Novel Immunotherapy-Based Combinations Prompt Key Treatment Considerations in RCC

Bradley McGregor, MD

Disease factors, such as risk of progression and patient preference can help inform treatment decisions between immunotherapy-based combinations such as nivolumab (Opdivo) plus ipilimumab (Yervoy) or nivolumab plus cabozantinib (Cabometyx) in the frontline setting for patients with advanced renal cell carcinoma (RCC), according to Bradley McGregor, MD. He added that the hallmark sustained treatment-free interval and short-term disease control associated with each approach, respectively, may be key in determining which regimen to pursue.

“It comes down to these discussions with patients. At the International Kidney Cancer Symposium we will probably be discussing which regimens we use for each patient. It is a great discussion to have because we do have many good options and, ultimately, you cannot make a wrong decision, provided that you have that informed discussion with the patient,” McGregor explained.

In an interview with OncLive^® preceding the 2022 International Kidney Cancer Symposium, McGregor discussed the factors that affect frontline treatment decisions for patients with advanced RCC, the importance of longer-term follow-up of phase 3 trials in kidney cancer, and the benefits of dual immunotherapy and immunotherapy/TKI treatment combinations. McGregor is a senior physician and the clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and an instructor in medicine at Harvard Medical School in Boston, Massachusetts.

OncLive^®: What are you looking forward to at this year’s International Kidney Cancer Symposium?

McGregor: I am looking forward to getting together with other researchers who are focused on improving outcomes of patients with kidney cancer. The International Kidney Cancer Symposium offers a nice interdisciplinary opportunity for surgeons, radiation oncologists, and medical oncologists to get together and learn more about the latest advances in kidney cancer research.

What will be the significance of updated, longer-term data from some of the pivotal phase 3 trials in RCC?

Ultimately, we are getting longer follow-up for many different combinations. Since the dual immunotherapy combination of nivolumab plus ipilimumab has some of the longest follow-up, we are going to see data presented on quality of life and treatment-free intervals.

We also will see extended follow-up for different TKI/immunotherapy [combinations], such as pembrolizumab [Keytruda] plus axitinib [Inyta], and cabozantinib plus nivolumab.

With continued follow-up for lenvatinib [Lenvima] plus pembrolizumab [from the phase 3 CLEAR trial (NCT02811861)], we found that the combination remains superior in terms of progression-free survival [PFS] with an overall survival [OS] benefit. The median OS has not yet been reached.

Continued follow-up will be important. Ultimately, what we want to know is if immunotherapy/TKI combinations lead to that tail to the [OS] curve. We are still not quite sure. Although we have long follow-up, we still need longer follow-up to get that definitive answer.

In addition to analyzing long-term follow-up, investigators have evaluated the effect of subsequent therapies in patients with advanced RCC who received lenvatinib plus pembrolizumab on the CLEAR trial. Why is this information important?

Although an immunotherapy and TKI doublet is superior to a TKI [alone], there is the question: [If a patient receives] a TKI and is guaranteed [a subsequent] immunotherapy, would patients do just as well? One of the things that we need to do to try to answer that question is look at the progression on next line of therapy [PFS2] and the impact of subsequent therapies. We presented this data at the 2022 ASCO Annual Meeting, and we showed that the PFS2 was superior with lenvatinib/pembrolizumab over sunitinib [Sutent].

Another study to note is the LITESPARK-011 trial (NCT04586231) with belzutifan (Welireg) plus lenvatinib vs cabozantinib. What data support the evaluation of belzutifan in the refractory setting?

This combination is being evaluated in the second-line setting. [LITESPARK-011] includes patients who have progressed on an immunotherapy-based therapy and [is exploring] what could be the best approach for the next line of therapy.

Belzutifan is an intriguing drug. It a HIF2α inhibitor that had some activity as a monotherapy in the phase 1 [LITESPARK-001] trial [NCT02974738], and we look forward to phase 3 data. However, belzutifan seems to be a good partner agent. We have already seen data presented for cabozantinib plus belzutifan in the treatment refractory setting [in the phase 2 LITESPARK-003 trial (NCT03634540)] with impressive responses with [short] follow-up, and impressive toxicity. [The LITESPARK-011 trial] is taking the next step. Can we add belzutifanto a TKI—in this case, lenvatinib—and will that be superior to cabozantinib? That is an intriguing question.

How has the phase 3 COSMIC-313 trial (NCT03937219) affected how we think about the treatment landscape?

COSMIC-313 evaluated combination therapy in the frontline setting. In the frontline setting, we have this big debate of dual immunotherapy vs immunotherapy/TKI [combinations]. Which is better? With dual immunotherapy, it seems like we have a tail on the [OS] curve, but we still see progressive disease as a best response in up to 20% of patients. Are we not getting patients to that durable response? COSMIC-313 evaluated nivolumab and ipilimumab as a backbone in those patients with intermediate- or poor-risk disease. By adding cabozantinib to that doublet, can we limit progressive disease as best response and maybe cure more patients?

Results [from COSMIC-313] presented at the 2022 ESMO Congress [showed] that the trial did meet its primary end point of PFS. Progressive disease as best response was decreased with the triplet, and there was an improvement in PFS, albeit at the cost of some significant liver toxicities. We need longer-term follow-up from COSMIC-313 to determine the exact role of the triplet, because to date, no OS data have been reported.

With so many new combinations in the frontline and refractory settings, what is important to keep in mind when it comes to treatment selection?

Ultimately, it comes down to a discussion with the patient. We are in a situation where we have an embarrassment of riches in the frontline setting. We must think about each option and talk with the patient. To that extent, when we have all these different combinations that are acceptable, patient considerations, [such as] how often they have to visit the doctor or what their insurance copay will be, will certainly come into play.

Overall, we have nivolumab and ipilimumab with a 40% objective response rate, but a 20% rate of progressive disease. However, there seems to be that tail to the [OS] curve where we get this treatment-free interval. Immunotherapy/TKI combinations have a much higher response rate, up to 70% with lenvatinab plus pembrolizumab. Moreover, there is a less than 10% rate of progressive disease as best response. However, we are not sure about that tail to the [OS] curve.

It comes down to discussion with the patient. Do we need to focus on the now, where it is a situation where if we do not get a good response in the initial couple months, the patient is going to become sicker and not be able to get a second therapy? If that is the case, you need to think about an immunotherapy/TKI approach because the chance for disease control in the short term is undoubtedly higher. However, if there is a situation where a patient needs treatment and if they were to progress, they could still be ok, then maybe in that situation, you can think about the long term with nivolumab/ipilimumab.