TKI and Immunotherapy Combo Efforts in RCC Remain of Interest as Treatment Arsenal Evolves

Final outcomes from the phase 1b/2 Study 111/KEYNOTE-146 trial (NCT02501096), evaluating treatment withlenvatinib (Lenvima) and pembrolizumab (Keytruda) in patients with advanced renal cell carcinoma (RCC) has sparked interest in the use of this combination, according to Chung-Han Lee, MD, PhD, specifically in patients previously treated with immune checkpoint inhibitors (ICI), as well as those who are ICI-naïve.

Data presented at the 2023 Kidney Cancer Research Summit (KCRS) demonstrated that treatment-naïve patients who received the investigational combination (n = 22) achieved an objective response rate (ORR) of 77.5% (95% CI, 54.6%-82.2%) with a median duration of response (DOR) of 24.2 months (95% CI, 10.3-40.4). Previously treated patients who presented as ICI-naïve (n = 17) saw an ORR of 52.9% (95% CI, 27.8%-77.0%) and those who were ICI-pretreated (n = 104) experienced an ORR of 58.7% (95% CI, 48.6%-60.2%). Furthermore, the median DOR was 9.0 months (95% CI, 3.5-not estimable) and 14.1 months (95% CI, 10.6-18.4), respectively.¹

“The takeaway is that this remains a highly active regimen. There is uncertainty about whether or not to continue ICI [therapy] in this setting, so it remains a topic of active research,” Lee explained at the KCRS event in an interview with OncLive^®. “We have to get more data to give firm recommendations.”

In the interview, Lee expanded on findings from the phase 1b/2 study in patients with advanced RCC, highlighted the rationale for conducting this research and the impact that these results have had on the treatment armamentarium thus far, and touched on next steps for patients in this space in terms of combining TKIs with immunotherapy.

Lee, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, also discussed the future directions for treating RCC and new developments that are underway.

OncLive: What was the rationale for combining lenvatinib with pembrolizumab in Study 111/KEYNOTE-146?

Lee: There are a lot of preclinical data that have demonstrated efficacy [with the use of] combination TKI and ICI. In 2015, we initially launched this phase 1b/2 clinical trial investigating this type of combination and it demonstrated high levels of efficacy within RCC and was later developed as the phase 3 [CLEAR] clinical trial [NCT02811861], which led to the regulatory approval [in 2021 for patients with advanced RCC].²

At that time, [oncologists] had amended this clinical trial to understand what the role of this type of TKI/immunotherapy combination would be for people who had progressed on an ICI. At that time, there were no data to guide us in terms of understanding what the role for that type of combination would be after that type of progression.

What were some of the key results from KEYNOTE-146 presented at the 2023 KCRS?

We presented the final analysis of the trial. From the last data cutoff, we now have 24 months of extended follow-up. We’re able to talk about what the long-term efficacy results would be and we demonstrated that within this population, patients who were treatment naïve [had] fairly long objective responses and good overall survival [OS] that mirrors what was initially seen in the phase 3 clinical trial.

More interestingly in the ICI-pretreated population, we had demonstrated an ORR north of 50% at our initial data cutoff, however, with more extended follow-up we were able to demonstrate that this is a population in which we can have durable responses.

Were any of the results surprising, especially keeping in light of findings from CONTACT-03 trial (NCT04338269)?

In CONTACT-03, investigators were looking to see what the role of continuing an ICI in [patients with advanced RCC who previously received an ICI] is. With a PD-L1 inhibitor in combination with cabozantinib,the suggestion was that there didn’t seem to be any sort of additive benefit in that setting.

The combination [examined in KEYNOTE-146] was a completely different TKI, and a PD-1 inhibitor as opposed to a PD-L1 inhibitor. We demonstrated [that OS] was still longer than expected compared with historic controls.

Because of the trial design, we’re not equipped to answer the question of what role pembrolizumab played and whether there’s any interaction between the TKI and the immunotherapy. However, based off historic comparisons, we still demonstrated superior efficacy and durability of response.

What are the next steps in terms of combining TKIs with immunotherapy?

Right now, we’re trying to better understand the interaction between the TKI and immunotherapy. We’ve learned from CONTACT-03 that it’s not an automatic given that more therapy is going to be better. The underlying hypothesis that we would have to demonstrate [regarding] combination [therapy of] lenvatinib and plus pembrolizumab is that to continue pembrolizumab there needs to be some sort of positive interaction between the 2 molecules. Whether we’re able to demonstrate that preclinically or clinically is the next step.

What have been some of the most exciting developments in non-clear cell RCC?

Historically speaking, most trials have been developed for clear cell RCC and we have demonstrated efficacy using some of the clear cell regimens within non-clear cell disease. With the first-generation TKIs we saw a fairly attenuated efficacy; however, with more novel TKIs we start to see rates of response that more closely mirror what we see in patients with clear cell disease, especially with regimens such as cabozantinib plus nivolumab [Opdivo] or lenvatinib plus pembrolizumab.

In these regimens of second-generation TKIs and an ICI, we’re seeing outstanding results in the non-clear cell space that we haven’t seen in the past. It becomes a question of: to what degree do the populations that respond to these treatments overlap? Even though the initial look at the individual ORRs looks similar, there’s no reason to believe that those are fully overlapping populations. Working out the science to try to figure out how to prioritize patients from 1 regimen to another [will be important].

Another thing that has come out in the non-clear cell space is the [examination of] triplet therapy with cabozantinib plus ipilimumab [Yervoy] plus nivolumab. We saw that when you try to combine too many agents at the same time though, you don’t get the same degree of dose intensity and tradeoffs are often made. Granted, the follow-up is still quite short, so the jury remains out on whether adding a triplet up front leads to durability down the line.

[Additionally, research demonstrates] the need for randomized clinical trials. Non-clear cell disease is so heterogeneous that in order to make a comparison, we [can’t] just do a cross-trial comparison.

There are a lot of randomized clinical trials currently open and in development. Those trials are going to be necessary for us to demonstrate and prove superiority of any of the regimens, but beyond that, it’s going to help us isolate what populations truly respond and how those may overlap. Hopefully knowing that with greater certainty gives us the subset of patients that we have to work on in terms of developing novel biologic rationales and biologically targeted agents outside of what we use from the clear cell side.

References

1. Lee CH, Shah AY, Rao A, et al. Final database lock results of the phase 2 cohort of lenvatinib + pembrolizumab for progressive disease after a PD-1/PD-L1-containing therapy in metastatic clear cell renal cell carcinoma. Presented at: 2023 Kidney Cancer Research Summit; July 13-14, 2023; Boston, MA.
2. Choueiri TK, Albiges L, Tomczak P, et al. Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study. J Clin Oncol. 2023;41(suppl 17):LBA4500. doi:10.1200/JCO.2023.41.17_suppl.LBA4500

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