Frontline Paradigm Continues to Evolve in RCC

Claud M. Grigg, Jr, MD

The frontline paradigm in renal cell carcinoma (RCC) continues to shift, with multiple new treatment approvals over the past year.

For example, in December 2017, the FDA expanded the indication for cabozantinib (Cabometyx)—a TKI that blocks VEGFR, MET, and AXL—to include previously untreated patients with RCC. The approval was based on the phase II CABOSUN trial, in which cabozantinib improved progression-free survival (PFS) compared with sunitinib (Sutent) as frontline systemic therapy in patients with intermediate- and poor-risk RCC.

In the overall study population, cabozantinib-treated patients had a median PFS per an independent review committee of 8.6 months compared with 5.3 months for patients treated initially with sunitinib. The objective response rate (ORR) was 20% with cabozantinib and 9% with sunitinib.

Intermediate-risk patients accounted for 81% of the study population. Key clinical features included bone metastases in about 36% of patients, prior nephrectomy in 75%, and 3 or more metastatic sites in about 35%. The most common sites of metastasis were lung (70%), lymph nodes (55%), and bone (38%).

“TKIs have really become the foundation of treatment for RCC, specifically clear cell RCC,” said Claud M. Grigg, Jr, MD, medical oncologist at Levine Cancer Institute. “The whole paradigm has been shifted in the last year with the approvals of multiple new frontline agents.”

In addition to TKIs, immunotherapy has also emerged as a frontline option in RCC. The FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in April 2018 for the treatment of intermediate or poor-risk patients with previously untreated advanced RCC.

OncLive: Can you discuss the phase II CABOSUN trial?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancer, Grigg discussed the evolving treatment options in the frontline setting for patients with RCC.Grigg: This was a randomized phase II trial looking at cabozantinib, which is dosed daily, versus sunitinib, which is dosed on a 4-week-on, 2-week-off schedule. It was a relatively small trial with only about 150 patients. CABOSUN was powered to detect an improvement in PFS for cabozantinib over sunitinib. It was a positive trial and it did show an improvement in this space.

How do you distinguish between cabozantinib and sunitinib?

If you look at ORR, they were really quite low in this study—only about 20% in the cabozantinib arm and 9% in the sunitinib arm. Similarly, the PFS was only 8 and a half months and 5 and a half months, respectively—much lower than what we predicted. This has been a criticism of the study. However, it is still reassuring to see positive results with cabozantinib in this very high-risk patient population.We call these drugs inhibitors of the VEGF receptor, but in reality, they inhibit many other kinases in the cell. For example, sunitinib is a potent inhibitor of KIT and FLT3. Cabozantinib inhibits MET and many others. It is important to look at the toxicity profiles of these drugs and look more carefully at data from the CABOSUN trial.

What are the next steps/challenges with TKIs in RCC?

Do you see a rationale to explore other TKIs?

What do you think the treatment landscape for RCC will look like in the near future?

We see that many of the toxicities associated with sunitinib are hematologic—cytopenias, neutropenia. For cabozantinib, we see higher rates of fatigue, anorexia, and others. So, probably the biggest way we differentiate between the 2 agents is through their side effects. It is important to tailor this to the patient. With that being said, if you are looking for a more dramatic response, then cabozantinib is probably the way to go.Sequencing is a challenge, but even more tricky is to determine what to start a patient on upfront. Clear cell RCC comes in many different shapes and sizes; the disease can be very aggressive or very indolent. We do not always know that upfront. Learning how to risk-stratify patients from the outset and then utilizing the right therapy from the start based on efficacy and tolerability is really the key.For frontline monotherapy, I do not see a need to examine the role of other TKIs. We already saw a phase III trial with axitinib (Inlyta) compared with sorafenib (Nexavar). This was a negative study, and there were a number of shortcomings with that drug. Now that we are seeing combinations with immunotherapy, I think that could take over the first line. We will have to wait and see how the clinical trials work out over the next 2 years.In the short term—the next 1 to 2 years—we will see these different combinations start to expand, but I worry about what is going to be left after those agents. Certainly, we know that cabozantinib is active in patients who have previously progressed on other TKIs. We may see other combinations in that respect, and novel immunotherapies will probably have a role in later lines of treatment. Hopefully, we see some newer agents come out over the next 5 years.

George DJ, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib for previously untreated patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk: subgroup analysis of progression-free survival (PFS) and objective response rate (ORR) in the Alliance A031203 CABOSUN trial. Presented at: 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, CA. Abstract 582.