PI3KCA Inhibition: Managing AEs in HR+ mBC

Andrew D. Seidman, MD: Before I ask Aditya to walk us through the landscape of emerging new antiestrogen agents such as oral SERDs [selective estrogen receptor degraders] and other partners for endocrine therapy, I’m going to ask Nick to comment a little about the management of some unique toxicities of PIK3CA inhibition, such as hyperglycemia and stomatitis. Any pearls for us?

Nicholas McAndrew, MD, MSCE: Certainly, Hope can speak to the very important Swiss study that she helped lead that makes giving an mTOR inhibitor much easier. This used to be a nonstarter for many clinicians in terms of using mTOR, PI3K, and AKT inhibitors such as everolimus. But with the addition of oral dexamethasone rinses 4 times a day for 8 weeks and then potentially longer after that, I’ve had great success with my patients in terms of their ability to tolerate everolimus.

In terms of the hyperglycemia, 1 of the most important aspects of monitoring alpelisib, I don’t start my patients on prophylactic metformin because only two-thirds of patients had clinically significant hyperglycemia. It’s a majority of patients, and it’s an on-target effect of this drug, but it’s important to note that some patients will not have a significant degree of hyperglycemia, and it may be managed by lifestyle alone. But I do monitor it closely. I monitor it weekly. I even ask my patients to get a home finger-stick monitor. I watch for that closely and have a low threshold to start something like metformin.

Finally, the rash, especially with alpelisib, can be really impressive. Although it can come up quickly, it can also resolve. I tend to recommend that my patients start something like Zyrtec or another antihistamine to help reduce the chances of developing that rash in the first place. There are some toxicities. We’ve all had patients who just could not tolerate them early, but we’ve also had patients who can stay on them longer term, or else these studies wouldn’t have been performed. It’s important not to get discouraged by some of the adverse-effect profiles and to remain optimistic.

Andrew D. Seidman, MD: Hope, do you use proactive cetirizine, Zyrtec, preemptively in your patients? How do you think about that for the skin reactions?

Hope S. Rugo, MD: I do. It’s really important. I wish we could do a prospective analysis of this, because I have that sense, having talked to my dermatology colleagues who use the nonsedating antihistamines 3 times a day. They do that often for rashes and have found it to be more effective. There doesn’t seem to be toxicity from doing that, so I tell people to start twice a day the day before they start their alpelisib and continue through. When I’ve seen bad rashes, it’s almost all—not all—patients who have not taken the antihistamine. I recently had a patient who had somewhat of an allergic reaction rash with swelling of her lips. You’ll see these reactions. It’s mostly been borne out in BYLieve a little different in cohort B than cohort A that if you use these preventive nonsedating antihistamines, it really reduces the rash rather dramatically, similar to what we saw with the mouth sores using the oral steroid mouthwash. It’s not completely gone, but you see a lot less of it.

Dejan Juric, MD: Andrew, a very important aspect of managing alpelisib is deciding not just whom to give the drug to—in other words, patients with PIK3CA-mutant, ER [estrogen receptor]–positive breast cancer who are resistant to AI [aromatase inhibitor]–based therapy—but whom not to give it to. One important patient population is patients with uncontrolled diabetes mellitus type 2. This was relatively strictly defined. If A1C [glycated hemoglobin] at baseline is 6.5% or higher, that’s already considered not necessarily a good candidate for our policy. Why? Because of the incidence of hyperglycemia and the frequency of these events. With the wonderful work that Hope was the first author on, it’s clear that these patients don’t do well.

We need to be careful to not necessarily jump to conclusions just after 1 thing matching, which is PIK3CA mutation. We really have to look for the metabolically appropriate patient for the treatment. If you select folks who have A1C under 6.5%, the most important thing is simply early recognition. These events happen in the first few weeks. If you see glucose that’s about 140 mg/dL—certainly 160 mg/dL—this is the time to start metformin, as opposed to, “Let’s wait. Let’s figure it out.” Usually, these patients will accumulate the drug a bit, and then the glucose will get much worse. Early recognition is critically important, and early intervention even more so.

Andrew D. Seidman, MD: It’s interesting how we, as oncologists, at various times when new drugs emerge turn into cardiologists who manage hypertension and left ventricular dysfunction, endocrinologists who manage hyperglycemia, and even pulmonologists who are managing interstitial pneumonitis. We have a full bag of tricks.

Transcript Edited for Clarity