Novel Agents, Combinations Advance Second-Line RCC Care

Robert S. Alter, MD

The treatment paradigm of advanced renal cell carcinoma (RCC) has been rapidly changing.

First, the FDA approved the combination of lenvatinib (Lenvima) and everolimus (Afinitor) in May 2016 as a treatment for patients with advanced RCC following prior antiangiogenic therapy.

The approval of the combination was based on the phase II Study 205, which demonstrated that the TKI/mTOR inhibitor regimen reduced the risk of progression or death by 63% compared with everolimus alone. Median progression-free survival (PFS) with the combination was 14.6 months versus 5.5 months with everolimus (HR, 0.37; 95% CI, 0.22-0.62). There was a 33% reduction in the risk of death with the combination versus single-agent everolimus.

The FDA also approved cabozantinib (Cabometyx), another TKI, in April 2016, based on the phase III METEOR trial, in which cabozantinib demonstrated a 42% reduction in the risk of progression or death compared with everolimus in patients with advanced RCC.

In addition, the anti—PD-1 agent nivolumab (Opdivo) was approved for second-line advanced RCC in November 2015 based on the CheckMate-025 study. The study demonstrated a median overall survival (OS) of 25 months with nivolumab compared with 19.6 months in those who received everolimus (HR, 0.73; P = .002).

OncLive: With several new agents and combinations approved, how do you determine the best sequencing for RCC?

To better understand what impact these newly approved agents and combinations have had on the treatment paradigm of RCC, OncLive spoke with Robert S. Alter, MD, the co-chief of Urologic and Head and Neck Oncology at the John Theurer Cancer Center. In his interview, Alter discusses optimal sequencing for these agents and how he determines the appropriate treatment for patients.Alter: Standard of care still for first-line therapy, if a patient is not a candidate for interleukin-2, would be a TKI. The 2 that have the most data are sunitinib (Sutent) and pazopanib (Votrient). When nivolumab got its FDA approval for second-line RCC in November 2015, the paradigm shift was that nivolumab became the more popular option for second-line. There were some believers that felt that the PFS data with nivolumab were not as impressive as TKI followed by TKI therapy, but the favor leaned toward nivolumab.

Then, in April 2016, when cabozantinib got approved and the combination of lenvatinib/everolimus got approved 1 month later, we had to consider the role of a TKI followed by a TKI all over again. A lot of physicians are still considering going back to the TKI followed by TKI phenomenon and using it as both first- and second-line therapy.

The way I look at it is that every patient is different, and there are a lot of different paradigms that we need to look at when deciding sequencing. If I have a patient who has a good performance status, who does not have a threatening tumor burden, I believe nivolumab is an excellent choice of therapy.

Which patients would you consider to receive the combination of lenvatinib/everolimus, specifically, for second-line treatment?

However, if the patient was a good responder to a previous TKI, that would be sunitinib and pazopanib, I would favor utilizing a TKI therapy as a second-line therapy and I would consider using nivolumab as a third-line agent. That is a broad statement, and it does need to be considered on an individual basis. One does need to discuss with the patients what the benefits and toxicities of each therapy are. Sometimes comorbidities can limit your options for therapy, as well, therefore making the decision easier for second-line treatment.If you look at the lenvatinib/everolimus data, you can see that they have very impressive numbers when it comes down to PFS, response rates, and OS. It is important to consider that these therapies, first of all, are a little toxic. When using TKIs as a second-line therapy, one may even need to do a dose adjustment. With that, one has to anticipate some toxicities with therapy. However, these agents are very tolerable and the dose adjustments are very effective.

The lenvatinib/everolimus clinical trial was a 3-arm study comparing the combination versus lenvatinib monotherapy, versus everolimus monotherapy. However, the lenvatinib monotherapy arm was eliminated because the FDA felt that doing so would prevent the physicians from being confused about the indication for label purposes. The FDA wanted the most efficacious version to reach the patients and eliminate the confusion.

I would still utilize the combination where I would use lenvatinib. These agents are very safe to be used in combination, but I would expect, again, that the patient has not had a prior mTOR agent because this is really for patients who previously received a TKI. Lenvatinib by itself does offer a benefit, but the data show that the combination is significantly better when it comes to all parameters.

Do you see any of these new agents moving into frontline?

Overall, the patient I would consider for this combination would be the one who had a good performance status, large tumor burden, and more symptomatic disease that yields a very high response rate and a prolonged PFS. In those patients, the combination would be beneficial as compared to using a single-agent TKI or immunotherapy.Several of the drugs that have been approved for second-line therapy are now trying to move into first-line therapy. Cabozantinib has moved forward now; there was a paper discussed at the 2016 ESMO Congress looking at its activity in first-line therapy. There is also as a phase III study comparing lenvatinib/everolimus versus sunitinib versus lenvatinib/pembrolizumab (Keytruda) in first-line RCC.