Yelena Y. Janjigian, MD: Immunotherapy has entered our practice for quite some time. It’s part of the clinical trials and we’ve learned a lot about using monotherapy and the combination of immune checkpoint inhibitors. Outside of a clinical trial right now, pembrolizumab is FDA approved for patients with PD-L1 by immunohistochemistry tumors. I tend to learn about the tumor biology and the immunohistochemistry and molecular characteristics of the tumor early on. I characterize these tumors in the first-line setting so that it helps you plan the second and third-line settings. What are the treatment options? I tell my patients it’s like a chess game, and you need to plan at least 1 or 2 steps, maybe more, ahead so you know what your strategy is.

For patients who we know are PD-L1 positive or have MSI tumors, immune checkpoint inhibitors are FDA approved and are used commonly and routinely in the third-line setting. We know that the majority of our patients, however, will not benefit from immune checkpoint inhibitors, and that’s the sobering reality of these agents. Yes, there’s always a tail on the curve and a plateau on the curve, and these agents actually have long-term survivors and this metastatic disease becomes quite manageable, but it’s a very small minority of patients. Where the field is really moving forward with these immune checkpoint combination is combinations of anti—PD-1 therapy with anti–CTLA-4 therapy, or even next generation immune checkpoint inhibitors.

Alan P. Venook, MD: For any disease, it’s always a balance between the standard therapies, the anticipated toxicities, and the newer therapies and the toxicities that we may not be able to predict. I would say that the checkpoint inhibitors, in particular, have a very unusual side effect profile, and most patients may do just fine with them. You’ll get a handful of patients, though, who get autoimmune disease. The checkpoint inhibitors essentially unleash the immune system, and there’s a certain sense of loss in what is self and what is cancer. We’ve seen patients with complications ranging from colitis— severe diarrhea, for example—to myasthenia gravis, literally paralysis.

These checkpoint inhibitors have major consequences and side effects. Usually, the side effects or the complications happen early in the course of treatment. But the practical management is that if it happens, you need to be respectful of it. We’ll monitor liver function tests; we’ll monitor thyroid function tests. With abnormalities, there may be more laboratory based than there are clinically. But we’ve seen patients with pulmonary toxicity or with renal toxicity. Almost any organ can be affected. And how you manage it is stopping the drug treatment and seeing if you can revisit it later on.

Yelena Y. Janjigian, MD: We know that these immune checkpoint inhibitors can have severe toxicity, and there’s this perception among patients that somehow, because it’s not chemotherapy, it’s safe and nontoxic. Well that’s certainly not the case. These immune checkpoint inhibitors can have severe toxicities that can potentially be devastating if they’re not picked up and managed earlier.

What I tell my patients is that we’re opening Pandora’s box. These agents can really take the brakes off the immune system and make the tumor, but also the normal cell, much more visible to the immune system. That can cause a plethora of side effects: autoimmune effects, effects on adrenal insufficiency, thyroid insufficiency, colitis, and other severe toxicities.

Alan P. Venook, MD: There’s an interesting question I’m asked all the time. Can we prevent the toxicities? I’m not aware of whether we can do that or not. For somebody who gets a little bit of diarrhea or a little bit of a rash, we may be aware of it, but you’re not going to use steroids in these patients if you can avoid it. With the colitis, for example, do we want to go with something like an anti-TNF drug, which is exceedingly expensive and has its own toxicities? It’s a balancing act. What we are trying to do on a research basis is figure out who’s going to get those toxicities because that would be far better than what we’re doing now. Right now, I’d have to admit that we’re flying blind in terms of how to do it, and we’re reactive rather than proactive.

My view is that patients who are obviously MSI-high patients, who are rare, are the patients we would select for these kinds of therapies. Otherwise, if not on-study, I think we’re rudderless. The expression level of PD-1 or PD-L1 has not been shown to correlate. So, until we’re guided by further data—and to their credit, Merck in particular, and BMS (Bristol-Myers Squibb) as well, are doing a lot of work at looking at correlative efforts to determine who benefits and who doesn’t—I would wait. I’m hopeful over the next year or so we’ll get clarity as to who to treat and how to treat them.

The question of when to use immunotherapy is an evolving one. As with any new treatment, you develop it in patients with advanced disease in the refractory setting. Right now, probably the most advanced studies of checkpoint inhibitors are in colon cancer. Those are now in first line, in fact, even in the adjuvant setting. But we don’t have any results yet. Until we have results, I’d loathe to incorporate it into the front line except on a study. As I said, if you happen to have a patient who gets a severe autoimmune effect, let’s say colitis, you may lose the battle before you even started to engage in it. And so, for all the promise, we have to really resist the temptation to jump these ahead. I think we need to be respectful of the risks associated with them, and use them very cautiously.

Transcript Edited for Clarity