Robert Figlin, MD
In the decade since the first tyrosine kinase inhibitor (TKI) was approved in renal cell carcinoma (RCC), the class of agents has dramatically improved patient outcomes, said Robert Figlin, MD.
“TKIs have changed both progression-free survival [PFS] and overall survival [OS] outcomes for patients with kidney cancer dating back to that first approval in 2005. We have had a decade of experience to learn about these drugs,” said Figlin, who serves as the director of the Division of Hematology/Oncology, associate director of Academic Program Development in the Samuel Oschin Comprehensive Cancer Institute, and a professor of Biomedical Sciences and Medicine at Cedars-Sinai Medical Center. “We have learned that the appropriate use of TKIs is giving them in sequence, and that monotherapy is superior to any combination therapies that we have tried.”
Today, TKI development in RCC continues to expand, with both cabozantinib (Cometriq) and lenvatinib (Lenvima) receiving breakthrough designations from the FDA in the summer of 2015.
Second-line treatment with cabozantinib reduced the risk of progression or death by 42% compared with everolimus (Afinitor) in patients with RCC, according to findings from the phase III METEOR study that were presented at the 2015 European Cancer Congress and simultaneously published in The New England Journal of Medicine
PFS with cabozantinib was 7.4 months compared with 3.8 months with everolimus (HR, 0.58; 95% CI, 0.45-0.75; P
<.001). The objective response rate was 21% in those treated with cabozantinib versus 5% with everolimus (P
Lenvatinib was also compared with everolimus in an open-label, three-arm phase II study presented at the 2015 ASCO Annual Meeting. Lenvatinib monotherapy improved PFS by 39% versus everolimus monotherapy (HR, 0.61; 95% CI, 0.38-0.98; P
= .048). The combination of lenvatinib and everolimus also demonstrated a 60% improvement in PFS over everolimus alone (HR, 0.40; 95% CI, 0.24-0.68; P
The use of more established therapies, such as sorafenib, has also evolved. New scheduling regimens, which aim to decrease toxicities, have shown success and are currently being investigated, said Figlin.
In an interview with OncLive
, Figlin discusses the evolution of TKIs in RCC, the novel agents and changes to established therapies he is most excited about, and the challenges that still remain.
OncLive: What new TKIs do you currently see the most potential for?
: There are two trials that are important right now. The first was presented at ASCO in 2015 using a drug called lenvatinib in combination with everolimus. Lenvatinib is a TKI against both VEGF receptors as well as FGF receptors, and when combined with the mTOR inhibitor everolimus, in a randomized phase II trial, the combination produced PFS benefits that were longer than either agent alone.
The other agent that has a lot of potential is cabozantinib; there was data recently presented on it at the 2015 European Cancer Congress. That is a drug that inhibits both the VEGF receptor as well as MET, another resistance pathway in kidney cancer. When compared to everolimus as monotherapy in the second-line setting, it produced PFS benefits that were better than everolimus, and comparable to or better than historical data in the second-line setting in refractory patients. This suggests that both of these drugs might be our first hint that inhibiting both the VEGF receptor pathway and resistance pathways may result in approved outcomes.
What are the next steps in understanding this?
The next step for both of these drugs is to gain regulatory approval. The big questions for many of us now are, “Is the benefit truly a contribution because of inhibiting resistance pathways? Are there more potent VEGF receptor TKIs, and what might they look in terms of their outcomes if compared to a better active competitor such axitinib [Inlyta], which is approved in the second-line setting?”
How has the use of more established TKIs, such as sunitinib, evolved in recent years?
When a drug has been on the market for an extended period of time, doctors start to learn how to better deliver it. Sunitinib was first approved on a 4:2 schedule, which involves 4 weeks of treatment and 2 weeks of rest. There have been attempts to modify the schedule while maintaining the dose, because we understand that maintaining the dose is associated with better outcomes. One way to do that is instead of offering the patient a 4:2 schedule, we offer the patient a 2:1 schedule, which is 2 weeks of treatment and 1 week of rest.