Immunotherapy Plus TKI Regimens Appear Promising for Patients With Renal Cell Carcinoma

Chung-Han (Joe) Lee, MD, PhD

A landmark treatment option for patients with renal cell carcinoma (RCC) had been sunitinib (Sutent), which was the mainstay for a long time until it was challenged by new and emerging targeted therapies, as well as more immunotherapeutic approaches. Now, the treatment landscape is enriched with combination regimens and the potential for more agents under development.

Cabozantinib (Cabometyx) received approval years ago for the treatment of advanced patients with RCC, and the landscape was quickly joined later in 2018 with the approval of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) as treatment of patients with intermediate- and poor-risk RCC in the frontline setting.

The combination of checkpoint inhibitor pembrolizumab (Keytruda) plus axitinib (Inlyta) further built onto this growing armamentarium with approval for the frontline treatment of patients with advanced RCC. Axitinib received an additional approval in 2019, as well, in combination with avelumab (Bavencio) for the frontline treatment of advanced RCC.

These regimens have been demonstrating promise in the treatment landscape since their approval over the last few years, but they have also paved the way for future research. One of these potential regimens includes the combination of an immunotherapy agent with a tyrosine kinase inhibitor (TKI), pembrolizumab and lenvatinib (Lenvima).

In an interview with Targeted Oncology, Chung-Han (Joe) Lee, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discussed the use of different targeted therapy and immunotherapy strategies for the treatment of patients with metastatic kidney cancer.

TARGETED ONCOLOGY: What is the rationale for combining pembrolizumab with lenvatinib?

Lee: Right now, the standard of care for metastatic kidney cancer in the first-line setting is looking at combinations of TKIs and immunotherapy agents or dual inhibition with 2 immune checkpoint inhibitors. However, what we don't have, despite the outstanding efficacy of these combinations in the first-line setting, is prospective data about regimens after people have progression on immune checkpoint inhibitors.

This study was a single-arm phase 2 study of the combination of lenvatinib plus pembrolizumab in patients who had previously progressed on an immune checkpoint inhibitor. It's providing the first prospective data for looking at a TKI/immunotherapy combination.

TARGETED ONCOLOGY: Could you discuss the potential controversy with giving PD-L1 blockade after failure in the first-line setting?

Lee: There is a lot of controversy about whether or not the addition of an immune checkpoint inhibitor after prior a immune checkpoint inhibitor is either necessary or effective. Especially in patients who have previously progressed, it's difficult to know whether or not continuation of the checkpoint inhibitor is necessary or whether or not when we use these things in combination, it represents just the activity of a single agent TKI, for example.

TARGETED ONCOLOGY: What were the results from this study?

Lee: We enrolled approximately 104 patients who had previously progressed on at least 1 immune checkpoint inhibitor, and progression of disease was defined as having at least 2 doses of immune checkpoint inhibitor, followed by evidence of radiographic progression that was either confirmed or in the presence of rapid clinical worsening. In this study, we had noted that the combination of lenvatinib plus pembrolizumab was associated with an objective response rate of approximately 58% by not only investigator review but 53% by independent radiographic review as well. The median progression-free survival that we saw was approximately 11.8 months, and we saw similar results across multiple risk categories.

TARGETED ONCOLOGY: What are the implications of these data?

Lee: These data represent our first prospective data looking at the TKI/immunotherapy combination in the post-immune checkpoint inhibitor refractory state. Most of the prior studies that have been done previously have all been retrospective looks at what these combinations are, and retrospective looks at single-agent TKIs. It certainly exciting to finally have prospective data looking at efficacy in the setting.

TARGETED ONCOLOGY: What is the potential role for this combination?

Lee: Based on this study, and the overall treatment landscape, we see very high activities of lenvatinib plus pembrolizumab, not only in this setting, but at least based on press releases, it does seem like even the phase 3 in the first-line setting appears to be positive. This reinforces the evidence of efficacy of this compound, not only in the first-line setting, but also in the checkpoint inhibitor-refractory setting. We are hopeful that after we get a chance to look more closely and have other reviewers look at the data that this would lead to subsequent regulatory approval of this combination.

TARGETED ONCOLOGY: What other regimens are appearing promising now in the research for this patient population?

Lee: In terms of looking at the TKI/immunotherapy combinations or immunotherapy-containing regimens for RCC, the 2 main approaches in the first-line setting is either using dual immune checkpoint inhibitors such as the combination of ipilimumab plus nivolumab or using a TKI/immunotherapy combination to date, there have not yet been head to head trials comparing these 2 types of approaches. In terms of which approach to take often relies on clinical data and the goals of the patient.

When we talk about TKI/immunotherapy combinations, there does appear to be a higher objective response rate. The median progression-free survival does appear to be longer. However, with longer follow -p that has been seen within trials like CheckMate-214. We know that in immunotherapy-immunotherapy combinations such as the combination of the ipilimumab plus pembrolizumab, there does appear to be a durable response in about a third of patients. Given the overall different clinical scenarios, oncologists do have to make a decision about whether or not they're prioritizing the front part of the PFS curve or the backend of the curves and thinking about responses in terms of the different immunotherapy and TKI combinations. There are multiple regimens that are currently FDA-approved, 2 of which involve the combination of axitinib with either a PD-1 or PD-L1 agent, so axitinib plus pembrolizumab or axitinib plus avelumab, both of which have received regulatory approval.

The combination of cabozantinib plus nivolumab demonstrated improvements in the ORR, PFS, and OS compared to sunitinib in the CheckMate-9ER study, which was reported recently at ESMO this year. That combination is not yet FDA-approved. However, given these encouraging findings, we certainly would expect or hope that this would obtain regulatory approval.

Another combination that has completed its phase 3 and at least reported initial results is the combination of lenvatinib plus pembrolizumab in the first-line space in the CLEAR study. This was a 3-arm clinical trial looking at the combination of lenvatinib plus pembrolizumab versus lenvatinib plus everolimus versus sunitinib as the control arm. Per the press release, it seems to have met its primary end point of OS, PFS, and ORR. However, the details of these responses are not yet available, and we certainly eagerly await the opportunity to finally see these results.

TARGETED ONCOLOGY: Following progression on an immunotherapy/TKI regimen, what treatment is appropriate in this setting.

Lee: Currently, after progression on an immunotherapy/TKI combination, we often do use subsequent therapy with FDA-approved regimens, and this includes a TKI that the patients have not previously been exposed to, and the other thing that can be considered is using a TKI plus mTOR combination, such as lenvatinib plus everolimus. There are certain circumstances in which you may even consider doing a dual immune checkpoint inhibitor with the combination of ipilimumab and nivolumab. We do have some phase 2 data showing the activity of that regimen.

TARGETED ONCOLOGY: What are your final thoughts?

Lee: We are living in a very exciting time in terms of RCC, especially with 2 positive studies looking at TKI/immunotherapy combinations that have led to regulatory approval, and 2 positive studies that have been reported are still pending further evaluation. This does open up a lot of opportunities for patients, and given multiple regimens that are showing improvements in overall survival, I think that this is a very encouraging time for RCC. As the data continue develop, we are moving closer and closer to having improved outcomes for our patients.