Expert Discusses Rapid Evolution of RCC Treatment

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.

OncLive: Can you discuss your presentation exploring adjuvant drug therapy in kidney cancer?

Can you discuss those differences?

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.Gupta: 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.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.

What do you envision happening next with these regimens?

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. 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.

Investigators are exploring immunotherapy in combination with VEGF inhibitors. Are there specific combinations showing promise?

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.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.

It makes sense to combine these 2 different pathways because kidney cancer is a VEGF-driven disease and immunotherapy is also quite active. The VEGF antibody bevacizumab (Avastin) and atezolizumab (Tecentriq) were looked at and compared to sunitinib in the phase II trial presented at ASCO GU. However, there were no differences seen. The objective response rates were higher, especially in the higher PD-L1 expressers but it was not statistically significant.

The phase III trial is ongoing. A key question is that we don't know whether PD-L1 is a predictive marker in kidney cancer. The study that got nivolumab approved showed that it was just a poor prognostic marker but in the atezolizumab trial, they are stratifying based on PD-L1. In the phase II data, it was shown that patients who had a PD-L1 expression higher than 5% did better than those who did not express it.

How reliable is PD-L1 as a biomarker?

There are many unknowns but this combination does make sense. The first-line treatment landscape will probably change very soon. There are also studies investigating cabozantinib (Cabometyx) plus nivolumab (Opdivo) and nivolumab plus ipilimumab (Yervoy).That is the big question that the community is dealing with. For kidney cancer, we don't yet know if it's a predictive marker. But for other cancers such as bladder cancer, the high PD-L1 expressers did better, but the benefit was seen even in the low PD-L1 expressers or patients who didn't express PD-L1.

Is there anything else you would like to mention regarding drug therapies for kidney cancer?

The biomarker question is something that needs to be tackled and a standardized recommendation guidance needs to be developed.The landscape for kidney cancer is changing rapidly. The first-line therapies are still sunitinib and pazopanib, however now we have cabozantinib and nivolumab approved for second-line therapies.

The sequencing is a key question we don't know whether to use cabozantinib first or nivolumab first. Sequencing trials need to be undertaken so we have a clear guideline as to which to use first.

The CABOSUN data which compared cabozantinib to sunitinib in the first-line setting did show improvement in progression-free survival. However, that was a small study and was focused on intermediate- and poor-risk patients while sunitinib was approved for all comers.

Where do you see this treatment landscape headed in the next 5 to 10 years?

The field is in a big flux right now and a lot of hope is for the immunotherapy combinations with other TKI's or VEGF antibodies.I would like to see more combination trials and if we do make a breakthrough in the adjuvant setting, move these agents earlier in the treatment landscape. This will raise the question, if patients receive a regimen as an adjuvant therapy, could that still be an option for them in the metastatic setting? This still needs to be investigated.