Targeted Treatments Still King in Kidney Cancer, Novel Combinations on the Horizon

James Hsieh, MD, PhD

In kidney cancer there are three “eras” in the history of treatment advances, said James Hsieh, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center.

Before 2005, kidney cancer was in what Hsieh called "the Dark Age."

“We only had two drugs available—interferon and IL2, which were both very toxic,” he said.

Then 7 new drugs, all VEGF and mTOR inhibitors, were approved throughout the next decade, nearly doubling survival. More recently, 3 new agents were approved in kidney cancer: cabozantinib (Cometriq), lenvatinib (Lenvima), and nivolumab (Opdivo). Hsieh calls this time— between 2005-2016— the Modern Age. It is here that patients first had a large variety of targeted treatment options, including lenvatinib and everolimus, a combination which Hsieh said is “extremely effective.”

Beyond 2016, Hsieh sees what he calls the “Golden Age.”

“I see a future where we can take a look at a patient’s cancer genomics, figure out what kind of treatment they will benefit from as a frontline, and then we can use a very good combination like VEGF treatment plus PD-1/PD-L1, and I think we should be able to achieve very durable remission for 30% or more of kidney cancer patients,” he said.

OncLive: How have the approvals of cabozantinib, lenvatinib, and nivolumab impacted treatment in kidney cancer?

However, there is still a lot to achieve before the “Golden Age” can truly take off, said Hsieh. In an interview with OncLive, he explained why targeted treatments still currently have more potential than immunotherapies, and what he sees on the horizon in kidney cancer.Hsieh: These 3 drugs are very different. Two are small molecules which, in addition to VEGF pathways, also targeted additional pathways. Cabozantinib targets VEGF and c-MET, and lenvatinib targets VEGF and FGF. c-MET and FGF pathways are bypass pathways for angiogenesis, so the resistance cases will benefit from it because you actually block the tumor progression upfront with 2 different pathways.

The third drug, nivolumab is a PD-1 antibody. This brings us back to immunotherapy, because the first 2 therapies approved in kidney cancer, interferon and IL2, were immunotherapies. Now, the PD-1 is more specific in terms of anti-cancer effect, and it is much more tolerable, but the problem is that the efficacy is very low. Only 23% of patients benefit from it, and it only lasts for about two years. The VEGF treatments, even in the old days, benefitted 75% of patients. VEGF inhibitors work, and they need to be in place. It is very difficult to convince me to put these patients on upfront nivolumab by itself because it only benefits 20% to 30%, and you sacrifice 70% to 80%.

At the present time, what do you think is the best second-line option for kidney cancer?

Ongoing trials suggest that a PD-1 or PD-L1 antibody plus VEGF-type treatment will be very effective. That is probably what we will see in the next couple of years. That is the future.In terms of treatment options, everybody treats patients very differently. It depends on how patients progress. When a patient progresses, we have to think about what to give them. The most promising therapy is probably lenvatinib plus everolimus; that actually works very well. That is working on 3 different pathways. To me, in terms of targeting pathways, that is the most comprehensive way of targeting renal cell carcinoma (RCC) at this moment.

In the phase II trial that led to the approval of lenvatinib, all of the patients previously failed VEGF-targeted treatment. So lenvatinib plus everolimus becomes a very promising second-line treatment to me. It is the most effective second-line therapy.

For patients that progress very slowly and you have time to wait, then maybe you can put them on nivolumab, which takes time to work. But for patients that progress very quickly, you just don’t have time wait. To me, I am very hesitant to put any patient on single-agent immunotherapy without knowing if the disease is progressing fast or slow.

What do you see on the horizon for kidney cancer?

In my opinion, lenvatinib and everolimus becomes the standard second-line therapy.There is a very interesting phase III trial that is ongoing now, comparing lenvatinib plus everolimus or lenvatinib plus pembrolizumab to sunitinib alone (NCT02811861). Those are the 3 arms. Depending on how that goes, we could have a new first-line standard treatment.

In the future, I think we should be able to genotype every single patient with kidney cancer, and find out what kind of cancer genotype they have, and put them on appropriate treatment. To reduce the toxicity and increase the efficacy, that is what we need to do. Some data have shown that kidney cancer can actually be categorized into 4 different subgroups by genomics. The future is really going to be about finding that combination of drugs that is effective for the specific patient, depending on the genotype of their tumors.