Individualized Approach Best Informs Choice of Frontline Immunotherapy or Targeted Therapy Combinations Across RCC Histologies

Benjamin Garmezy, MD

The evolving landscape of immunotherapy and targeted therapy combinations in renal cell carcinoma (RCC) reflects the need for a personalized approach to therapy, according to Benjamin Garmezy, MD, who added that considering key tumor features, patient preferences, and potential toxicities when selecting among current options is key to optimizing treatment outcomes.

“Overall, all [3 available] IO [immuno-oncology]-TKI [tyrosine kinase inhibitor] regimens are reasonable for frontline use in a patient with clear cell RCC,” said Garmezy, who is a medical oncologist and the assistant director of Genitourinary Research at Sarah Cannon Research Institute at Tennessee Oncology in Nashville. “Until we learn more about how to select patients for immunotherapy [alone] vs IO/TKI, it’s [often up to] patient preference and understanding what the patient needs.”

In an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on prostate cancer/RCC, Garmezy discussed challenges associated with navigating the current frontline armamentarium in both clear cell and variant RCC, the impact of frontline IO doublets and IO/TKI regimens on patient outcomes, and the importance of ongoing combination studies for patients with variant RCC.

OncLive: What are some difficulties faced when selecting between current frontline treatment options in RCC?

Garmezy: The key question is: How do we identify patients [with clear cell disease] in the frontline [setting] for an immunotherapy doublet with a PD-1 inhibitor and a CTLA-4 inhibitor such as ipilimumab [Yervoy] and nivolumab [Opdivo], vs a PD-1 inhibitor in combination with a VEGF TKI. Sarcomatoid features are reasons to choose an immunotherapy doublet. [Additionally, immunotherapy doublets may be considered for] a young patient who doesn’t need a rapid response and wants to swing for the fences for that durability that we may see slightly increased with these doublets. Patients who need an IO/TKI [regimen] are the patients [for whom] having a response is the most important factor. For most patients who don’t have sarcomatoid features, I’ve transitioned my practice towards giving more IO/TKI combinations.

How do you navigate the current landscape of IO/TKI regimens for patients with clear cell RCC?

Choosing which of those [combinations] is best is complicated, and there are a lot more similarities than differences [between approved options]. If you don’t want to use them all that’s okay, but I recommend using 1 of the combinations to get familiar with the toxicity, how to [approach] dose reductions, how to [implement] dose interruptions, and how to keep patients on therapy.

The 3 regimens that are approved are pembrolizumab [Keytruda] and axitinib [Inlyta], pembrolizumab and lenvatinib [Lenvima], and cabozantinib [Cabometyx] and nivolumab. Axitinib is a more selective VEGF TKI, and lenvatinib and cabozantinib are more multi-targeted TKIs. Though, they all hit different targets when you look at the data and the chemistry of how they were developed. There are some nuances. Less selective VEGF TKIs may interact better with the immune system, [although we don’t know that for certain]. [Conversely], axitinib’s half-life is much shorter than [that of] cabozantinib and lenvatinib. 

The highest response rates [have been seen with] pembrolizumab and lenvatinib, but this was in a different trial population with more favorable-risk patients than those who received cabozantinib and nivolumab. We must keep in mind that cross-study comparisons can be difficult [and should be interpreted with caution].

What factors influence treatment selection for patients with variant RCC?

When we move to the variant space, things get a little bit more complicated because our evidence [does not] support any one indication or any one trial [as strongly]. Cabozantinib and nivolumab looks interesting in patients with papillary [disease] based on some early phase data we have but may be less interesting in some of the other variant diseases. We don’t have as much data with pembrolizumab and axitinib, and we know that the immunotherapy doublets also don’t have high response rates [in this population]. Then we look at pembrolizumab and lenvatinib, which also seems to work well in patients with papillary disease as well as other variants. In patients with chromophobe disease, response rates in a small sample size were 28% [with this combination]. That could challenge early phase data for lenvatinib plus everolimus [Afinitor]. Realistically, [for] patients with papillary disease pembrolizumab plus lenvatinib, cabozantinib alone, or cabozantinib plus nivolumab, are all reasonable options. In patients with chromophobe disease, lenvatinib plus everolimus or pembrolizumab and lenvatinib are reasonable. In these other variants that we know even less about, I’ve shifted my practice to pembrolizumab and lenvatinib until we see more data.

How have frontline combination regimens changed both patient outcomes and experience in RCC?

What we’ve argued about with the IO/TKI combinations is whether we can have patients who stop therapy when they go on an IO/TKI [regimen]. We’re seeing median progression-free survival rates close to the 2-year mark. We are seeing patients at the tail end of a curve where we can take them off therapy at 2 years and watch them, knowing that some of those patients may recur. Many patients are still alive on an IO/TKI [regimen after 3 years of treatment]. [Although we are] still struggling on the cure rate, we do think we cure some of these patients and we’re trying to increase that [percentage]. It is overall a very treatable and manageable disease. When we compare [the durability of response with IO/TKIs] with sunitinib [Sutent], which was the control arm in all 4 of these studies, patients are doing a lot better, they’re living longer, and they’re living better.

These are great regimens. Very few patients have primary progressive disease on the IO/TKI [regimens]. These patients do well, and they often [show] a response [on] that first set of scans, which is so anxiety-provoking for a provider as well as a patient. If you start them on one of these 3 regimens, chances are [higher that] you’re providing good news at that visit. That helps establish that patient-provider relationship and decreases patients’ anxiety [by showing] that they’re managing this disease, and they can start to move forward and adjust to their new normal. We don’t talk enough about [how] having that initial positivity and optimism at that first scan can set a patient up for success as to how they view and psychologically approach their disease.

In what scenarios would you select a given IO/TKI regimen for patients with RCC?

This [decision] can be challenging. I do things in a way that I might not recommend the average community doctor do, because you must have a lot of patients with RCC.

If you’re worried about how a patient might react to the drug and about having to determine if toxicities [are associated with] immunotherapy or the TKI, that might be a good time to use axitinib. For example, if I have a patient with a remote history of some rheumatologic issue and I’m nervous about the checkpoint inhibitor, but I don’t want to deprive that patient of a checkpoint inhibitor because that’s the best chance of getting [a durable response], then I choose pembrolizumab and axitinib. I can [stop administering] axitinib if they develop the toxicity, and I can find out if it’s an immune-related or VEGF TKI–related toxicity.

For young patients who aren’t candidates for surgery and need a rapid response, I’m giving them pembrolizumab and lenvatinib if I think they can handle lenvatinib at 20 mg. The response rates [with that combination] are very high, probably because that dose of lenvatinib is very high. It’s not comparable to cabozantinib at 40 mg, which we see in the other approval. The other patients I treat are getting cabozantinib and nivolumab. [This regimen] has quality of life data showing that it is less toxic than sunitinib. Cabozantinib plus nivolumab is my default regimen outside of those other options. When I break it down, I find myself using all 4 regimens relatively equally.