Long-Term IO-IO Data Contest the Role of Frontline TKIs in Advanced RCC

The increasing range of immuno-oncology (IO)–based treatment regimens for patients with renal cell carcinoma (RCC) is both enhancing and complicating treatment decisions, which are typically informed by symptom manifestation and patient characteristics in the absence of predictive biomarkers, according to Alan Tan, MD.

“The big question is: How do we decide when to use what? To simplify it the most, when do we use IO-TKI regimens?” Tan emphasized in an interview with OncLive®.

In the interview, Tan discussed the nuances of navigating combination regimens for patients with advanced RCC, including the ins and outs of choosing the most suitable combination based on disease factors and patient characteristics, his predictions for future research to combat resistance to immune checkpoint inhibition, and how symptom burden influences the role of systemic therapy in individual patients.

He highlighted the 8-year follow-up data from the phase 3 CheckMate 214 trial (NCT02231749), in which nivolumab (Opdivo) plus ipilimumab (Yervoy) generated a median overall survival (OS) of 52.7 months (95% CI, 45.8-64.5) vs 37.8 months (95% CI, 31.9-43.8) with sunitinib (Sutent) in patients with treatment-naive advanced RCC (HR, 0.72; 95% CI, 0.62-0.83).¹

In light of these 8-year follow-up data with the IO-IO combination, he also noted questions that remain regarding the use of IO-TKI regimens, such as pembrolizumab (Keytruda) plus lenvatinib (Lenvima), which is the most recent IO-TKI regimen to gain FDA approval for the treatment of adult patients with previously untreated advanced RCC. This combination was approved in August 2021 based on findings from the phase 3 CLEAR trial (NCT02811861). In the final OS analysis of the trial, the median OS was 53.7 months (95% CI, 48.7-not evaluable [NE]) with the combination vs 54.3 months (95% CI, 40.9-NE) with sunitinib (HR, 0.79; 95% CI, 0.63-0.99; nominal P = .0424).²

Tan is a genitourinary oncology and melanoma specialist at the Vanderbilt-Ingram Cancer Center, as well as an associate professor of medicine in the Division of Hematology Oncology at the Vanderbilt University Medical Center in Nashville, Tennessee.

OncLive: What IO-based combination therapies are available for patients with advanced RCC?

Tan: Kidney cancer is a heterogeneous solid tumor where we don’t have good biomarkers to help us select therapies. We have the International Metastatic RCC Database Consortium [risk criteria], but [those were not] intended to be predictive; [they are] more of a prognostic categorization. We have emerging data on angiogenic signatures, RNA signatures, and immune-inflamed signatures that may help us select dual immunotherapy combinations in the frontline setting vs immunotherapy plus TKIs.

Four major [doublet] regimens are FDA approved [for patients with RCC]. With ipilimumab plus nivolumab, we have an 8-year follow-up, the longest follow-up [of any of the regimens]. That’s a pure IO combination. Then, we have 3 IO-TKI combinations. [The question then is] when to use a TKI in a patient.

[Between] the 3 [IO-TKI] regimens—pembrolizumab plus axitinib [Inlyta], cabozantinib [Cabometyx] plus nivolumab, and lenvatinib plus pembrolizumab—there are more similarities than differences in the efficacy and tolerability profiles. The tornado plots for tolerability show family class effects of TKIs, including hand-foot syndrome, taste changes, dysphonia, and fatigue. All those TKIs are going to have a cumulative effect, building up in [the patients’] systems, and will probably require breaks to wash out the toxicity.

[Although we are] seeing longer follow-up with the IO-TKI regimens, and there is a significant progression-free survival benefit and higher overall response rate compared with the IO-IO regimen, we’re not sure that these regimens are extending OS compared with the comparator arms of [their respective trials, such as] sunitinib. We’re not even using sunitinib [in RCC] anymore. There’s activity [with these IO-TKI regimens] across favorable-, intermediate-, and poor-risk populations, but are we helping patients live longer without toxicity and with the durability that we’ve seen from IO-IO treatment with ipilimumab plus nivolumab?

What data have been shared that may help oncologists choose between these available regimens?

We now have 8-year follow-up data [with nivolumab plus ipilimumab, which] is FDA approved for patients with intermediate/poor-risk disease. However, we’re now seeing the OS Kaplan-Meier curves cross and switch places [between the IO-IO and IO-TKI trials in the favorable-risk populations]. We now see [an OS] hazard ratio [HR] of 0.82 in the ipilimumab/nivolumab favorable-risk population, which is better than the HRs [seen in] the IO-TKI trials. The newest [information] is that ipilimumab plus nivolumab, the pure IO combination, can be a treatment option for patients with favorable-risk disease.

How do we decide which patient needs what? [We consider an IO-TKI regimen] if a patient doesn’t pass the eyeball test. We see a lot of patients with kidney cancer who are huffing and puffing because they have a lot of disease burden. They’re in a wheelchair. They have oxygen because they have pleural effusions, or maybe they have malignant ascites. These patients are in trouble if they don’t get a response quickly, so getting them on an IO-TKI regimen right off the bat will help them [achieve] that long-term survival [data] we’re seeing with these combinations that can now go up to 5 years. However, [discontinuing] those regimens forever [in these patients] is probably going to be difficult and sometimes not possible.

In CheckMate 214, 35.1% of patients [who received nivolumab plus ipilimumab] were alive at 90 months and perhaps even longer now. Approximately one-third of patients [in this arm] were off therapy, maintaining disease control and possibly even cured. Longer-term follow-up is needed to see whether these patients are truly cured. However, so far, 8 years is the longest follow-up we have [with an immunotherapy doublet regimen in RCC]. There’s more excitement in the future for other combinations to build upon immunotherapy doublets.

What novel targets may become applicable for RCC management in the future?

The phase 3 LITESPARK-12 study [NCT04736706] is [investigating] a triplet regimen [in patients with advanced RCC]. [It is not] adding another TKI to a CTLA-4 and PD-1 [inhibitor combination]. It is adding a new mechanism of action, what I consider the third or fourth pillar of RCC management: a HIF2α inhibitor, which addresses the pathogenesis of clear cell kidney cancer. We’re excited to see what that [regimen] provides. 

Additionally, how do we overcome resistance to immune checkpoint inhibition? What other mechanisms [can be used]? We haven’t tested, LAG-3 in kidney cancer yet. Trials are ongoing [investigating agents with this target, and LAG-3 inhibitors] have demonstrated to be efficacious in melanoma. Even though they’re different cancers, [the RCC field] oftentimes eventually catches up to the innovations we see in melanoma, [after] a few years. I’m interested to see what other immunologic targets will be successful in the future [in RCC].

The long-term data from CheckMate 214 show that nivolumab plus ipilimumab could be used in the favorable-risk population. However, in clinical practice, without biomarkers, how confident are you when determining whether a patient should receive this regimen?

Patients with favorable-risk disease probably have no symptoms of their cancer. They will all pass that eyeball test to see whether they can have durable benefit and come off therapy. The patients who are symptomatic don’t have that luxury. You can’t put all your eggs into 1 basket. However, for the favorable-risk patients, if you think their body can tolerate the combination, [you can give it to them]. [Tolerability is] hard to predict because even among healthy patients, you don’t know which ones will develop the endocrinopathy or severe neuropathy that we see occasionally.

One other caveat is not every patient with favorable-risk disease needs systemic therapy. If you have a patient who is amenable to stereotactic radiation for maybe 1 to 3 lung lesions, they could probably have long-term disease control or maybe even cure with an ablative procedure or surgery. That should be considered before entering the systemic treatment discussion.

References

1. Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): long-term follow-up data from the phase 3 CheckMate 214 trial. J Clin Oncol. 2024;42(suppl 4; abstr 383). doi:10.1200/JCO.2024.42.4_suppl.363
2. Motzer RJ, Porta C, Eto M, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol. 2024;42(11):1222-1228. doi:10.1200/JCO.23.01569