I’m Dr Jules Cohen, Clinical Associate Professor of Medicine at Stony Brook University. In my practice, I have many patients with HER2-positive metastatic breast cancer who have progressed on first-line therapy.

As part of our discussion today, we’re going to review the characteristics of patients with HER2-positive mBC who have progressed on first-line therapy.

Patients with metastatic breast cancer demonstrate a variety of clinical and nonclinical characteristics, all of which factor into my decision about what to do next.

Important considerations for the next line of therapy include the age of the patient, their performance status, their overall burden of disease, whether or not they have visceral metastases, prior therapies that they’ve received, and of course, whether or not they have brain metastases.

Other important aspects to consider when determining the appropriate second-line treatment for a patient include, but are not limited to, duration of treatment and rate of disease progression on first-line therapy, as well as the current severity of disease.

Gaining knowledge of these factors assist in understanding how severe the disease is at this stage and what direction we can proceed in terms of treatment.

There are nonclinical factors to consider as well, such as the goals of each individual patient, their financial capacity, and their ability to understand treatment and monitor for known side effects.

I’d like to share with you an example of one of these patients from my practice, what decision we reached together, and how she fared on that treatment.

My patient was diagnosed with de novo HR-positive HER2-positive mBC and she had recently progressed on her initial treatment with THP. She’s a 55-year-old female with good performance status.

Historically, it was understood that HR-positive patients also described as triple positive could benefit from hormonal therapy, a combination of an anti-estrogen and HER2-targeted treatment. This combination therapy typically included an aromatase inhibitor and trastuzumab in early lines of therapy.

More recently, however, medical oncologists have been shifting the treatment pattern by using chemotherapy in earlier lines. With the current recommendation in first-line therapy, THP, the consensus is that all patients with HER2-positive mBC should get this first-line treatment regardless of ER status.

After a patient progresses on first-line therapy, you are faced with the same challenge in second line. A medical oncologist could theoretically give a historically reliable therapy to these triple positive patients, considering their diagnosis and progression, but the data for newer HER2-directed treatments may be balanced for efficacy and safety, supporting the use in these patient types as well.

My patient received six cycles of THP with an excellent radiologic response. She continued on maintenance HP every three weeks with restaging scans every three months. After 32 months on therapy, restaging CT scans showed the development of new liver lesions. Biopsy of the liver lesions showed metastatic carcinoma consistent with breast primary. ER was strongly positive and HER2 was 3+ by IHC, consistent with HER2 overexpression. Additionally, a brain MRI was performed and did not indicate brain metastasis.

This news was upsetting for her to hear, but she was relieved and hopeful for the future when I discussed her options for second-line treatment.

First and most importantly, we discussed what her goals were moving forward. My patient has an incomparable passion for life. She is ready and willing to fight this battle with all her might. As a wife, a mother, and a business owner, her desire to maintain an active lifestyle, participate in family activities, and continue to work meant we needed to carefully consider the benefit-risk profile of every available treatment.

The two treatment options we discussed were ENHERTU and T-DM1. Comparing ENHERTU versus T-DM1 is a common discussion point when determining the appropriate option for second-line therapy. Based on the guidelines, it is standard to give THP in the first line and ENHERTU in the second line. While these guidelines are influential, it is the role of medical oncologists to manage treatment with approved dosing, dosing schedules, proper monitoring of adverse reactions, and treatment with prophylactic interventions.

After discussing the benefits and risks of both treatment options at length, we ultimately decided to proceed with ENHERTU.

Prior to initiating ENHERTU, I reviewed the efficacy results from DESTINY-Breast03. I explained that this was the first head-to-head trial of ENHERTU versus T-DM1 and noted that this treatment was the alternative option that we had discussed.

With ENHERTU administered as monotherapy, the adverse reactions observed in the trial are established, and thus healthcare providers may be able to anticipate and use proactive management.

One of those key adverse reactions is interstitial lung disease, or ILD, and pneumonitis. ILD is categorized according to its severity and necessary intervention. Grades 1 and 2 indicate asymptomatic or mildly symptomatic patients who can be managed by observation or medical intervention. Grade 3 ILD indicates severe symptoms, while Grade 4 represents life-threatening respiratory compromise requiring urgent intervention. And Grade 5 refers to cases resulting in death.

Although ILD is a serious concern, it is manageable when caught early, and so we focused on the signs and symptoms that she should look out for, such as coughing, dyspnea, fever, or new or worsening respiratory symptoms.

I explained our protocol for investigating any evidence of ILD/pneumonitis, recognizing signs and symptoms with a synergistic approach based on my patient’s self-assessment and evaluation of vital signs such as respiratory rate and O2 saturation, performing CT scans to screen patients with asymptomatic ILD and to scan patients with symptomatic ILD for diagnosis, initiating steroids, in addition to a potential suspension of treatment with ENHERTU, and considering formal pulmonary consultation depending on severity.

Other potential adverse events included nausea and vomiting. Because ENHERTU can induce delayed nausea and or vomiting, I always administer prophylactic antiemetic medications per my institution’s guidelines.

Alopecia is also a common adverse event with ENHERTU. Some of my patients have experienced Grade 1 alopecia, which is consistent with the majority of alopecia events in DESTINY-Breast03. Grade 1 alopecia is defined as hair loss of less than 50% of normal for that individual that is not obvious from a distance, but only on close inspection. Grade 2 alopecia is defined as hair loss of greater than or equal to 50% of normal for that individual that is readily apparent to others. In an ideal setting, most patients would prefer to maintain their physical appearance, but when balancing efficacy versus safety, especially with ENHERTU, it’s important to review the benefit-risk profile and keep the patient’s goals and desires in mind.

Let’s reflect on my patient’s previous combination therapy. With current recommendation for first-line treatment, the incidence of alopecia is high and expected. As discussed earlier, the consensus is that all patients with HER2-positive mBC should receive THP in the first line regardless of ER status.

Historically, I’ve always tried to spare patients the toxicity from treatment in the mBC setting because there was not a lot of data to suggest that one treatment was better than another.

The PFS and OS data for ENHERTU were superior to T-DM1, which has established this treatment as the standard of care in second-line HER2-positive mBC.

There is a dose reduction schedule, the ability to provide supportive care, and monitor for adverse reactions.

For the majority of patients in DESTINY-Breast03, Grades 1 or 2 neutropenia were observed; similar to fatigue, diarrhea, and constipation, which had a majority of Grade 1 occurrences.

These data align with what I see with most patients taking ENHERTU in my practice.

I often share with my patients that efficacy and toxicity are not directly related to each other. If a patient has an adverse reaction, it doesn’t mean that the treatment is or is not working; it just means they’re having an adverse reaction.

Not all treatments are one size fits all. Each patient reacts differently, and it’s important to evaluate dosing on an individual basis using the dose reduction schedule.

A restaging scan showed improvement in all metastatic sites with no evidence of progression. She did experience some nausea during the first three or four cycles, but this was managed with ondansetron. She did experience Grade 1 alopecia, but this did not worsen by cycle five of ENHERTU. I observed Grade 1 neutropenia in this patient that did not increase in severity throughout treatment. She did not experience diarrhea but did report fatigue and constipation.

We will continue the course of treatment with ENHERTU as planned, as well as continue to monitor closely for any safety signals of interest such as ILD/pneumonitis.

Because my patient’s clinical profile fit those of the patients in DESTINY-Breast03, I was encouraged to see the positive results she achieved while on treatment with ENHERTU.

DESTINY-Breast03 was a Phase 3 head-to-head study of ENHERTU versus T-DM1 of 524 previously treated adults with HER2-positive mBC. A range of patients were studied, including those with good performance status and visceral metastases in the liver who’d received trastuzumab and a taxane, just like my patient.

The initial PFS data from DESTINY-Breast03 demonstrated clear superiority of ENHERTU over T-DM1. It is clear that ENHERTU has established itself as the standard of care for this patient population in HER2-positive metastatic breast cancer.

In the updated analysis, patients receiving ENHERTU experienced 28.8 months median progression-free survival, whereas those in the T-DM1 arm experienced 6.8 months median PFS.

Additionally, ENHERTU demonstrated a superior overall survival benefit versus T-DM1.

ENHERTU was associated with common adverse reactions, including laboratory abnormalities. The nausea, alopecia, fatigue, constipation, and neutropenia my patient experienced were all in line with the expectations set by the ENHERTU safety profile in DESTINY-Breast03.

The pooled safety data for ENHERTU 5.4 mg/kg further highlights the key safety signals of interest—ILD, neutropenia, and left ventricular dysfunction—and confirms the risk-benefit profile of ENHERTU.

In what types of patients would you consider treatment with ENHERTU? Based on the clinical data, many types of patients may be eligible for treatment. Evaluate the efficacy and safety results of ENHERTU for yourself to see if this treatment is appropriate for your patients with second-line HER2-positive mBC.