High Hopes for Immunotherapy Combinations in Kidney Cancer

Though significant progress has been made in kidney cancer, there remains a need for therapies that produce long-term and durable remissions, especially for patients with late-stage disease, says Robert Figlin.

“There are a lot of drugs, many targets, and still no cures,” says Figlin. “There is still an unmet need, despite the plethora of agents that have been approved in this space.”

Checkpoint inhibitors do show some promise, he says. Several ongoing trials are currently exploring agents for patients with previously untreated metastatic/advanced kidney cancer, including a phase 3 study of Opdivo (nivolumab) in combination with Yervoy (ipilimumab) and a phase 3 trial of atezolizumab in combination with Avastin (bevacizumab).

The JAVELIN Renal 101 trial (NCT02684006), which is investigating the combination of avelumab and Inlyta (axitinib) in patients with previously untreated, advanced kidney cancer, just treated its first patient. This is the only phase 3 trial currently evaluating an anti—PD-L1 agent in combination with a VEGFR tyrosine kinase inhibitor (TKI) in this setting.

Time will tell if this approach can provide the groundbreaking advance that is needed in the field of kidney cancer, says Figlin.

“We are really waiting to see the long-term benefits of checkpoint inhibitors,” he says. “These are trials that are using standard of care agents like Sutent (sunitinib), for example, in the control arms. If one of them were to be a positive trial, it would be practice-changing.”

CURE: What clinical trials are you excited to see the results of in kidney cancer?

Do you see great potential for immunotherapy in kidney cancer?

In an interview with CURE, Figlin, professor of Medicine and Biomedical Sciences, Steven Spielberg Family Chair in Hematology Oncology, director, Division of Hematology Oncology, deputy director, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, discusses some of these emerging agents and ongoing trials that could transform the treatment landscape of kidney cancer.Figlin: There are a series of trials taking place in the frontline setting for the previously untreated kidney cancer population. There is the Merck/Pfizer JAVELIN trial looking at the combination of avelumab and Inlyta. There is also a trial from Bristol-Myers Squibb (BMS), which looks at Yervoy/Opdivo and is close to accrual. Additionally, there is a Roche trial, which uses their checkpoint inhibitor atezolizumab in combination with Avastin. All of these trials are efforts to bring checkpoint inhibitors, either alone or in combination, into the frontline setting. They all have pros and cons. The difference between them is that the BMS trial uses checkpoint inhibitors alone, while the Roche/Genentech and the Merck/Pfizer trials combine targeted therapies, which have known activity in the frontline setting, with checkpoint inhibitors. Based on phase 1 data, these have been shown to be safe to give in combination. It will be interesting to see which approach turns out to be more successful in this patient population.Kidney cancer is the classic immune-responsive disease. In 1982, interleukin-2 (IL-2) was approved in this space. This works in kidney cancer because of its ability to stimulate an immune response. Unlike a disease such as lung cancer — which is rather late to the conversation around possibly being immunogenic — kidney cancer has a long-standing history of this.

Opdivo produces a survival benefit when compared with Afinitor (everolimus). There is an absolute benefit. The problem is the response rate is approximately 20 percent and it is unclear how to identify — other than responses — which patients will benefit. Progression-free survival is not helpful because there is evidence of pseudoprogression, as well as inflammation of the tumor.

Do you see a role for vaccines in kidney cancer?

Why might these two agents work well together?

Despite having multiple drugs to choose from, we don’t have a biomarker and we don’t know which patients will benefit. We also don’t know how long patients should be treated with these agents, and we don’t know how to identify the value proposition to support the use of expensive drugs in a large number of patients when only a few benefit.The ADAPT trial, which I am the global principal investigator of, is a trial combining a TKI and a dendritic cell-based vaccine. The trial has met its accrual goals, and we are just waiting for a number of events to determine if a vaccine plus a TKI is better than a TKI alone in a previously untreated population of patients who present with their primary tumor intact. We have 450 patients. We will probably have some information of that in 2017.Most people — including myself — believe that TKIs, specifically Sutent, have activity both as an antiangiogenic as well as an agent that modifies myeloid-derived suppressor cells, regulatory T cells, and the immune system.

What are the biggest challenges that remain in kidney cancer?

There is a rationale to think that combining a TKI and a vaccine would be better than a vaccine alone and there is a phase 1 trial that we published in the Journal of Immunotherapy that suggests that, yes, we can see a response with these two agents together, and that there is a group of patients who do better than one would have expected from just the TKI or the vaccine alone. That gave the rationale for combining them in a phase 3 trial.We as investigators have to both search for novel pathways and durable remissions, and start to have a discussion about how we can deliver value in this setting. Many of these new drugs are expensive, and we can’t just keep giving them absent data about the value.

We would welcome agents that produce complete remissions. Thus far, we do not have agents that produce complete remissions, except for high-dose IL-2. We would also welcome a durable and maintained remission so patients can eventually be taken off of their drug.