Reviewing a New Treatment Combination for Advanced Kidney Cancer

There is a promising treatment option for patients with renal cell carcinoma (RCC) who have progressed on Cabometyx (cabozantinib) and Opdivo (nivolumab), says Sumanta Kumar Pal.

“Lenvima (lenvatinib) plus Afinitor (everolimus) represents something that patients with heavily pretreated disease can potentially be approached with,” says Pal. “If a patient is fit enough to receive this regimen after having progressed on agents such as Cabometyx and Opdivo, it is a reasonable treatment option. It is always beneficial to have additional therapeutic options for these patients.”

The TKI Lenvima was approved in combination with Afinitor, an mTOR inhibitor, in May 2016 as a treatment for patients with advanced RCC following prior antiangiogenic therapy. The approval was based on a phase 2 trial, known as Study 205, which demonstrated that the combination reduced the risk of progression or death by 63 percent versus Afinitor alone. Median progression-free survival (PFS) with the combination was 14.6 versus 5.5 months with Afinitor and there was a 33 percent reduction in the risk of death with the combination compared with the monotherapy.

This combination represents the first FDA-approved TKI and mTOR inhibitor treatment regimen in RCC. To gain more insight on the two-drug therapy, as well as other updates in RCC, CURE spoke with Pal, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research, and co-director of the Kidney Cancer Program at City of Hope.

How was this pivotal trial designed and what were the key findings?

Can you explain the mechanism of action of Lenvima? What role does the VEGF pathway play in RCC tumor progression?

This was a randomized phase 2 trial, with between 50 and 60 patients per arm. It included a total of three arms; one arm had Lenvima alone, another had Afinitor alone and the third explored the combination. The study identified that Lenvima with Afinitor significantly delayed cancer progression as compared with Afinitor alone.We think that the VEGF pathway is very critical throughout the natural history of RCC by promoting blood vessel growth and formation. Lenvima goes well beyond that by targeting multiple receptors at the cell surface and, by virtue of this, it possibly has greater antitumor activity than some of the other agents we have been exposed to in the past.

What synergy is there between Lenvima and Afinitor?

Certainly, we see more than we would anticipate with other combinations of drugs. Other combinations of VEGF inhibitors with Afinitor have been somewhat disappointing, in terms of the results that they have generated clinically. Here, we have significant efficacy and I would propose reasonable safety; however, it should be used cautiously in patients.

In terms of toxicity, what should patients and oncologists expect with this combination?

This combination will be well known to physicians who have used both VEGF-directed drugs and mTOR inhibitors in the past. Nevertheless, there seems to be some non-overlapping toxicities between the two. Clinicians should be prepared for a greater scope of toxicity.

Where does Lenvima plus Afinitor fit into the treatment paradigm, in terms of sequencing?

The level of evidence is higher with Cabometyx and Opdivo, as both of those agents were approved on the basis of randomized phase 3 trials that included many more patients.

In my opinion, the standard second-line treatment should be Cabometyx, because we know the agent led to improvement, not just with PFS and response rate, but also in overall survival (OS), as well. The third-line treatment of choice would be Opdivo, given that this agent has been shown to improve both response rate and OS. Beyond that, perhaps Lenvima plus Afinitor represents a reasonable option. Certainly, the combination is preferred to Afinitor alone now.

What are the biggest challenges that remain in advanced RCC?

One thing that is critical to keep in mind is that renal cell carcinoma remains an incurable disease. It is a bit of a paradox that we have multiple targeted therapies available in RCC but we do not apply them in a targeted fashion.

A better understanding on which patients will benefit from which targeted therapies would perhaps maximize outcomes. Personally, I believe that broader use of molecular testing is essential for us to gain a better understanding of how to appropriately apply therapies in this disease.

At this point in time, we don’t use any molecular testing as the standard of care for patients with metastatic disease, although I would argue that molecular testing does provide certain potential signals that have been well vetted in literature that can predict response to certain drugs.

Are there any other studies in this space on the horizon that you are interested in?

Perhaps the most interesting set of studies on the horizon are those exploring PD-1 inhibitors in the frontline setting. That may shake up the way in which we are currently applying those drugs. I am also excited to see the results of first-line treatment studies examining Cabometyx.* These may potentially shift the paradigm, as well.

*Editor’s note: Since our interview with Pal, Exelixis reported that frontline Cabometyx significantly improved PFS compared with Sutent (sunitinib) in patients with advanced RCC in the phase 2 CABOSUN trial.