TKI/Immunotherapy Combos Lead Advances in mRCC, But Questions Remain

Chung-Han Lee, MD, PhD

Three immunotherapy combinations have transformed first-line treatment for patients with metastatic renal cell carcinoma (mRCC), yet questions remain on what the optimal strategy is for patients who progress on these regimens, explained Chung-Han (Joe) Lee, MD, PhD.

The combinations of pembrolizumab (Keytruda) and axitinib (Inlyta), as well as avelumab (Bavencio) and axitinib, are both approved for the frontline treatment of patients with advanced RCC. Moreover, the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) is also available as a frontline treatment for intermediate- and poor-risk patients with advanced RCC.

Yet, research surrounding approaches for patients who progress on these treatments is limited.

“‘What can we do to improve upon outcomes?’ We are in a space where there are limited data because there are drugs that did not exist in the space before. There is a lot of extrapolation that we have to do, so it is a very exciting time to be in kidney cancer and it is going to continue to rapidly evolve,” said Lee.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Lee, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed advancements in mRCC regarding combination regimens and ongoing questions of how to treat patients upon disease progression.

OncLive: What are the available treatment options for patients with mRCC?

Lee: Right now, for the treatment of patients with mRCC, there have predominantly been 3 classes of medications. One class of these medications target the blood vessels that feed the kidney cancer. The second class of medications work by altering the metabolism of kidney cancer with mTOR-targeting agents. The last class of medications are checkpoint inhibitors.

What other treatment options are available after patients progress on frontline therapy?

Historically speaking, in the second-line space, we have been using TKIs after [treatment with] other TKIs. In addition to cabozantinib (Cabometyx), we have considered using axitinib, which was also explored in a randomized trial. Since 2005, there was some interest with different combination therapies.

The combination of lenvatinib (Lenvima) plus everolimus (Afinitor) was approved following results of a randomized, phase II trial comparing [that combination] with each agent alone. The trial showed outstanding results with improvements in objective response rates, progression-free survival, and OS [with the combination].

Were there any surprising findings with that trial?

One surprise was the type of efficacy the investigators ended up seeing. There were combination therapies we were trying but very few medications can be combined. The combination of lenvatinib plus everolimus became one of the first combination regimens that not only showed greater efficacy, but also tolerability. Since then, we now have various combinations that we use—mainly with both immune checkpoint inhibitors and TKIs.

What combination regimens with immunotherapy/TKIs have been beneficial in mRCC?

There is a lot of interest in evaluating some of the medications or approaches that are being used in the first-line space, or even in earlier lines of therapy.

Right now, the data are very limited. For example, there was a combination of lenvatinib plus pembrolizumab (Keytruda). That is the only perspective that we have for TKIs and immunotherapy combinations after progression on checkpoint inhibitors. Based on our initial analysis, it does seem to be an active regimen. The combination of lenvatinib plus pembrolizumab is not FDA approved, but the results are very encouraging. Hopefully, that will be added to the list of medications that are available for our patients with metastatic disease.

What is being done for patients who have progressed on immunotherapy?

Concerns have been raised on whether or not you have [gone] through 2 lines of therapy at the same time when you use a combination of a TKI and a checkpoint inhibitor. [There are also the questions of] whether there is an interaction between the medications. Will it be additive or detrimental? Would make sense to start with a monotherapy rather a combination?

One of the things we always looked at was, in terms of retrospective studies, whether or not TKIs are effective after TKI/immunotherapy combinations and whether we are maintaining efficacy afterward.

In the retrospective studies, the activity seems to be a bit higher than what we would have seen in the prospective studies. However, there is a lot of caveat to whether or not that is a matter of patient selection or if there is some sort of residual effect of the prior immunotherapy that is maintained. Those are very speculative and require actual data and perspective validation to get a better sense of what might be the case.

What other approaches are being explored in patients who progress on a TKI/immunotherapy combination?

When we think about this type of approach, we have established many different TKIs that are now FDA approved. The direction of the field is trying these types of approaches and expanding upon potential treatments. There has been some interest in establishing new pathways, such as HIF-2 inhibitors or metabolic inhibitors. These are promising things that are expanding beyond the typical approaches for RCC.

What are some of the challenges when choosing the optimal treatment for these patients?

When I approach this in clinical practice, there are multiple things I take into account. First, [I evaluate] what drugs the patient already received and what data, either prospective or retrospective, are available to back up this treatment choice.

Clinical decision making is critical because it is the evaluation of performance status, the intangibles of their support system, and if we believe they are going to be able to manage potential toxicities. We are looking to maximize patient survival.

What is your take-home message?

We are entering a new space. With the movement of immunotherapies into the frontline setting, there are a lot of things that we do not yet understand. A lot of the data that we have are in immunotherapy-naïve patients. How this changes the space remains unknown and a lot of research has gone into looking at how to salvage patients who are immunotherapy refractory.