NCT03937219) have further shed light on potential approaches in the clear cell RCC treatment landscape.1,2

“The bar is already high in the first-line setting with immuno-oncology (IO)/TKI combinations, so how much triplet therapy will add to the frontline remains to be seen,” Zakharia said in an interview with OncLive® regarding a recent State of the Science Summit™ on genitourinary (GU) cancers, which he chaired.

In the interview, Zakharia highlighted the efficacy of ipilimumab (Yervoy) and nivolumab (Opdivo) in intermediate/poor- vs favorable-risk populations; initial data with triplet therapy from COSMIC-313; and emerging treatment modalities in clear cell RCC, including triplet combinations.

In a concurrent interview, he also discussed updated data with standard IO/TKI combinations from several key trials in the GU cancer field. Zakharia is a medical oncologist, vice chair of the Genitourinary Malignancy Disease Group at the Mayo Clinic Comprehensive Cancer Center, and medical director of the Experimental Therapeutics Clinic at Mayo Clinic in Arizona.

OncLive: What are the current standard therapeutic approaches in metastatic clear cell RCC?

Zakharia: We have 2 big categories [of therapeutics] in metastatic clear cell RCC. We have immunotherapy with checkpoint inhibitors, and that includes CTLA-4 inhibitors plus PD-1 inhibitors [with] ipilimumab and nivolumab. Then we have different combinations of PD-1 inhibitors plus TKIs. Three [of these] regimens are currently commonly used in the clinic: Pembrolizumab [Keytruda] plus lenvatinib [Lenvima], pembrolizumab plus axitinib [Inlyta], and nivolumab plus cabozantinib [Cabometyx] .

What do updated findings from CheckMate-214 indicate about the long-term benefits of nivolumab plus ipilimumab according to risk status in clear cell RCC?

CheckMate-214 was one of the very first combination clinical trial in metastatic clear cell RCC that randomly assigned patients in a first-line setting to ipilimumab and nivolumab in combination vs sunitinib [Sutent]. The trial enrolled 1096 patients with coprimary end points of objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) among intermediate- and poor-risk patients and did meet these primary end points in the intermediate- and poor-risk feature [groups].

The most recent data [from CheckMate-214] were presented at the 2024 Genitourinary Cancers Symposium. The long-term follow-up in this patient population [showed that approximately] 40% of patients with intermediate- and poor-risk [disease], per International Metastatic RCC Database Consortium [IMDC] risk criteria, were still alive at 6 years. It is quite interesting to see that those patients who used to live, on average, 2 years if they had intermediate-risk and approximately 6 months if they had poor-risk [disease] are living many more years now.

The other finding from the long-term follow-up [data] was in the favorable-risk patient population. When the very first preliminary analysis was presented, patients with a favorable risk per IMDC risk score did better with sunitinib compared with ipilimumab and nivolumab, and that’s why a lot of us in the field did not adopt [this combination] for patients with favorable-risk disease. However, with longer follow-up, we are seeing more of a flip of the OS curve in favor of ipilimumab plus nivolumab in the favorable-risk patient population. That’s why the National Comprehensive Cancer Network [recently added] ipilimumab plus nivolumab as another preferred treatment option for patients with favorable-risk disease [to their guidelines].

In what scenarios would you recommend a single-agent TKI vs combination immunotherapy for patients with favorable-risk metastatic clear cell RCC?

The question of whether we should offer IO/TKI combination to all favorable risk patients vs single agent TKI in certain situations remains, given the lack of OS benefit with the combination in favorable risk patients. I would argue it’s a case-by-case scenario. If a patient has minimal disease burden and is asymptomatic, I would still offer them a single-agent TKI if they had favorable-risk disease. For example, if they had their nephrectomy 10 years ago and are now experiencing recurrence with tiny metastatic lung nodules, I would argue that a single agent TKI would be appropriate. [This is] opposed to patients who had their nephrectomy 2 years ago and are now experiencing recurrence with metastatic disease and liver metastases—technically by IMDC, they could still be considered to have favorable-risk disease, but we know they have more aggressive disease with the liver involvement. Those are the patients [for whom] I would consider IO/TKI or possibly ipilimumab and nivolumab in the favorable-risk setting.

What are the clinical implications of findings from COSMIC-313, and how might toxicity concerns and differences in survival outcomes among subgroups impact the future use of triplet therapy in RCC?

COSMIC-313 is an important study because it was the very first clinical trial in metastatic clear cell RCC to ask about the role of triplet therapy, and was in the intermediate- and poor-risk patient populations. This clinical trial randomly assigned patients to the standard dose of ipilimumab plus nivolumab with 40 mg of cabozantinib daily vs ipilimumab and nivolumab plus placebo. The primary end point was PFS by blinded independent review and secondary end points included OS and many others. [A total of] 855 patients were randomly assigned to either arm. Technically, this clinical trial did meet the primary end point of improved PFS in the intention-to-treat population. However, looking at the subgroups, the benefit was [driven by] the intermediate-risk patient population as opposed to the poor-risk patient population, which did not show a [PFS] advantage.

We are still waiting for the longer-term follow-up of this clinical trial, especially when it comes to OS, so this triplet therapy combination is not yet ready to be used in the clinic. However, it’s great to see that this is the first trial to study the role of triplet therapy.

The one major disadvantage of this triplet is the significant toxicity, especially when it comes to liver toxicity. [There is] significant elevation of grade 3/4 [>20%] liver toxicity with elevation of liver function test, and up to 60% of patients on the triplet combination used high-dose steroids. Significant liver toxicity and high utilization of steroids dampens the enthusiasm about using this combination, especially with the lack of PFS improvement in the poor-risk patient population.

What is the potential role of emerging therapies, such as triplet combinations, in advancing treatment for patients with advanced clear cell RCC?

We are [examining] a triplet therapy in the first-line setting combining an immunotherapy PD-1 inhibitor, TKI, and the HIF-2α inhibitor belzutifan [Welireg]. We are awaiting the clinical trial read out for this first-line [phase 3] clinical trial [NCT04736706] with pembrolizumab, lenvatinib, and belzutifan.

When it comes to the refractory setting, there are multiple therapies [that are] still in early development, including CAR T-cell therapies. [For example,] we have a clinical trial that we are opening here at our center using CAR T therapy [directed] towards carbonic anhydrase 9. Additionally, we have other clinical trials [evaluating] bispecific antibodies and other small molecules, but these are very early in development.

References

1. Choueiri TK, Powles T, Albiges L, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma.N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851
2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 20185;378(14):1277-1290. doi:10.1056/NEJMoa1712126