Transcript:Robert H.I. Andtbacka, MD, CM: Mike Postow, when the patient comes to you and they ask you questions, like what is anti-PD-1 therapy and how does this work, how do you explain this to the patient?

Michael A. Postow, MD: It’s a very interesting concept, now that we have immune therapies, to explain that this is different from traditional chemotherapy that we may be considering for other patients with other diseases that we’re treating. So, I like to just tell patients that the immune system is like a police force within their body, policing against viruses and bacteria and things trying to invade them, but also polices against cancer. And, for whatever reason, in that individual patient, their body is just not fighting the melanoma strong enough. So, anti-PD-1 is a way of enhancing the patient’s immune system to try to help their own body’s immune system destroy the tumor. The general fundamental framework is usually really helpful for patients, and also explaining that they’re not going to need to walk around with a mask, that they’re not going to be immunosuppressed, and that the side effects that they may experience from this are related to our enhancing their immune system’s strength, not so much that we’re giving them chemotherapy that would make them more susceptible to infections and/or have hair loss—because a lot of patients come in and they’re worried about looking like a cancer patient, or needing to walk around with a mask, or losing their hair. And, I think, education about this being an entirely different approach than chemotherapy, not necessarily without any toxicities—and it is important that we understand that—but, first, just explaining the rationale for this in a broad picture is important. Most patients do take well to the concept.

Robert H.I. Andtbacka, MD, CM: And speaking of the toxicities, Georgina, how do you explain the toxicities to the patients? What are the most common toxicities, and how do you manage these in Australia?

Georgina Long, MD: So, that’s a really important point, particularly when you’re talking about the combination immune therapy. I use a very similar framework to Mike. I talk about the mode of action that we’re stimulating in their immune system, and, in doing so, we’re hoping to kill the melanoma cancer cells, but we may start attacking some of their normal tissue. Their immune system may start attacking some of their normal tissue. I highlight the fact that it can actually attack any tissue, and we have no way of predicting which one. I usually really use gestures so that they get a visual, as well. There are five common gestures, for example: skin; diarrhea—because their bowel can be attacked by the immune system; endocrinopathies, particularly thyroid when we’re talking about anti-PD-1, but also hypophysitis, which is very rare with anti-PD-1 alone, and is much more common with the combination of CTLA4 and PD-1; and hepatitis. And then, when I talk about anti-PD-1, I do mention some of the rarer things, as well, definitely with the combination, but I do say sometimes your lungs can be affected. You can get inflammation of the lung, and we’ll be asking you every time we see you about whether you’re getting a cough or whether you’re short of breath, just so they can contextualize it. The most important thing, though, is that there is a framework for the patient to contact the cancer center to let them know or even to ask whether this is something they need to be worried about—because the last thing I want is one of my patients sitting at home with diarrhea and not acting upon it for 24 to 48 hours, or even 3 days, and then we’ve got a really big problem on our hands. The other principle is, if you know about it early, you can treat it or monitor it early, and patients do a lot better and get through their treatment with a much higher quality of life. So, it’s very important.

Michael A. Davies, MD, PhD: It’s also one of the points that I reinforce with patients because, again, as Georgina said, our real concern is if patients develop these side effects and don’t notify a physician, the side effects can become very severe and even quite dangerous. And, we know that, again, patients are often maybe reluctant to tell physicians about side effects because of the fear that their treatment will be stopped. And one of the interesting things we’ve observed, over time, is that patients who do develop these side effects seem to actually have a higher chance of benefitting from the treatment. And, indeed, if we see those types of toxicities, stopping their treatment and using immunosuppressant medications to get them under control does not obviate the ability of the treatment to work. This appears to be separable, the toxicities that come from the regimen versus the anti-tumor activity. And so, again, really reinforcing with the patients how important it is for them to let us know if these side effects start.

Robert H.I. Andtbacka, MD, CM: Another question that we often get about patients when they start on these therapies is: how soon do you expect to see a response to these therapies? How do you advise patients on that? Let’s say they’re on monotherapy, anti-PD-1 therapy, versus being on the combination of nivolumab plus ipilimumab?

Michael A. Postow, MD: I know there’s a notion that immune therapy responses take a long time, but the reality is we see shrinkage of the tumor, sometimes very quickly, even with anti-PD-1 monotherapy, certainly with the combination. A lot of the data in the clinical trials will report something like median time to response, and, often, that’s median time to RECIST-defined partial response. But, these patients are having tumors that are shrinking the entire time from the beginning of therapy. So, I don’t know. For patients, I don’t think it matters so much to them when the median time to the RECIST partial response is. And so, sometimes if that’s 3 months or 6 months, they want to know, “Are my tumors going to start shrinking right away?” I think in many of the responders, you do see that shrinkage right away. However, it is important to note, some patients don’t shrink right away. Some will remain for a while, and then shrink slower over longer periods of time. Some people will have shrinkage of existing disease with presence of new lesions, and that doesn’t necessarily mean that the treatment isn’t working in those patients, and therapy can be continued. And then, there’s the notion of these pseudo-progressive cases or immune-related responses where patients may have apparent worsening of their tumor before ultimate benefit and shrinkage. I think the important message, there, is that is still, unfortunately, a rare phenomenon. That isn’t what we expect to necessarily happen in all patients. We do usually see that the majority of the patients who are having really clear progressive disease, unfortunately, do progress. So, we really have to take care of those patients very cautiously. And, although we can’t rule out the possibility of a late benefit, we should start thinking about, what if this really isn’t working, what are my other options at that point.

Transcript Edited for Clarity