Insights From: Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center; Thomas Hutson, DO, PharmD, FACP, Baylor University Medical Center; Texas Oncology; James J. Hsieh, MD, PhD, Washington University School of Medicine
Martin H. Voss, MD: We’ve talked quite a bit about treatment of metastatic disease now. Obviously, there is heavy investigation on using many of the medications we’ve discussed today in the nonmetastatic space. Over the last 10 years, many such trials have been conducted and we’ve been anxiously awaiting the results. And over the past 2 years, we have now started to see the first efficacy results come back for some of these large phase III randomized trials conducted in the adjuvant space.
There was surprise that, after it was seen on the randomized ASSURE trial, 1 year of TKI therapy postoperatively in a patient with nonmetastatic disease failed to improve disease-free survival compared to placebo. And shortly thereafter, we saw the results of the S-TRAC trial—which was an industry-sponsored study of one of these medications, sunitinib, also given postoperatively for 1 year compared with placebo—and here we saw improvement in disease-free survival.
This, of course, has spurred many discussions now and ultimately, the impression is not only the difference in patient characteristics going on to the trial, specifically the degree of high-risk versus low-risk patients, but also clear-cell versus non–clear cell variants. And secondly, dose exposure, meaning how hard patients were pushed to stay on full dose during the course of the trial, may have had a major impact that explains the difference in outcomes seen on these 2 studies.
For community oncologists, it’s important to bear in mind that sunitinib has no FDA approval as of yet in the treatment of nonmetastatic disease. And the standard, as of today, in the adjuvant space remains active surveillance.
Thomas Hutson, DO, PharmD, FACP: Probably one of most exciting areas besides combination strategies for patients with metastatic disease is trying to actually increase our cure rates for patients with locally advanced disease. As most are aware, there has only been 1 positive trial in the adjuvant setting. We heard about this this past year, called the S-TRAC trial with sunitinib. At ASCO 2017, we see the results of a negative phase III trial called the PROTECT trial evaluating pazopanib as a therapy in the adjuvant setting.
Although the trial was negative, when one looks at a subset analysis, it appears that the full-dose 800 mg cohort seemed to have some degree of benefit, which brings to mind why the S-TRAC trial may indeed be positive and other trials may not be. In the S-TRAC trial, patients were started at full dose of sunitinib, 50 mg, and the dose intensity reported out on that trial was greater than 40 mg, unlike other trials that may be done where they start at lower, less effective doses because of toxicity concerns. Beyond TKIs in the adjuvant setting, we have great hope that I-O therapies may provide great value as adjuvant options. And there are several clinical trials. For instance, I’m aware of a phase III trial of pembrolizumab in the adjuvant setting for patients with high-risk renal cell.
The advantage of an I-O strategy is hopefully less toxicity that allows patients to complete a prescribed length of time of adjuvant therapy. Our goal is not only to improve disease-free survival, but to improve cure rates.
James J. Hsieh, MD, PhD: The most important thing at this juncture is when we get into the golden age, really, we need to think about the way that we can cure our patients instead of just putting them under control. And we should actually start to think about that possibility, but we also need to redefine the definition of “cure”.
The unmet need was with the golden age arrival. We have 12 drugs the FDA approved in the United States. We are going to double the survival, but we cannot double the survival with just by randomly using the trial drugs in any sequence. We need to use them in different ways, mainly based on mechanisms. As I said, there are many drugs but at this moment, we can think of VEGF as 1 arm, mTOR’s 1 arm, VEGF FGF is 1 arm, VEGF c-MET is 1 arm, and PD-L1 is 1 arm. It also looks like CTLA-4 will be 1 arm. So, there are many, many different options available.
The only unmet need is we have by grace through an era, I call it the dark age, we don’t know how to truly tell patient, “We’re going to give you 100% toxicity, you can live a few more months.” To a modern age then, we can double their survival, but most of them still die of their disease. In the golden age, what we need is to strive for curing some of them. I really like to talk about this a little bit in terms of the definition of cure. We all have cancer, I think, in the human body. OK, think about it: each DNA is 3 billion base pair of DNA. Each DNA goes up 2 copies, so we have 6 billion base pair of DNA.
We have about 50 trillion cells in our body, and with the turnover, it’s hundreds of billion cells every day. The transaction of nucleotide, I call it gazillion, is that it’s 21:0 behind 1. How can you have not even any error? It’s impossible. So, there is error. We always encounter facing the error from happening. But the reason we didn’t develop tumors every day is because our immune system actually detects when we have early mutations. It gets rid of it already. That’s why I think we all come with a mutation, we all come with the cancer most of the time in our life. But it never manifests as disease because our immune system is actually doing a very, very good job.
So, in the old targeted therapy era, people needed to take medications every day, actually reminding the patient that they have the disease every day. In the era that I call the golden era, basically the idea is if you give a patient the most effective treatment and get their disease into maybe invisible, or very, very stable, you can take them off treatment and they just monitor their disease. If after 2 years their disease doesn’t change at all, or there’s nothing coming back, they should live their life. So, the modern definition of “cure” shouldn’t be if you live 5 years, it’s a cure. No, it’s not. But nowadays, it’s how do you define cure? It’s almost impossible to. Any patient who had a cancer encounter in their life, they always think they have cancer their whole life, until the day they die. So, I think the definition of “cure” should be changed and everybody needs to embrace the new definition, otherwise, we’re getting nowhere.