Some of the most exciting work in cancer immunology today is happening in the context of clinical trials. Clinical trials are a standard part of medical research. Before drugs or treatments can be approved by the FDA, they must be rigorously tested in clinical trials to determine their safety and efficacy. Patients who participate in clinical trials not only help move science forward, they also get access to cutting-edge therapies that are not yet widely available. And they are treated at some of the best hospitals in the world.
Jedd Wolchok, M.D., Ph.D., knows better than almost anyone what clinical trials can do for patients. As chair of the Cancer Research Institute’s clinical trials network and director of immunotherapy clinical trials and monitoring at Memorial Sloan Kettering Cancer Center in New York, he is leading some of the most important clinical trials being conducted today. We spoke to Dr Wolchok about his specialty: developing combinations of immunotherapies for patients with advanced melanoma.
CRI: Tell us about the patients you treat.
Dr. Wolchok: The majority of the patients that I treat have metastatic melanoma, which as many people know, is a skin cancer that is usually curable when diagnosed early. However, if melanoma metastasizes to a distant organ or even to other sites on the skin, it can be a very difficult problem to treat. The statistics surrounding treatment of metastatic melanoma are changing and I personally try to get away from timeframes in terms of prognosis. But with all those caveats aside, the textbooks would say that a patient with metastatic melanoma lives, on average, a bit more than a year.
CRI: How has treatment of melanoma changed in recent years?
Dr. Wolchok: Historically, treatment has focused on chemotherapy, with some use of immunotherapy in the form of the drug interleukin 2. But more recently, there have been two significant advances in the treatment of metastatic melanoma. One has been the identification of several mutations in the tumor that seem to drive proliferation of the cancer cells. And for two of those mutations, BRAF and c-Kit, we have medicines that effectively block those mutated proteins and control the disease for a period of time— about six or seven months on average.
The other area of advance is obviously in immunotherapy. We had some clinical trials that were exploring different immunotherapeutic drugs and one in particular that was exploring a combination of two immunotherapeutic drugs. That combination was composed of ipilimumab [anti-CTLA-4] and another drug. Ipilimumab was the first medicine ever proven to prolong the survival of patients with metastatic melanoma. And in fact, it was the first drug in 13 years to be approved by the FDA for the treatment of melanoma. So it was a landmark event.
With all that said, the number of people who benefit from ipilimumab is probably between 20% and 30%. That leaves a significant proportion of patients who are in need of a better answer. One possibility would be to combine that immunotherapy with another immunotherapy, in this case, a medicine called nivolumab [anti-PD-1], which is another immune modulating antibody that blocks a checkpoint called PD-1.
Our enthusiasm for this trial was quite high because of the significant pre-clinical scientific analysis that had been done, supporting the possibility that this combination could be more effective than either of its components. But knowing that both of the medicines have side effects, we also were very careful to watch for any evidence of increased toxicity with the combination.
CRI: Tell us a little bit about how you work with patients to help them understand the potential benefits and risks of clinical trials.
Dr. Wolchok: Clinical trials remain an extremely important part of the care of people with melanoma and, I would say, for many cancers where the standard therapies do not provide an adequate solution to the problem. In melanoma, it has always been our firm priority because the FDA‑approved options did not benefit that many people for a long period of time. But individual patients have different responses when you present to them what's essentially an experiment being done in people.
Some people recoil a little bit and will say, “Well, I don't want to be anybody's guinea pig,” or “I don't want to be a lab rat.” And that's normal because it is an experiment. We don't know what the results are and we will be collecting data just like any other scientific experiment.
The other feeling that people have is, “Do I know what I'm getting? Am I getting a placebo?” I think that's the most common question that people ask. “Am I going to volunteer for this and then get nothing?” And we are very upfront with people that there are some clinical trials where a group does get a placebo. These early phase clinical trials, which are exploring new combinations or new medicines, usually are not placebo‑controlled trials, but we are very upfront about that because it's an important part of the decision-making process.
I often tell patients that I'm not in the arm-twisting business in terms of clinical trials. I don't get paid more for putting people on a study, and I am their doctor regardless of whether they choose to take part in the study or whether they choose a standard option. It doesn't affect the way that I approach their care or them as a human being.
However, people come to us for the possibility of a new and better treatment option, and that's what we believe clinical trials offer.
CRI: Tell us about current available FDA-approved treatment options for melanoma.
Dr. Wolchok: We now have several approved medicines. One of them is ipilimumab. The others are BRAF inhibitors called vemurafenib and dabrafenib. Another targeted therapy, a MEK inhibitor known as trametinib, has been approved and can be given with dabrafenib. In the case of ipilimumab, the people in whom the drug shows clinical activity can manifest it not just for weeks or months, but for years. There are people I have treated with ipilimumab as part of clinical trials who are now out several years with no evidence of melanoma that's growing again. One of them actually went on to have two children after receiving just four doses of ipilimumab in 2005. So we're now approaching 10 years for that patient.
CRI: What special considerations are involved in taking care of a patient on a clinical trial?
Dr. Wolchok: Taking care of patients in clinical trials is an extraordinary privilege because you have been entrusted with taking care of a patient with a medicine or a combination of medicines that may not have been tested in people before. And so the heightened awareness of even the most subtle thing being wrong is extremely important.
We tell patients who are on clinical trials, especially with novel medicines or novel combinations, that even the slightest change in their usual body functions are of great interest to us and not to ignore it; let us decide whether this is something that requires more attention or not.
Some of the side effects of immunotherapy can present as being quite normal symptoms: I'm tired, I'm not hungry, I'm not sleeping well, I have a headache. But on a clinical trial, this could represent a unique toxicity of the medicine and we need to pay attention to that. So there is this need to have one's antennae raised a bit higher when taking care of people in clinical trials.
CRI: What do you think is the best part of working with patients on clinical trials?
Dr. Wolchok: I think the best part of working with patients, who are in clinical trials like this, is sharing the joy of a good result, of seeing them move onto life's next milestone. I mean, when you have a patient who is 22 when she's diagnosed with metastatic melanoma and goes on to have two babies, honestly, what is better than that? And so I think, sharing in the human joy of seeing someone have their life back is the most that I could ever hope for.
CRI: What are your hopes for the future of immunotherapy?
Dr. Wolchok: I really believe that immunotherapy is what holds the promise for durable control, not just of melanoma, but of many cancers. The successes that we've had with ipilimumab in melanoma have given rise to robust enthusiasm throughout the medical and scientific communities for the development of other immune-modulating medicines.
We now have not just one possible medicine, but an entire portfolio of immune-modulating drugs that I think will form the firm basis of combination strategies for the treatment of cancer. We all know how important immunotherapy is, but I think that the future is with combinations.