Lenvatinib Plus Everolimus Induces Responses in Rare RCC Population


In an interview with Targeted Oncology, Thomas E. Hutson, DO, PharmD, discussed the difficult-to-treat nccRCC patient population and the promise of lenvatinib plus everolimus, as well as other combination regimens.

Thomas E. Hutson, DO, PharmD

The responsibility of treating non-clear cell renal cell carcinoma (nccRCC) is said to be a challenging task for oncologists, as the disease is rare, and no therapies have been developed specifically for this group of patients. In fact, many of the agents utilized to treat nccRCC were developed to treat clear cell disease.

In a joint cancer center effort, 31 patients with nccRCC were enrolled in a phase 2 clinical trial of lenvatinib (Lenvima) plus everolimus (Afinitor; NCT02915783) and assessed for the primary end point of objective response rate (ORR). Results presented during the 2020 International Kidney Cancer Symposium (IKCS) showed clinical activity in patients with nccRCC, which notably was most impressive in patients with chromophobe histologies.

Overall, the ORR observed was 25.8% (95% CI, 11.9%-44.6%), the clinical benefit rate of the combination was 61.3% (95% CI, 42.2-78.2), and the disease control rate was 3.9% (95% CI, 66.3-94.5). Lenvatinib plus everolimus also led to reductions in tumor size from baseline in most patients.

The safety of each agent appeared similar to that observed in prior studies with either drug alone.

In an interview with Targeted Oncology, Thomas E. Hutson, DO, PharmD, director of the Urologic Oncology Program and co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center, discussed the difficult-to-treat nccRCC patient population and the promise of lenvatinib plus everolimus, as well as other combination regimens.

TARGETED ONCOLOGY: Why is non-clear cell RCC a difficult to treat population?

Hutson: nccRCC is difficult to treat because it's encompasses a population of patients that aren't very common, and we know the least about them in regard to the biology and natural history of the disease. All of the therapies that we use in the normal treatment paradigm for kidney cancer have been developed in clear cell RCC.

Based upon improved understanding of the biology of the disease which we know from 1990s research, the recognition of the von Hippel Lindau gene mutation is the most common abnormality both in hereditary and sporadic, clear cell RCC. It leads to the ability to understand exactly what that mutation resulted in. We know that downstream from that mutation is an increase in HIF and an increase in angiogenic factors such as VEGF. Therefore, we target that VEGF receptor to inhibit angiogenesis, and we produced a result that that whole mechanism has not seen. That's not a mutation that is seen in the nccRCC histology, which represents a diverse collection of specific entities that have their own genetic abnormalities, their own natural histories, and their own responses to therapies, for instance.

TARGETED ONCOLOGY: What is the current role of lenvatinib in the general landscape of renal cell carcinoma?

Hutson: Lenvatinib being a multi-targeted, newer generation tyrosine kinase inhibitor (TKI) has an established early role in the management of RCC now, and we expect that role to continue to increase, as this agent has proven to be combinable with other therapies such as immunotherapies. For instance, there is a study that recently reported that lenvatinib in combination with pembrolizumab was positive on its 3 efficacy end points. We don't know the specifics yet. [The results] from that that will come out in a future meeting, but this is encouraging because it is telling us the lenvatinib, as a newer generation multi-targeted TKI, is combinable with a checkpoint inhibitor.

Based upon that, lenvatinib is going to have a future rule likely as initial therapy in

combination with checkpoint inhibitors.

Currently, lenvatinib is approved in combination with everolimus as a second line and beyond therapy based on a phase 2 study that was led by Robert Motzer, and I was also involved in [this as well]. In the study, we saw significant levels of activity with the combination when compared to single-agent everolimus, which was chosen as an appropriate comparative in the refractory setting. In fact, the study showed progression-free survival improvement, a good efficacy rate, and at least hints at overall survival.

The combination is approved in the United States, and now it's getting approved throughout the world as a therapy to use in the second-line setting and beyond. It sits there with 2 other major therapies that are newer generation therapies. These therapies are cabozantinib (Cabometyx) and nivolumab (Opdivo).

The 2020 goal for all of us when we treat a patient with clear cell kidney cancer is to make sure that these patients in the first few lines of therapy good access to these three types of drugs because these 3 kinds of drugs are superior that those will begin a checkpoint inhibitor.

TARGETED ONCOLOGY: Can you provide background on the how the combination of lenvatinib and everolimus can about? What was the rationale for this combination in RCC?

Hutson: Across the board, there has been a willingness to combine active agents in kidney cancer. We are taught that 1 of the ways for drug development is to use a regimen. In fact, that thought that just 1 drug is going to have a Gleevec effect and just dramatically improve outcomes is unlikely for most cancers. One of the goals is to combine agents with different mechanisms of action that hopefully do not have overlapping toxicities. The thought would be that you take these 2 agents, and you have a scenario where they show synergy.

In kidney cancer, we tried this with a variety of our older generation agents. The 2 active pathways that we had at the time were the mTOR pathway, and we the VEGF pathway. It seemed like the combinations of the 2 were toxic without much gain. Naturally, we then thought about whether we could combine a newer-generation drug to create synergy. That was on concept for this study.

The other reason was that there's some basic science research to suggests that there is a positive interaction when one inhibits the FGF pathway in VEGF with lenvatinib and using an mTOR inhibitor. With the mToR inhibitors, it is difficult to pinpoint the exactmechanism of action in kidney cancer. We know that mTOR is ubiquitous and a pathway that is involving with normal cell homeostasis, glucose metabolism, protein translation, and in HIF production. There is a variety of mechanisms there. The thought was that a good way to attack would be to try to inhibit FGF, VEGF, and mTOR in all its pathways to get a positive interaction. When we studied this in the laboratory, it suggested that there indeed was synergy.

TARGETED ONCOLOGY: Can you discuss the recently presented phase 2 study of lenvatinib plus everolimus in non-clear cell RCC?

Hutson: The results were pretty significant. The overall blinded independent assessment and investigator assessment were very similar. We saw that the overall ORR is just under 26%. These 2 responses were all partial responses. When we looked at the individual classified subgroups, papillary, chromophobe, and the unclassified tumors, we saw in the papillary group, a 15% objective tumor response rate, which is greater than what historically has been published with older-generation drugs such as significant sunitinib and sorafenib, where the had objective to response rates were less than 10% .

Chromophobe tumors seemed to have a significant level of activity with the partial response rate of 44.4%. This is once again a dramatic level of response that is similar to what we see traditionally with clear cell RCC when one uses agents like sunitinib. Then, in the unclassified group, which had a limited number of patients, we saw a 50% response rate.

I think the take home point is that we saw a degree of activity at 26%, which puts it in the ballpark of some of the therapies that we use for clear cell. From that, differentially, we see that there are some subtypes of nccRCC that do exceptionally well, such as the

Chromophobe tumor.

TARGETED ONCOLOGY: What can be concluded from these data?

Hutson: Overall, we felt that the degree of activity of lenvatinib andeverolimus place this newer combination as an active regimen greater than what we had historically seen with the older agents. As I mentioned before, this puts lenvatinib plus everolimus right there alongside two other treatments, cabozantinib and checkpoint inhibitors as being therapies with are demonstrating high levels of activityin clear cell and non-clear cell histologies. This suggests that those agents should be predominantly used earlier the treatment course. Also, with lenvatinib and everolimus, there is a greater level of activity among patients chromophobe tumors.

TARGETED ONCOLOGY: There were a significant number of dose interruptions and dose reductions observed in this study.Can you explain what was seen in the safety analysis and how toxicities were managed?

Hutson: Looking at the 5 most common treatment emergent adverse events (AEs), they were fatigue at 71%, diarrhea at just under 60%, reduced appetite at about 55%, nausea at 55%, and vomiting in 52%. This was any grade AEs. The bulk of the great toxicity is going to be the level of grade 1 to 2, which lends itself to modification and over the counter remedies.

It's the grade 3 or 4 AEs that generally require dose interruption or dose reduction and those events were far less than 10%.

In terms of treatment-emergent AEs that led to study drug dose adjustment, we saw a dose reduction in 45% of patients, and interruption in 67% of patients. Despite having that much need to interrupt dosing or lower the dose, 2 out of 3 patients were still able to stay on therapy. We saw a withdrawal or discontinuation rate of about 30%. Although this is a higher need to adjust in order to manage toxicities, doing so allowed a significant number of patients to remain on treatment and continue to benefit.

TARGETED ONCOLOGY: Can you explain why were new starting doses explored?

Hutson: In another analysis, they looked at both 18 mg and 14 mg starting doses of lenvatinib with the everolimus dosage still at 5 mg. This was done with the understanding that you don’t have to start at the high dose, especially with a drug that required dose interruptions in over 50% of patients. It has been the dogma that we use with all of our treatments to start with the higher dose and reduce as we need to. What the analysis ultimately found was that there is really no advantage to starting at a lower dose. In fact, to get the greater efficacy, it appears that the higher dose is needed.

[Oncologists] can consider going in a 14 mg dose but would being doing so with the understanding that they may compromise some efficacy. In clinical practice, we do this for patients who are frail and for whom we are concerned about tolerance. Even in that situation, [oncologists] have to understand that if you start the patient on the 14 mg dose, you need to try to go up to 18 mg.

TARGETED ONCOLOGY: What does the future look like for lenvatinib and other agents being explored in the RCC landscape?

Hutson: I think that's the excitement. There are 2 broad areas of excitement. One is the development of regimen that provides a chance of synergy to the level that the combination of agents may produce clinical benefit for benefit rates at nearly 100%. We don’t have that yet, but getting therapies that get everyone to stable disease is a home run.

The other area of excitement is that studies are utilizing next-generation sequencing to look at the gene expression profiling and find genomic signatures that translate to clinical phenotypes types that predict response to 1 type of therapy or the other.

These are 2 areas that we’ve seen the beginnings of and have seen presentation at meetings this year that are showing that we are making steps forward.


Hutson TE, Michaelson MD, Kuzel TM, et al. A phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Presented at: 2020 International Kidney Cancer Symposium. November 6-7, 2020. Abstract 1.

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