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After going through the "Dark Ages," we're approaching the "Golden Age" of kidney cancer care, with more options available than ever, says James Hsieh.
We are entering the “Golden Age” of kidney cancer care, says James Hsieh, M.D., Ph.D., 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.
(cabozantinib), Lenvima (lenvatinib) and Opdivo (nivolumab). Hsieh calls this time — between 2005 and 2016 — the Modern Age. It is here that patients first had a large variety of targeted treatment options, including Lenvima and Afinitor (everolimus), a combination which Hsieh said is “extremely effective.”
Then seven new drugs, all VEGF and mTOR inhibitors, were approved throughout the next decade, nearly doubling survival. More recently, three new agents were approved in kidney cancer:
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 percent or more of kidney cancer patients,” he said.
How have the approvals of Cabometyx, Lenvima and Opdivo impacted treatment in kidney cancer?
targets VEGF and c-MET, and Lenvima 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 two different pathways.
However, there is still a lot to achieve before the “Golden Age” can truly take off, said Hsieh. In an interview with CURE, he explained why targeted treatments still currently have more potential than immunotherapies, and what he sees on the horizon in kidney cancer.These three drugs are very different. Two are small molecules which, in addition to VEGF pathways, also targeted additional pathways.
The third drug, Opdivo is a PD-1 antibody. This brings us back to immunotherapy, because the first two 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 percent of patients benefit from it, and it only lasts for about two years. The VEGF treatments, even in the old days, benefitted 75 percent 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 Opdivo by itself because it only benefits 20 percent to 30 percent, and you sacrifice 70 percent to 80 percent.
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 Lenvima plus Afinitor; that actually works very well. That is working on three 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 2 trial that led to the approval of Lenvima, all of the patients previously failed VEGF-targeted treatment. So Lenvima plus Afinitor 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 Opdivo, 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, Lenvima and Afinitor becomes the standard second-line therapy.There is a very interesting phase III trial that is ongoing now, comparing Lenvima plus Afinitor, versus ceritinib plus Lenvima or Opdivo. Those are the three 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.