Powles Sheds Light on Shifting Landscape in Kidney Cancer

Thomas Powles, MBBS

The treatment of patients with kidney cancer will differ greatly in the next decade because of changes in the landscape that occurred in 2017, according to Thomas Powles MBBS, MRCP, MD.

Notable this past year was the emergence of a frontline immunotherapy combination in a study that challenged the standard-of-care, sunitinib (Sutent). In the phase III CheckMate-214 trial, nivolumab (Opdivo) plus ipilimumab (Yervoy) reduced the risk of death by 37% versus sunitinib in patients with intermediate- and poor-risk renal cell carcinoma (HR, 0.63; P <.0001).¹

“We have witnessed the replacement of VEGF-targeted therapy with combination immune therapy,” said Powles regarding CheckMate-214. The extension in survival with this combination has completely changed the standard of care, he said.

Other immunotherapy combinations are also being explored for patients with metastatic kidney cancer, Powles noted. Recently released findings from the ongoing phase III IMmotion 151 study assessing the PD-L1 inhibitor atezolizumab (Tecentriq) with bevacizumab (Avastin) versus sunitinib alone showed that the combination reduced the risk of progression or death by 26% for patients with untreated, advanced PD-L1—positive mRCC.²

Additionally, cabozantinib (Cabometyx) has continued to show improvements in survival and quality of life for patients with kidney cancer, highlighted by the approval of the agent in the frontline setting, based on the results from the phase II CABOSUN trial. This study demonstrated a reduction in the risk of progression or death by 52% compared with sunitinib for patients with advanced kidney cancer.³

OncLive: Please discuss some of the recent advances in the treatment of patients with kidney cancer.

In an interview with OncLive, Powles, a clinical professor of genitourinary oncology, Barts Cancer Institute in London, United Kingdom, discussed the findings from the CheckMate-214 trial, as well as continuing studies in immunotherapy and targeted therapy in kidney cancer, and how this new data might affect the treatment of kidney cancer going forward.Powles: There has been a change in kidney cancer over the last year. It has been an enormous change; in fact, things will never be the same again. The change has been the essential replacement of frontline VEGF-targeted therapy with combination immunotherapy. That change happened because of a trial called CheckMate-214, which combined ipilimumab and nivolumab. It showed that those 2 drugs in patients with intermediate- or poor-risk disease outperformed sunitinib in terms of response rate and, importantly, overall survival [OS].

We haven’t seen those sort of figures before in kidney cancer. We did not see those figures when we originally compared interferon with sunitinib; there was no spectacular survival advantage there. Essentially, we now have an immune combination that is better tolerated than we thought, has better quality of life than sunitinib, and also much better OS. Therefore, it has changed the way that we think about kidney cancer.

What questions remain about the future of immunotherapy in kidney cancer?

There are some complicating issues in the data, as you can imagine. There is a group of good-risk patients, who obviously have good prognostic factors, performance status, and blood parameters. In their premature analysis, this group of patients didn't seem to do better with immunotherapy than sunitinib. In my opinion, that data are immature, and we will have to see how that pans out. But certainly VEGF-targeted therapy for that group of good-risk patients is still a viable option. Although, I would argue that you could also give immunotherapy to that group.During this period of transition in kidney cancer—away from oral VEGF-targeted therapies to immune therapies—there is a question of, “What will the landscape look like?” Is that going to be immune combination therapy with ipilimumab and nivolumab? Is it going to be immune and VEGF-targeted therapies such as atezolizumab and bevacizumab, or pembrolizumab [Keytruda] and axitinib [Inlyta]?

I am really trying to pick through some of the issues that we are going to face over the next year or 2. Which drugs should we use? Can we select patients for particular therapies? How is the community going to deal with the new toxicity profiles of drugs that we haven't used widely before? How will we integrate these options into clinical practice? What I mean by that is, if we are giving sunitinib or pazopanib (Votrient) as standard of care, and then we give ipilimumab and nivolumab in 6 months, what do we do when the immunotherapy fails? Do we give the same drugs as we gave originally? Should we move to second-line therapy with axitinib and cabozantinib?

There are some newer data on cabozantinib with CABOSUN, which is also exciting because just at the time where immunotherapy comes along, there is this big tidal wave of OS benefit, new combinations, and 1000-patient randomized phase III trials. We then have atezolizumab and bevacizumab following very close behind. In parallel, we also have a study that suggests that cabozantinib outperforms sunitinib.

What should community oncologists know about this evolution in kidney cancer?

It is a more colors of a rainbow than a black-and-white situation in kidney cancer at the moment, and I am not sure how the story will pan out. My personal opinion is that the data on the immune combination with the hazard ratio of 0.63 is really compelling. However, for example, if the atezolizumab and bevacizumab combination comes in with equally good results, then there will need to be a discussion about how we choose patients. I'd like them to take home 3 key messages. The first is that kidney cancer has changed, we need to change the way we look to our patients, and we need to offer them the latest therapies that have been proven in randomized trials—such as the immune combination therapies and the role of cabozantinib in the frontline space. The second message would be that there are a series of trials coming through, particularly the VEGF-targeted studies with immunotherapy, [which include] bevacizumab and atezolizumab; axitinib and pembrolizumab, and axitinib and durvalumab [Imfinzi]. [The third message is] what do we do when that treatment fails?

References

1. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.
2. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2018;36 (suppl 6S; abstr 578).
3. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.