The availability of long-term follow-up data now provides more valuable insights into the use of immuno-oncology (IO)/TKI and IO/IO combinations for the treatment of patients with advanced clear-cell renal cell carcinoma (ccRCC), according to Hans Hammers, MD, PhD.
“The most important development is that we now have long-term follow-up. It’s important to stress that we never directly compared these regimens, so we can only infer from these long-term follow-up data,” Hammers explained in an interview with OncLive®. “However, there is a general sense that IO/TKI combinations have a very high upfront response rate, in the range of 60% to 70%, depending on the regimen.”
During the interview, Hammers discussed efficacy differences between IO/TKI and IO/IO combinations, differences related to adverse effects (AEs), clinical considerations prior to treatment selection, and the likelihood of patients responding to upfront treatment.
Hammers is a professor in the Department of Internal Medicine, a member of the Division of Hematology and Oncology, coleader of Clinical Research and Immunotherapy for the Kidney Cancer Research Program, and the Eugene P. Frenkel, MD Scholar in Clinical Medicine at the UT Southwestern Medical Center in Dallas, Texas.
OncLive: What are the main efficacy differences between IO/TKI and IO/IO combinations?
Hammers: The most important development is that we now have long-term follow-up. It’s important to stress that we never directly compared these regimens, so we can only infer from these long-term follow-up data. However, there is a general sense that IO/TKI combinations have a very high upfront response rate, in the range of 60% to 70%, depending on the regimen. Typically, there is [also] a much longer median progression-free survival [PFS] in the range of 16 to 24 months, meaning high upfront activity. For [a patient] who is in trouble with regards to symptomatic tumor burden, these are important regimens because the progressive disease as best response is in the single digits for at least the cabozantinib [Cabometyx] and lenvatinib [Lenvima] combinations, and a little bit higher for the axitinib [Inlyta] combination because that’s a more tailored agent, and is not as broadly active as cabozantinib and lenvatinib. The downside of [cabozantinib/ lenvatinib] is that the 5-year PFS [rate] is not as appealing, because if you look at the 5-year data sets that we have for axitinib/pembrolizumab [Keytruda], and cabozantinib/nivolumab [Opdivo], the PFS rates at the 5-year mark are [approximately] 18% and 13%, respectively, and that contrasts what we see with IO/IO. [A drawback with] pure immunotherapy includes intensified immunotherapy; therefore, the need for steroids is higher. [Approximately] 10% to 15% of patients on IO/TKI need prednisone. However, this rate is doubled with dual immune checkpoint [inhibitors], but the quality of life is still unmatched.
What are some of the similarities and differences in terms of safety between IO/TKI and IO/IO combinations?
[With dual checkpoint inhibitors], patients don’t have the daily AEs, typical of a VEGF TKI, although they can get significant autoimmune AEs. Most of the time, we get them quickly under control [with] prednisone. The quality of life is still unmatched. Patients don’t have the daily metallic taste, fatigue, diarrhea, or hand-foot syndrome. [However,] the response rate is lower: it’s 40% for IO/IO. In progressive diseases, the best response is approximately 20%, which is significantly higher. In my practice, most patients have a disease burden and aggressiveness of their disease that prevents them from going on an IO/IO. I just monitor them closely. If I’m worried, I do an extra scan a bit earlier, but most of the time, I [lean towards monitoring closely]. Not everybody needs an IO/TKI, but it also depends on the comfort level of the provider and in discussion with the patient.
What would be an indicator that a patient should be receive a scan earlier?
[Typically signs of] symptoms because if there is more pain, they’re calling you and saying, ‘Hey, [there’s more] pain, and calcium [levels] are rising.’ Any of these lab values and clinical parameters [inform us] that we [could be] facing disease progression. Sometimes we discuss pseudo-progression with patients. However, the truth is, it’s not that common. If a patient is feeling worse, [and are experiencing] more pain, you really want to err on the side of a true progression, which is the truth the vast majority of the time. [At this time,] you want to deploy a VEGF TKI.
What are some clinical considerations for selecting an IO/IO or IO/TKI combination?
At the 5-year mark, which for a lot of patients becomes more important because they want to think about the potential of being cured, it’s approximately 30% of patients who have not progressed, double, roughly, of what you would expect with the IO/TKI combination. The long-term outcome tends to be better. [Those are] the two [aspects] people have to consider when they engage with upfront immunotherapy. We saw a data set [during] the 2025 Genitourinary (GU) Cancers Symposium, where we got the long-term follow-up for cabozantinib/nivolumab. For lenvatinib/pembrolizumab, we unfortunately only have 4 years of follow-up.. With IO/IO nivolumab, we now have follow-up data for 99-plus months. In fact, the follow-up revealed that if you evaluate the favorable-risk group for which normally, none of the regimens have shown an overall survival [OS] benefit, we saw a separation of the OS curve in favor of patients getting treatment on IO/IO vs a single-agent TKI. That has affirmed our conviction that we can offer IO/IO to favorable-risk patients. These are all important data sets. It took us a while to get it, and it was never directly compared. [Nevertheless,] that’s what I would take away from it [in order to] discuss the data with my patients.
Is there an understanding of which population of patients are long-term responders who receive TKI/IO, and, consequently, upfront responders to IO/IO?
We don’t know [this] before we treat [the patient], but in the early treatment phase, we may get a hint of that. Patients who respond on the first scan or later, or who have tumor shrinkage on the first scan and [patients] feel better, then that is very favorable. The homogenous response is often misunderstood. When you combine immunotherapy with a VEGF TKI, you typically see shrinkage across all lesions. However, if the immunotherapy was also affecting all lesions, or if lesions 2 and 3 were affected by the VEGF TKI and there was no immune effect, you would see [greater shrinkage] when you use pure immunotherapy, and you get a sense of tumor heterogeneity.
[Additionally, we wonder if] the immune system is going after all of the lesions, or if we can only see [it affecting] a few. These are all issues that can have an impact on long-term outcomes. It also affords the opportunity to target those lesions. If 9 out of 10 lesions are shrinking, why not radiate the tenth one, or cut it out? Or, if you treated a patient who has the primary tumor in place, and all of the metastatic disease sites are shrinking, but the primary tumor is unchallenged, maybe even growing, then you certainly are encouraged to consolidate. The most important part is that the distant metastatic disease responds. The primary tumor doesn’t always [respond] in the majority of its bulk and doesn’t necessarily reflect the metastatic disease burden. [It wants to] be a small clone out of the large primary tumor that remains and try to conquer the patient’s body. [In my practice, I look for] early responses, homogenous responses, and then if [I don’t observe any] progressive events for 2 years, I stop [treatment]. This is a good situation where most of the patients are potentially cured if you get these deep, homogenous responses, and they don’t progress, which is good news.