Charles Drake, MD, PhD
In the treatment of genitourinary (GU) cancers, immunotherapy continues to move toward the frontline setting. Charles Drake, MD, PhD, says he is optimistic about the future of immunotherapy, as trials are showing promising results in various GU cancers, echoing trials in lung cancer.
Immunotherapy is showing progress primarily in bladder and kidney cancer, but researchers are beginning to turn to prostate cancer, as well.
“Now that immunotherapies are approved in later settings, there is a lot of enthusiasm to move these earlier. In prostate cancer, we are very excited to try some trials for men who have rising PSA after surgery and to give immunotherapy either alone or with hormonal therapy to try to reset their whole course of disease. We're seeing this in kidney cancer and bladder cancer where immunotherapy is being used in the first line, and we'd like to do the same in prostate cancer,” says Drake.
In an interview with OncLive
, Drake, director of Genitourinary Oncology at NewYork-Presbyterian/Columbia University Medical Center and associate director for Clinical Research at the Herbert Irving Comprehensive Cancer Center, discussed pairing immunotherapy with chemotherapy, the efficacy of current immunotherapy agents, and the future use of immunotherapy in the treatment of GU cancers.
OncLive: What are some key recent developments with immunotherapy in GU cancer?
The big developments are mostly in bladder cancer. In bladder cancer, the anti–PD-1 antibody pembrolizumab (Keytruda) showed level 1 evidence for activity. At the 2017 Genitourinary Cancers Symposium
, we saw randomized data from a large trial comparing pembrolizumab to chemotherapy in second-line bladder cancer. This will certainly lead to this drug being used widely. Its joining a drug that is already out there—the PD-L1 inhibitor atezolizumab (Tecentriq)—and the other PD-1 antibodies can be used in this setting as well. By the end of the year we might have even another PD-L1 antibody, durvalumab. It’s fascinating, by the end of the year bladder cancer will have multiple treatment options with immunotherapy—I think it is moving into the mainstream.
In prostate cancer, I think the significant development is that we are starting to see signals. Pembrolizumab has shown activity in prostate cancer, in the context of patients who responded to hormone therapy, and now they are progressing on enzalutamide (Xtandi). Also, if you add anti–PD-1, some of them respond.
It is interesting, though, because these are very different settings. The bladder cancer setting is like phase III randomized data, "Here we go!" While prostate cancer has this early indication of activity. To me, these were the most significant developments in immunotherapy.
Will immunotherapy pair well with traditional therapies?
In my lab, we spent a lot of time modeling the combinations of immunotherapy with chemotherapy in mice. And you can do it, and you can get an additive signal—usually not synergistically though. It was tricky, though, you had to give lower doses of chemo, and the timing was absolutely critical. For example, low-dose cyclophosphamide given 1 day before immunotherapy—when you add that to immunotherapy it is actually really nice, it’s additive and the low dose of cyclophosphamide kills these suppressive cells, these regulatory T cells. But if you gave full-dose chemotherapy on the same day as the immunotherapy it was really bad, actually—neither of them worked particularly well. You don't really lose much of the chemo efficacy but it was not a beautiful thing.
In humans, this is not what happens, actually. It is really interesting—in lung cancer, clinical trials were done that I originally thought were, frankly, kind of stupid experiments. The idea was that they gave full-dose chemo with immunotherapy and kind of hoped for the best. And honestly, the best sort of happened—the response rate was much, much higher. It looked like the immunotherapy was adding to the response rate of chemotherapy, so progression-free survival was really improved. The problem with this is that we do not know whether that is going to translate into overall survival. So, the question is, do you use up all of your bullets in the beginning of the game, get beautiful responses and a long progression-free life? If so, will that translate to the patient living longer in the end or not? Nevertheless, I was completely wrong, it turns out that chemotherapy and immunotherapy—particularly checkpoint blockade—work reasonably well together.