Shilpa Gupta, MD, MBBS
The treatment paradigm for kidney cancer is undergoing significant change, said Shilpa Gupta, MD, MBBS. While sunitinib (Sutent) and pazopanib (Votrient) remain the standard for first-line therapy, cabozantinib and nivolumab (Opdivo) provide new options in the second-line, and other novel monotherapy and combination approaches are also emerging. The changes bring uncertainty, but also give physicians reason to hope that they’ll soon be able to provide better treatments to their patients.
“The field is in a big flux right now and a lot of hope is from the immunotherapy combinations with other tyrosine kinase inhibitors (TKIs) or VEGF antibodies,” she said.
In an interview with OncLive
at the 2017 American Urological Association Annual Meeting, Gupta, an assistant professor in the division of hematology, oncology, and transplantation at the University of Minnesota, discussed the future of drug therapies for kidney cancer, and the challenges facing the research landscape.
OncLive: Can you discuss your presentation exploring adjuvant drug therapy in kidney cancer?
There have been many mixed results with adjuvant therapy in kidney cancer. All the trials have not shown any benefit of adjuvant therapy. The ASSURE trial was negative when they used sunitinib and sorafenib (Nexavar) compared with placebo, but this is the first time that the S-TRAC results appear to be positive for disease-free survival in the adjuvant setting for sunitinib. Overall survival is not mature, making the community very interested in seeing if this will be practice changing and determining the differences from the ASSURE trial.
Can you discuss those differences?
In the ASSURE trial, patients were randomized to sunitinib at a starting dose of 50 mg a day for 4 weeks, then had 2 weeks off. The other was sorafenib versus placebo. The main differences in the dosing was that sunitinib could go down to 37.5 mg, and then the protocol amendment allowed a starting dose of 37.5 mg and could go down to 25 mg.
However, in the S-TRAC trial, the starting dose remains to be 50 mg a day and only 1 dose-level de-escalation was allowed. It was thought that there could be a difference in the dose intensity in the ASSURE trial patients. In the ASSURE trial, patients receiving sunitinib experienced 77% intensity whereas in the S-TRAC trial patients experienced 88% intensity. We are wondering if the dose intensity makes a difference in the results.
Another key difference was that low-risk patients were enrolled in the ASSURE trial whereas only the intermediate and high-risk population were enrolled in S-TRAC. The high-risk patients are more likely to recur, which translated into a positive result compared to the ASSURE trial where, in the low-risk setting, the adjuvant treatment did not make any difference.
A thought to consider is that sunitinib has met disease-free survival but overall survival has not matured. We will see how the data looks going forward, and whether a year of treatment that results in many adverse events is worth it for the disease-free survival benefit. Sunitinib is not an easy drug to take. Over 44% of patients discontinued therapy from adverse events.
What do you envision happening next with these regimens?
There is a lot of interest in adjuvant therapy in kidney cancer. There are a couple of trials investigating adjuvant immunotherapy versus placebo. A question that stems from this is if sunitinib does get an indication in this setting, is placebo the right comparative arm? The immune therapy should probably be compared to sunitinib, but that depends on what the FDA decides for this regimen.
The other key point is to include a higher proportion of patients with non-clear cell cancer in adjuvant trials because those are the patients most likely to recur. All these adjuvant trials have traditionally focused on patients with clear cell kidney cancer to determine if we are not seeing an overall survival advantage because there are many other therapies when patients get metastatic disease. However, for patients with non-clear cell, there are very limited therapies in the metastatic setting, which is a high-risk population that is most likely to recur and adjuvant trials should focus on those.
Investigators are exploring immunotherapy in combination with VEGF inhibitors. Are there specific combinations showing promise?
We've participated in the combination of VEGF inhibitors and immunotherapy like the axitinib (Inlyta) plus pembrolizumab (Keytruda) trial and the axitinib plus avelumab (Bavencio) trial.