Combination Improves Responses in RCC After Progression on Immune Checkpoint Inhibitor

Chung-Han Lee, MD, PhD

The combination of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) demonstrated a high objective response rate (ORR) as treatment of patients with clear cell renal cell carcinoma (RCC) who progressed on prior treatment with an immune checkpoint inhibitor, according to findings from a phase 2 study (NCT02501096).

The ORR by immune-related RECIST criteria was 55% and 52% by RECIST v1.1. The median duration of response was about 10 months, and most patients remained on treatment at the time of data cutoff. This trial is particularly promising in this space as many patients who are treated with an immune checkpoint inhibitor, such as the approved regimens of axitinib (Inlyta) plus avelumab or pembrolizumab, or the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy), will eventually progress.

The median progression-free survival (PFS) was 11.7 months in this study with the combination regimen, and 45% of the population remained progression-free at 12 months. There were no new safety signals with the combination regimen as well.

In an interview with Targeted Oncology, Chung-Han Lee, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discussed the findings from the phase 2 study of pembrolizumab plus lenvatinib in patients with metastatic clear cell RCC who have progressed on prior immune checkpoint inhibitor therapy.

TARGETED ONCOLOGY: What was the rationale for conducting this trial?

Lee: Right now, we have been seeing this trend as we've been adapting the types of treatments that we use for kidney cancer. Historically, we had always used a single agent TKI for the management of disease, but in the last couple years, we've seen the introduction of immune checkpoint inhibitors. Now we have a lot of things that are building upon an immune checkpoint inhibitor backbone, so either the combination of anti-CTLA4 with the nivolumab plus ipilimumab combination, or the FDA approval of axitinib and avelumab or axitinib/pembrolizumab. However, even though we've seen great improvement with those regimens, we still do see people progress. What this study was looking at is whether or not the combination of lenvatinib plus pembrolizumab, a TKI-immunotherapy combination, could help salvage people after they've progressed on prior checkpoint inhibitors.

TARGETED ONCOLOGY: How was this phase 2 trial designed, and what were the goals of this study?

Lee: This phase 2 trial is an open-label multicenter trial of the combination of lenvatinib plus pembrolizumab in patients who had previously progressed on an immune checkpoint inhibitor, so this represents the first prospective study that has been done looking at a TKI-immunotherapy combination in people who progress after an immune checkpoint inhibitor.

For this combination of drugs, we initially had studied it in the phase 2 setting for people who are immune checkpoint inhibitor-naive and saw increasing high efficacy results, with a high ORR of about 70% and a median PFS of about 20%. We were very interested in seeing whether this type of combination is still very effective in people who progress on a checkpoint inhibitor.

TARGETED ONCOLOGY: What were the findings from this trial?

Lee: In this setting, we actually were able to demonstrate a high ORR of 55% by immune-related RECIST and 52% by RECIST 1.1. For those people who responded, the median duration of response was 12 months, with almost all or most of the people still remaining on treatment at the data cutoff point. For the entire population, we saw a median PFS of about 11.7 months with about 45% of the total population remaining progression-free at the 12-month time-point.

TARGETED ONCOLOGY: Speaking to the safety profile, is it in line with what we would normally expect from an immunotherapy and TKI combination?

Lee: When we do combinations of drugs, the expectations are that you're probably going to get side effects related from the TKI and side effects related from the immune checkpoint inhibitor, and that's essentially what we saw. There were no unexpected side effects, so there are no synergistic side effects that kind of arose out of this. From a safety profile standpoint, it was what we expected and very much in line with using these drugs in combination.

TARGETED ONCOLOGY: What are the next steps for this trial?

Lee: At least as of right now, lenvatinib plus pembrolizumab is not yet FDA-approved for the treatment of metastatic kidney cancer. There is an ongoing phase 3 study investigating the combination of lenvatinib plus pembrolizumab in the first-line setting, but we still do not yet know the results of that, as the analysis and follow-up are ongoing. However, given the high efficacy that's been seen in the past, we're all very optimistic about what that may end up showing. That, my guess, will likely be the registrational trial, and then this will add to the body of evidence supporting the use of this type of combination for metastatic kidney cancer.

TARGETED ONCOLOGY: How do you think this regimen will fall in line with the other combination regimens in RCC?

Lee: What we have to figure out is what the results of phase 3 are. Assuming that those look positive, a lot of that will be based on the characteristics, the PFS, the ORR, and the durability of response that we see with it. For our study, what we demonstrated was even high levels of efficacy, not necessarily in the first-line setting, but if we had to use this in subsequent line settings, we also see high levels of efficacy. I think that from that standpoint, the comparisons are really to some of the other regimens, given that other regimens have only had retrospective data. Those types of comparisons are very challenging to make. However, you know, at least based off of the retrospective data from looking at single agent TKIs, this regimen certainly seems to be more efficacious

TARGETED ONCOLOGY: Is there anything else about this trial that you think is important to mention?

Lee: I think that the most important thing right now is sequencing, which is a very, very interesting question. There's a lot of research going into it, and I think that we're still in the point about learning more about these medications and what we can do to better treat patients and optimize their outcomes, as well as really trying to stratify patients to optimal approaches. This is really within the larger body of work, and that's certainly going to be incredibly important.