T-DM1 Toxicity Management in Breast Cancer

Jane L. Meisel, MD

Data from the pivotal phase 3 KATHERINE (NCT01772472) has led to the addition of ado-trastuzumab emtansine (T-DM1; Kadcyla) to the HER2-positive breast cancer treatment arsenal, but the toxicities associated with the approach must be appropriately managed so that patients can continue to receive it, according to Jane L. Meisel, MD.

The phase 3 KATHERINE trial examined ado-trastuzumab emtansine (T-DM1; Kadcyla) vs trastuzumab (Herceptin) and showed that the former resulted in a 50% reduction in the risk of invasive disease recurrence or death (HR, 0.50; 95% CI, 0.39-0.64; P <.0001). These data led to the May 2019 FDA approval of T-DM1 for use as an adjuvant treatment in select patients with HER2-positive early breast cancer.

Notably, 25.7% of the patients in the T-DM1 arm experienced a grade 3 or higher adverse effect (AE) vs 15.4% in the trastuzumab arm. Additionally, 18% of patients in the T-DM1 arm experienced AEs that lead to discontinuation of treatment.¹

“It's tricky because these patients have been through a lot,” Meisel said. “It's a diagnosis of breast cancer, first of all, and it is a relatively toxic, intense, up-front therapy. It’s not the easiest thing, but for many patients, particularly those with high-risk disease, it really does make a difference. We try to do all we can to support patients through that.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on breast cancer, Meisel, an associate professor for the Departments of Hematology and Medical Oncology, and Gynecology & Obstetrics at Winship Cancer Institute, Emory University School of Medicine, discussed the use adjuvant T-DM1 and the management of associated toxicities and the benefit of the combination pertuzumab (Perjeta)/trastuzumab in HER2-positive breast cancer.

OncLive®: What were the implications of the phase 3 KATHERINE and FeDeriCa trials (NCT03493854) now that more mature data have read out?

Meisel: KATHERINE was a fascinating study because it not only allowed us to take a very high-risk group and randomize them to a potential intervention, but it also showed that they really did much better when, instead of being given just 1 year of trastuzumab after not achieving a pathologic complete response [pCR], they were switched over to adjuvant T-DM1. That 3-year progression free survival [PFS] difference of 11% is really statistically significant, as well as clinically significant, and this has changed the way we treat our patients. Routinely, we are switching [patients] over to T-DM1 as was done in KATHERINE, and I believe this will start to change outcomes, as we see more and more of these patients do better.

FeDeriCa was a study that looked at pertuzumab and trastuzumab given subcutaneously as opposed to intravenously, with the primary end point being pertuzumab concentration, so more of a pharmacologic/pharmacokinetic end point as opposed to a clinical end point. The authors also looked at PCR rates with the subcutaneous administration and found that both the trough concentrations as well as the PCR rates were the same with subcutaneous versus IV administration.

[This is an] intervention that changes convenience for the patient, and in terms of safety, particularly during the pandemic, [it can prevent] time spent in the infusion center. This is a preparation which, technically, could be given in one's home as opposed to even in the clinic. Certainly, for patients who want to have the port removed or don't want to receive IV treatment for longer than they have to, this offers an opportunity to do just a little injection as opposed to an infusion. In terms of quality of life for patients, which really is a huge [factor] after they've been through so much, this represents a major step forward.

Were there any prohibitive toxicities observed in KATHERINE?

In the study, approximately 18% of patients discontinued T-DM1 because of toxicity. Generally, the populations that we see in studies are inherently a motivated, relatively well population of patients, while those we see in clinic may have more comorbidities or may not be as motivated as those who choose to join trials. As such, more [efforts are needed] to monitor these patients and to encourage them to stay on the T-DM1 because it is a little more challenging than the pertuzumab/trastuzumab. However, the benefit is there, so when patients seem as though they're going to benefit and they fit the criteria for the trial, we do try to get them to stay on [the drug].

I find it works best if I tell patients about the possibility [of toxicity] in the beginning. When I describe the neoadjuvant, anti-HER2–directed regimen, I talk about the fact that we'll use their surgery as both a part of their treatment, but also as an information-gathering piece. The result of the surgery, whether they get to PCR or not, will inform the next step. If they get to PCR, [they] would [then receive] trastuzumab, likely plus pertuzumab, or switch to T-DM1 if they don't. Once I get closer to that time point after the surgery, and if the patient is going to receive T-DM1, then we talk about what that will look like.

Often, I do see the patients each visit with T-DM1, at least in the beginning, just to see whether they're experiencing [effects] like nosebleeds, gastrointestinal distress, or worsening neuropathy. These are some of the most common [effects] that we see with the T-DM1 regimens, so we prefer to get on top of these effects and manage them right away. [Then] patients can either make the decision to discontinue and go back to pertuzumab/trastuzumab if they need to or can feel empowered that we have ways to manage the AEs and get through as much of that year of T-DM1 as possible.

Could you elaborate on some of the strategies used to manage those toxicities?

With neuropathy, one of the main strategies that we have is gabapentin, which can be helpful. Additionally, there's solid clinical trial data that support that icing the fingers and toes during chemotherapy treatment helps prevent neuropathy from getting worse; that can also be empowering: to know that there's something they can do, or can try, to help with that. In terms of the nosebleeds, which can happen with T-DM1, it's important to keep the nostrils moist. Vaseline or nasal sprays [can be used] sparingly if the nosebleeds are particularly bothersome. If a patient is having recurrent nosebleeds, we will refer them to an ear, nose, and throat [specialist].

In terms of liver function abnormalities, we do encourage patients to not drink heavily while they're on treatment and to abstain from Tylenol or other medications that might interfere with liver function tests.

Also, [we see] fatigue, [which] is multifactorial. We certainly see that [when patients are] on breast cancer therapies of all kinds.

Turning to FeDeriCa, now that the subcutaneous administration is approved, do you believe that patients will be more likely to pursue that option if they experience a milder toxicity?

They might, because options are everything. Some patients may be sticklers for the data, who may say they want to wait a little longer and see more before they make the switch. For other patients, the pharmacokinetics, and the fact that it's FDA approved, may be enough for them. They may want to make the switch if they feel like it's palatable.

Insurance coverage may be another issue. I'm not sure that every insurance company is going to cover it to the same degree as they cover intravenous administration. Finances may play a role, but I do believe this is going to be something that has legs, for sure.

Reference

von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017