Akash Patnaik, MD, PhD, MMSc, Assistant Professor of Medicine in the Section of Hematology, Oncology at the University of Chicago talks about the Checkmate 650 trial.
Interview conducted by Ivanhoe Broadcast News in July 2018.
I wanted to ask you a little bit about prostate cancer and treatments. For some men at certain stages of life with some slower growing cancers we’ve heard of the wait and see approach. Is that still really an option for a lot of men with this particular cancer?
Dr. Patnaik: Yes. Prostate cancer can be subdivided into two broad categories. The indolent cancers are the slow growing cancers which is what you’re referring to, are cancers that can happen in an individual’s lifetime but may never progress to the point of becoming aggressive cancer that would ultimately result in the demise of the individual or mortality. And that’s a very different type of cancer from the more aggressive cancers that can ultimately result in mortality that stems from the disease itself. And in terms of the indolent or slow growing cancers we usually have active surveillance which is what was previously called watchful waiting as one way of following these patients. As the name suggests, we actively screen with PSA’s and if there is any sign of progression or concern for disease progression or a diagnosis of prostate cancer we would do a biopsy. And so that is still something that we offer patients; it’s a select patient that we would make that determination for. So it’s very individualized, it’s not an option for all patients and several factors come in to play when you think about selecting a patient for active surveillance. These include age other co-morbidities, Gleason score, other types of diseases that they have that might influence how well they would tolerate surgery or radiation therapy.
How do you treat prostate cancer generally?
Dr. Patnaik: If you are talking about the early stage of prostate cancers, we will obtain multidisciplinary input from a urologist, a radiation oncologist as well as a medical oncologist to come up with a consensus of how best we should treat this patient. In addition to active surveillance, radiation therapy is certainly an option for low to intermediate risk prostate cancers. In that setting, we would offer external beam radiation therapy versus brachytherapy which is a very localized seed therapy. And then surgery usually takes the form of a radical prostatectomy where we would resect the prostate and lymph nodes that might be involved with the disease. In locally advanced prostate cancer that has not metastasized, we would offer radiation therapy as a standard of care in combination with hormonal therapy. We give a short course of hormonal therapy to make the radiation work better. And so that’s another treatment option for somebody that has a high-risk prostate cancer with a higher Gleason score.
We’ve heard a lot in cancer treatment over the last few years about immunotherapy, is that something that has been an option in prostate cancer?
Dr. Patnaik: Yes, that’s a great question. So, immunotherapy is an option for patients with metastatic, castrate-resistant prostate cancer. Sipuleucel T which is a personalized cancer vaccine that was FDA approved in this setting.. So this is when the cancer has spread outside of the prostate and the patient has become resistant to standard hormonal therapy or androgen deprivation therapy, but otherwise doing well with minimal symptoms.
Talk to me a little bit about the current trial, Checkmate 650.
Dr. Patnaik: This is a very interesting clinical trial that is looking at combining two different types of immunotherapy that essentially activate T-cells to attack the cancer. There’s been a lot of excitement about immunotherapy and cancer and both of these agents were actually first FDA approved in melanoma because of the striking responses that we’re seeing in about half of all the metastatic melanoma patients. Since that time, these agents have also been investigated in other cancers and have been shown to have striking anti-tumor efficacy, resulting in the FDA approval of the PD1 inhibitors in several different malignancies. In prostate cancer however the responses to these immune checkpoint blockade strategies that activate T-cells has been very limited. And so the Checkmate 650 trial investigates the additive effect of two of these agents, one that targets protein called CTLA-4 on T-cells with another antibody that targets a protein called PD-1 which is present both on immune cells as well as certain types of suppressive immune cells. And the idea here is that if you combine these agents you might get additive benefit relative to single agent CTLA-4 antibody or PD-1 antibodies. Both of those have been investigated as single agents in prostate cancer and have not shown promising responses of single agents across the entire spectrum of patients that have been investigated.
What is it about adding the two together, having them work together that appears to be working in some patients?
Dr. Patnaik: Some of these are ideas that are being explored in the research setting including my own laboratory. There is a school of thought that if you were to block one of these proteins on the surface of T-cells you may not be able to overcome the exhaustion of these T-cells because the other checkpoint may still be active. And so if you can now come in with a combinatorial strategy where you can target both of these checkpoints on the immune cells you might now be able to get more of a dramatic response than you have with just either agent alone.
How many patients are on the trial right now and can you tell me a little bit about the results?
Dr. Patnaik: This is a ninety patient multi-center clinical trial sponsored by Bristol-Myers Squibb, and the trial is now officially close to enrollment. The final results have not been reported.
If you could explain how it works. You’re talking about activating the T-cells to fight the cancer. If you could explain how this is working and this is fighting the cancer.
Dr. Patnaik: One of the major problems in cancer therapy is cancers are a lot smarter than we are. They figure out ways to paralyze the immune system and essentially hide themselves behind a fortress of immunosuppression. The cancer is composed not just of the cancer cells themselves but several other cell types that can suppress the immune system. The immune system is a fine balance between cells that can promote the growth of the cancer and cells that can actually suppress the growth of the cancer. So what we’re trying to do with these approaches and Checkmate 650 is one of many approaches where we are trying to enhance the ability of the good immune cells, the T cells to be able to enter the tumor and be able to overcome this fortress of immunosuppression and be able to have a net balance of an anticancer response. And that’s what we’re trying to achieve with these types of approaches.
Does that allow the body immune system to fight the cancer, does it give it a cancer fighting boost?
Dr. Patnaik: Yes. There is growing evidence that in patients that do respond to these therapies if we were to take a biopsy or a piece of tissue from these cancers, we would find that the cancers that do respond actually have more T-cells that are entering the microenvironment of these cancers.
Could you give me the names of the two agents?
Dr. Patnaik: Yes. One is CTLA-4 antibody called ipilimumab and the other is a PD-1 antibody called Nivolumab. And both are agents that have received FDA approval in melanoma and some other cancers as well.
Are they given as an infusion?
Dr. Patnaik: These are all IV intravenous infusions that are typically given in our outpatient infusion center. So they don’t require hospitalization.
And how often?
Dr. Patnaik: Usually it depends on the agent, as there are several of these types of agents now that have entered clinical trials. And typically they’re given as a IV infusion every two weeks or every four weeks depending on the agent. In some cases every three weeks but they are not daily injections.
If you could talk to me a little bit about the Stewarts, how you met Mr. Stewart and just the experience he’s had with the trial.
Dr. Patnaik: Mr. Stewart has been my patient for a little over two years now. I first met with Mr. Stewart when I was starting my practice here at the University of Chicago and moved from Beth Israel Deaconess Medical Center and Harvard Medical School in Boston. And he was actually one of my first patients when I moved here. And it was a real pleasure to meet both Mr. And Mrs. Stewart. At that point Mr. Stewart had already been diagnosed with metastatic prostate cancer. His cancer had progressed and he had also received several lines of therapy, including hormonal therapy, which is the standard backbone for treatment of metastatic disease. He had progressed on primary androgen deprivation therapy as well as second line androgen receptor targeted therapy and chemotherapy as well. And so he was at a point in his treatment course where he was running out of options. At that point we decided to profile his cancer from a genetic standpoint and perform next generation sequencing, which is a platform that enables us to characterize what are the individual driver mutations that may be important in the individual’s cancer and help us decide whether he is or is not going to respond to certain type of therapies. We did not discover any specific genetic mutation that would render his cancer susceptible to a specific type of therapy. And that’s when we decided that he would likely be a good candidate for the immunotherapy combination trial Checkpoint 650.
Tell me how he’s done.
Dr: Patnaik: It’s been a remarkable story. He had a very dramatic response even after receiving the first cycle of treatment. We gave him his first infusion and brought him back in four weeks and already there was a pretty sharp decline in his PSA. He had a striking response very early which was a bit of a surprise for us, as the dogma in the field is that immunotherapy often takes longer to work. But in his case he actually responded very quickly. And his PSA kept declining with subsequent cycles and he was already down to undetectable levels of his PSA by the end of the first couple cycles. So we were obviously very excited for him and for his family. And continued treatment to four cycles of the combination therapy.
Where is he now in terms of treatment, is he still part of the clinical trial?
Dr. Patnaik: He came off the clinical trial after about four cycles. He was doing reasonably well but there were some changes in his memory. The patient’s wife was concerned, and given that these are investigational agents, we are not always certain if this is drug related or not. It seemed less likely to be drug related. He otherwise tolerated the treatment very well. We had him come off the study after four cycles so he did not get the maintenance phase of the single agent Nivolumab (PD-1 inhibitor). We are very happy to report that he continues to be doing very well with an undetectable PSA.
Is there anything I didn’t ask you about this trial or treatment that you would want people to know?
Dr. Patnaik: I think we covered the broad strokes of the trial. Happy to answer any other questions.
Phase II trial?
Dr. Patnaik: This was a Phase II trial, yes.
How much longer does it run?
Dr. Patnaik: The trial is actually closed to accrual so we’ve met our target in terms of patient numbers. We should hopefully have the final reporting of the data in the next several months.
Will you then go to Phase III?
Dr. Patnaik: That is certainly what the intent of the study is. We’ll have to take a closer look at the toxicities associated with this type of combination therapy, as there have been toxicities that have prohibited people from being on these agents longer than a few cycles. We certainly need to take a close look because safety is our first priority. Checkmate 650 serves as a proof of concept that this type of approach can work in a subset of prostate cancer patients. It also provides a foundation ties for our ongoing research efforts both in the laboratory and clinical trials. The goal now is to determine whether we can push this therapeutic response further by combining immunotherapy with targeted therapies against specific genetic alterations , which could drive an immunosuppressive phenotype within the tumor.. And that’s what we’re doing now. We already have a clinical trial that is up and running stemming from work coming out of my laboratory where we’re looking at combining a PARP inhibitor which blocks DNA repair within cancer cells, in combination with PD-1 inhibitor . And we’re very excited about this concept. We have some early data in the laboratory that this strategy may have some interesting synergy and we want to test this now in the clinic in patients. We are in the early days of this clinical trial now but we should hopefully have more to talk about in a year from now.
END OF INTERVIEW
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