Rini Stresses Axitinib Remains Significant in RCC

Brian Rini, MD

The tyrosine kinase inhibitor (TKI) axitinib (Inlyta) has been standard in the management of advanced renal cell carcinoma (RCC) for about 5 years now, but the emergence of new agents has made some members of the oncology community concerned that its significance will be overlooked in favor of more recently approved treatments.

At the 2016 Kidney Cancer Symposium, Brian Rini, MD, professor of Medicine, Cleveland Clinic, presented on the continued role for axitinib in kidney cancer. Rini said axitinib is distinct from other agents, in part, because it is well tolerated. The drug has a short half-life of 4 to 6 hours. This allows greater flexibility with dose adjustments, which enhances toxicity management.

Rini says tolerability is one of the key reasons why axitinib is often the “combination TKI of choice” in trials examining regimens combining TKIs with PD-1/PD-L1 inhibitors, such as pembrolizumab (Keytruda) and avelumab.

OncLive: Could you provide an overview of your presentation?

In an interview with OncLive at the Kidney Cancer Symposium, Rini discussed the current relevance of axitinib in the RCC treatment paradigm and its likely integral role in immunotherapy combination regimens on the horizon.Rini: Axitinib has been approved for about 5 years now in the refractory kidney cancer space and my talk today was highlighting some of the features that make it a good drug in that setting. It is a potent and selective VEGF inhibitor that has the ability to titrate the dose up and down, which effects the efficacy, as well as the tolerability. Its pharmacologic properties allow it to be fine-tuned to each individual patient, which is relatively unique among the oral agents and I think provides some advantages.

What are some remaining questions concerned with this agent?

What are your thoughts on axitinib in combination therapy?

There is clinical data supporting its efficacy in that setting—large scale, phase III clinical trials. It also has a biomarker of hypertension that can sometimes can be used to guide therapy. I think from a balance of benefit and risk—which matters since these drugs, unfortunately, aren’t curative for patients—I feel it is an ideal choice in that setting.The optimal way to titrate—it’s been a question that I've been interested in for about a decade and the manufacturer has done a nice job of building it into development but still, I don't think we've figured it out precisely. We've started to look at other titrating schemes, more rapidly getting people to where they need to be but also more gradually—not taking big jumps as in the label, which I think is a problem for many people. That’s an area of ongoing effort and I think we’re closer to getting it right, it’s just taking a long time.That is probably the most exciting aspect. Axitinib is being examined in combination with both avelumab, which is a PD-L1 inhibitor, and pembrolizumab, a PD-1 inhibitor. I think one of the reasons that it’s been the combination TKI of choice is that it is very well tolerated.

Do you look at this rise in combination regimens as the future of this field?

Right now, how do you think you would best decide if a patient is treated with monotherapy or tested with one of these combinations?

What do you hope community oncologists take away from your presentation on axitinib?

Some of the other drugs, like pazopanib (Votrient) weren't combinable because of liver function test abnormalities. Kind of by default, axitinib became sort of the darling combination partner. I think ultimately as this field—frontline and second line—evolves rapidly over the next few years, axitinib will go from a predominately second-line refractory drug to being a component of frontline therapy.Yes, the large phase III trials that are ongoing are all combination based for the investigational arm against sunitinib (Sutent) monotherapy. It is hard to believe that they would all be negative, in fact all or the majority likely will be positive given some preliminary hints of activity we've seen in the phase II trials. So yes, I think that combination therapy will be the frontline standard of care then it will go to monotherapy after that, pending further developments.I think as the combination data comes out we'll have a handle on efficacy and toxicity and certain subsets that either don't do well or don't tolerate. I guess the question is, in 3 to 5 years from when the data comes out, are there patients who will only get monotherapy? I think most patients will be a combo, but is there a subset that might get monotherapy? I think the answer is yes, I'm just not sure who it is quite yet.It is always nice to play with the shiny new toy, like cabozantinib or everolimus, and that is fine, I understand it, but you must back up and realize that we aren't curing patients with these TKIs. That balance between benefit and risk is really important—especially in the refractory setting where people are, frankly, worn down from prior therapies. Axitinib was the best tolerated drug, the efficacy data is robust and especially in the refractory setting, I think that they shouldn't forget about it. It’s easy to forget about drugs when there isn't new data right in front of you. Good drugs are good drugs, whether there is new data or not.