Joyce A. O’Shaughnessy, MD: Let’s go to the other side of the coin. I’ve heard general enthusiasm for these data particularly in patients who are high risk and node positive. As Adam said, stage III; as Sara said, our highest-risk patients getting large deltas. That’s really important. It’s probably pretty compelling in practice, but let’s look at the toxicity. Adam, could you lead us off? What are some of the key findings on toxicity from the curative setting and the metastatic setting, for example?

Adam M. Brufsky, MD, PhD: I’ll do the curative, and then we can open the metastatic to everybody else. The bottom line is that in IMpassion031, just about everybody had an adverse event. The grade 3/4 was about 68%. One patient died on each arm of IMpassion031. Most of the adverse effects, at least the typical ones, were related mostly to chemotherapy. But when you start going into the adverse events of special interest, which are mostly the immune ones, the big 1 appeared to be—this is also in KEYNOTE-522, but I don’t have the data in front of me, but I remember it’s a little more—the hypothyroidism.

Any-grade hypothyroidism is 6.7% in the atezolizumab arm vs basically 1.2%. There was 3% hyperthyroidism, there was pneumonitis, and there was a little colitis but not a lot. Not as much as we’ve seen in the metastatic trials. Some diabetes and encephalitis. Rash seemed to be a pretty big one, but it was in both arms and infusion-related reactions. There was this ocular inflammatory toxicity, which I assume is a keratitis. The thing is that, at least to me, you saw most of these adverse events of special interest. My impression—and I’d like to hear my colleagues—is that these adverse events of special interest were there. They seem to be a little less frequent than in the metastatic setting, and the thyroid issues were what dominated this.

I remember this because at the Miami Breast Cancer Conference this year, I had a debate with Hope Rugo about this. We asked the audience, and it was really interesting what happened. Hypothyroid was a little higher in KEYNOTE-522. It was at least 10% or 15%. We asked is it OK to give a woman long-term hypothyroidism? I have women who got pembrolizumab in some of the trials, not on this 1 but on others, who are still getting thyroid hormone 3, 4, 5, 6 years later.

Is it OK to give someone long-term hypothyroidism? Especially someone who is young, who has triple-negative breast cancer. Yes, she’ll survive breast cancer, but on the other hand, now you’ve given her hypothyroidism. I just bring that to my colleagues. I don’t know the answer.

Joyce A. O’Shaughnessy, MD: Thanks for that great summary of the things we’re facing every day with these immune-related adverse events. The question is, what’s your take on these in this setting? This is curative disease, long-term glandular toxicity, whether it is thyroid, whether it is adrenal; it is rarely pituitary. Some are probably reversible—hepatitis, colitis, pneumonitis are in the single digits but reversible. I want to hear you correct me if I’m wrong. The glandular stuff seems to be longer term, albeit rare, but these are serious.

Adam M. Brufsky, MD, PhD: Remember, we’re uncovering women. We forget we’re in endocrinology, right? We’re oncologists. We forget that. A lot of women float around with subclinical hypothyroidism, right? I mean, 15% to 20% of the population is the age that gets chemotherapy for breast cancer, immunotherapy for breast cancer. They have antithyroid antibodies. All we’re doing is giving them clinical hypothyroidism. So they have it anyway.

Joyce A. O’Shaughnessy, MD: No doubt. That’s right. Exactly right where that might have come out anyway in a portion of patients. Kevin, what do you think? How do you balance this in the curative setting in these sometimes uncommon but pretty serious immune-related adverse events?

Kevin M. Kalinsky, MD: It’s a real issue, and it’s why we need to be thoughtful in terms of who we’re considering giving checkpoint blockade. I’ll give you an anecdote because this is actively going on with 1 of my patients right now. This is a patient who was responding great to taxane-based therapy and was insistent on getting a checkpoint inhibitor. Somehow, with discussions with the family, discussing with a company, we were able to get the checkpoint inhibitor. She got 1 dose and developed the severe skin reaction and then dropped her hemoglobin down to 3 g/dL and developed a red cell aplasia. Twelve units of packed red blood cells later, she’s on high-dose steroids.

Just to put this in context a bit with what Sara Hurvitz was saying earlier. It takes just 1 patient who gets an anthracycline and has leukemia or a cardiac event for you to think, “Who should I really be using this for?” This is an example of how these drugs can have rare adverse effects, and when you see 1 it does give you a bit of pause. Even though it’s rare, you know, some of these toxicities can be long term. The other thing is that in I-SPY2, the rates of adrenal insufficiency were higher than what’s been reported as some of these other studies. The question is, is this just being monitored differently, captured differently, etc. I’m not underestimating the associated toxicities with these drugs.

Joyce A. O’Shaughnessy, MD: Thank you. That’s very compelling. I want to hear from the Saras too. In terms of your gestalt, how do you balance this all? Let me start with Sara Tolaney this time.

Sara Tolaney, MD, MPH: As Kevin was saying, just a couple of cases of significant immune-related toxicity always make you pause and really want to be very thoughtful about decisions about who gets treated. I’ve certainly had patients who have developed hypophysitis, thyroid abnormalities, and primary and secondary adrenal insufficiencies of both. It’s hard to see. They’re young women who are going to have this long term, and some of them are going to have lifelong steroids, and that’s a serious issue. In the metastatic setting, I’ve even had cases of type 1 diabetes develop. I have 1 patient now on an insulin pump. In a curative setting, this is much more of a lifetime impact, and we don’t know about fertility impact. Particularly in our young patients, we have no idea what that could be.

I do think we have to be very thoughtful about this, and that’s why in my mind, right now I’d want to restrict utilization to the high-risk patients, who need additional therapy that is providing significant benefit. In that case, it’s worth the potential toxicity risks that there are. As Kevin alluded to, these are rare things we’re mentioning. Obviously, if you look at the percentages, they’re not common. The challenge is we’re also still learning how to monitor for all this. We know to check the thyroid function all the time, but we’re not drawing routinely all the time. Cortisol is not in the guidelines. How many times may we be missing some adrenal insufficiency? We just need to be cautious.

Joyce A. O’Shaughnessy, MD: Thank you. Sara, have the last word on this.

Sara A. Hurvitz, MD: I couldn’t agree more with my colleagues. The East and West Coasts are really coming together here. I completely agree. I shared an anecdote of a couple of patients I treated. One of them came in with these little lumps under her skin behind the knee, and I foolishly thought it was a Baker’s cyst—because I don’t remember general orthopedics or general internal medicine—and then it popped up behind her elbow. We had an ultrasound, and they were hard, hard masses that were growing. It was from 4 doses after pembrolizumab. It’s this granulomatous condition that can happen subcutaneously. This isn’t as serious as what Kevin and Sarah have shared, but clearly we are impacting their bodies and potentially in a harmful way. These patients are potentially cured with chemotherapy. I just want to underscore what everyone has already said. We have to take it very seriously, which is why we’re all very eager to see the EFS [event-free survival] and OS [overall survival] data come out.

Joyce A. O’Shaughnessy, MD: Right. There’s really great consensus here. Let’s see some EFS, but for our highest-risk patients who we know we’re not making it, we’re not getting there with them. That’s a different matter because we know their prognosis is going to be abysmal. That’s where we’re going to be thinking about it. Thanks, everybody. Great conversation.

Transcript Edited for Clarity