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TKI Sequencing in RCC Will Bring in New Paradigms, Outcomes

Brielle Urciuoli
Published: Sunday, Nov 27, 2016

Robert A. Figlin, MD

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.

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.

Different Mechanisms of Action

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.

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