TKI Sequencing in RCC Will Bring in New Paradigms, Outcomes

Robert A. Figlin, MD

In the past decade, the addition of tyrosine kinase inhibitors (TKIs) has had a huge impact on the treatment of renal cell carcinoma (RCC) in the first- and second-line settings. Currently available agents include sorafenib (Nexavar), sunitinib (Sutent), pazopanib (Votrient), axitinib (Inlyta), and the recently-added cabozantinib (Cabometyx), and lenvatinib (Lenvima).

After the results of the CABOSUN and S-TRAC trials were presented last month at the 2016 European Society of Medical Oncology (ESMO) Congress, Robert A. Figlin, MD, FACP, is sure that TKI sequencing for kidney cancer will continue to evolve, ultimately shifting the treatment paradigms—and outcomes—for patients with the disease.

First, the phase II CABOSUN trial showed that cabozantinib significantly improved progression-free survival (PFS) over sunitinib, the current standard, in patients with high-risk newly diagnosed metastatic kidney cancer.

“CABOSUN is an interesting observation because it is the first illustration in a selected population of newly diagnosed metastatic patients where there may be an agent that has superior efficacy when it comes to the 10-year standard—sunitinib,” said Figlin, the Steven Spielberg Family Chair in Hematology-Oncology and associate director of academic program development in the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center.

In the trial, 157 patients with previously untreated clear-cell metastatic RCC with intermediate or poor prognosis were randomized to either cabozantinib or sunitinib for 4 weeks on, 2 weeks off. The cabozantinib group showed a 31% reduction in median rate of progress or death compared to the sunitinib group. “I think that this trial offers the opportunity for intermediate and poor-prognosis patients to be offered cabozantinib as the first treatment for their metastatic disease. So, it definitely has the capacity for a paradigm shift,” Figlin said.

However, Figlin is still unwilling to predict that cabozantinib will be a more viable option for all newly diagnosed patients with metastatic disease. “I’m a very evidence-based guy, so I’m not willing to think that cabozantinib would be appropriate for good-prognosis metastatic patients,” he said. “I’ll wait to see the data to make sure that the two populations of patients were equally balanced in terms of the risk groups in the intermediate population.”

Figlin emphasized that intermediate kidney cancer patients are a heterogeneous group. “They’re not all one group of patients, and they can often be divided by number of risk factors—one versus more than one,” Figlin said. These risk factors can include hemoglobin, LDH, weight loss, and performance status, and Figlin uses the Memorial Sloan Kettering Cancer Center Motzer score to stratify patients according to intermediate and poor risk.

“If you have one of those factors, we’ve shown that you do differently with sunitinib than if you have two of those risk factors, along with performance status. As such, I would hold that for the results of this trial to be applied to all patients, I’d like to be sure that the two groups were well-balanced,” Figlin said.

Different Mechanisms of Action

Also, now that cabozantinib was proven to be more effective than sunitinib in intermediate and poor prognosis metastatic patients, Figlin is hoping that the design of future clinical trials will reflect that. “Many of the pivotal trials that are taking place in the frontline setting with immuno-oncology approaches use sunitinib as the control arm. Then the question is, how are we going to be able to interpret that data when we now have an agent that may be superior to the control arms and the pivotal trials?” he said.Cabozantinib and sunitinib, while both TKIs, have different mechanisms of action. Cabozantinib targets MET and AXL, whereas sunitinib targets VEGFR. This latter drug proved to be beneficial in the phase III S-TRAC trial. In the S-TRAC trial, sunitinib met its primary endpoint of disease-free survival when used as adjuvant therapy in patients with high-risk RCC patients after nephrectomy. The trial randomized 615 patients to either placebo or suntinib. After a year, the patients on sunitinib had a disease-free survival of 6.8 years, compared with the average of 5.6 years for those on a placebo.

This was the first trial to show that adjuvant therapy is helpful in this patient population, and it’s an important discovery, especially after the results of the ASSURE trial—which compared sorafenib to sunitinib with a placebo control arm—failed to demonstrate efficacy in any of the cohorts studied.

Figlin said that he is eager to see if sunitinib will prolong overall survival in addition to the extension in disease-free survival already demonstrated. If so, yet another question will arise. “So then the question becomes, if disease-free survival is enhanced by 1.2 years, is that worth the treatment when we have better treatments for those people at the time they were to progress? It becomes a ‘treat now or treat later’ phenomenon,” Figlin said.

TKI Questions Linger

Once these questions are answered, there likely will be some major changes in how oncologists are sequencing their TKIs for this group of patients. “One can imagine that for high-risk resected patients, the treatment could easily be sunitinib; and that for newly diagnosed intermediate and poor prognosis metastatic patients, the treatment could be cabozantinib; and for good prognosis patients with metastatic disease, the treatment would be sunitinib, which would be a major paradigm shift as compared to the last decade,” he said.While trials such as CABOSUN and S-TRAC answer some questions, other questions linger regarding TKI sequencing in kidney cancer, such as how to treat patients who develop metastatic disease if they have already been on a TKI inhibitor in the past. Seeing what kind of role immunotherapy agents will eventually play in the frontline setting will help to answer this question, said Figlin.

“You could imagine a couple of scenarios,” Figlin said. “Suppose a person receives a TKI and then relapses very quickly, maybe a TKI isn’t appropriate at all. But, what if a person relapses a year later? A TKI might totally be appropriate.”

And while survival benefit is obviously key in determining which agents to use, it is not the only factor considered in the decision-making process.

“Every patient we treat, we think about comorbidities, how the person will tolerate the drug, whether theres are any drug-drug interactions, as well as overall endpoint of survival benefit,” Figlin said.

TKIs have been shown to present numerous adverse events, though their benefits will usually outweigh the hardship that patients undergo, according to Figlin.

“These agents are associated with effects such as hypertension, fatigue, hand-foot syndrome, and other things that are associated with changes in quality of life, but there are quality of life metrics that demonstrate that those are still superior over alternative placebos or less effective treatments,” Figlin said. “There are manipulations that doctors have become comfortable with to make sure the patient has the opportunity to benefit but doesn’t suffer any unacceptable side effects.”

TKIs, administered both simultaneously and in sequence, have changed the treatment landscape for patients with kidney cancer over the past decade. As these agents continue to be tested in different settings, and alongside immuno-oncology agents, the role of TKIs will continue to shift.