CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: February 07, 2024
Expiration: February 06, 2025
DESTINY-Breast04: T-DXd–Related AEs
In the DESTINY‑Breast04 trial of T-DXd vs physician’s choice of chemotherapy for HER2-low, unresectable, and/or metastatic breast cancer, the most common all-grade T-DXd–related adverse event (AE) was nausea (73%), followed by fatigue (48%) and alopecia (38%), and the most common grade ≥3 treatment-emergent adverse event (TEAE) was neutropenia (14%).4,10 The most common TEAE that led to the discontinuation of T-DXd was ILD or pneumonitis, which occurred in 8.2% of patients, and 2.3% of patients discontinued chemotherapy because of peripheral sensory neuropathy. Dose reduction occurred on the T-DXd arm mostly because of nausea and fatigue (4.6%). As expected, neutropenia was the most common reason for dose reduction on the chemotherapy arm (14.0%). In total, on-treatment deaths were reported in 3.8% of patients who received T-DXd vs 4.7% of patients who received chemotherapy.
DESTINY-Breast04: Drug-Related TEAEs by Age
Analysis of the DESTINY-Breast04 trial according to age demonstrated that the TEAE profile for T-DXd was independent of whether patients were younger than 65 years of age or 65 years of age and older.11 The toxicity profile for T-DXd was consistent with that reported in the overall patient population and independent of age group.
Summary of AEs of Interest With T-DXd From Phase III Trials
The DESTINY-Breast02 trial investigated T-DXd vs treatment of investigator’s choice for HER2-positive advanced breast cancer previously treated with T-DM1. The DESTINY-Breast03 trial assessed T-DXd vs T-DM1 in HER2-positive advanced breast cancer, and DESTINY-Breast04 investigated T-DXd vs physician’s choice of chemotherapy in HER2-low advanced breast cancer. Across these 3 different phase III trials of T‑DXd, the most common TEAE was nausea, which was observed in 73% to 77% of patients, with grade ≥3 nausea occurring in 5% to 7% of patients.4,12,13 All-grade diarrhea was observed in approximately 20% to 30% of patients, with a low incidence of grade ≥3 events, which occurred in 1% to 3% of patients. It is important to be cognizant that fatigue and alopecia also can occur with T-DXd; however, <1% of the patients on these trials experienced grade ≥3 alopecia. Grade ≥3 neutropenia was noted in 8% to 16% of patients.
ASCO Antiemetic Guidelines Update 2020
Because nausea is the most common TEAE associated with T-DXd, it is important to be aware of current antiemetic guidelines. In my practice, for patients with moderate emetic risk, I have found the use of a 3‑drug prophylaxis regimen with a neurokinin 1 receptor antagonist, a 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone on Day 1 of treatment to be very helpful.14 For patients with a high emetic risk, a 4-drug regimen with the addition of olanzapine on Day 1 of treatment is recommended. I have found that the 4-drug regimen can control the severity and prevalence of nausea seen in patients receiving T-DXd.
ADCs: Interstitial Lung Disease
ILD is a distinct AE associated with T-DXd.15 We need to be aware of it so that it can be rapidly diagnosed and appropriately managed. ILD is characterized by an ineffective gas exchange due to alveolitis, disrupted alveolar structures, and fibrosis. The exact mechanism through which ILD occurs in patients receiving T-DXd is unknown, although it is thought that it may occur as a result of a target-independent uptake of the DXd cytotoxic payload in immune cells via a bystander effect of the released cytotoxic payload or as a result of damage from the circulating cytotoxic payload after its release. Of note, ILD can be fatal, and it has been associated with different ADCs, including T-DM1, T-DXd, and the investigational HER2-directed trastuzumab duocarmazine. Therefore, ongoing monitoring, early diagnosis, and prompt intervention are necessary to avoid treatment-related deaths resulting from this unique toxicity.
T-DXd: Occurrence of Treatment-Related ILD/Pneumonitis in Phase III Trials
In different phase III trials of T-DXd, including DESTINY-Breast02, DESTINY-Breast03, and DESTINY-Breast04, the incidence of any-grade T-DXd–related ILD/pneumonitis ranged from 10.4% to 15.2%, but the incidence of grade 5 ILD/pneumonitis was low at <1%.4,12,13 Nonetheless, the importance of carefully monitoring for ILD/pneumonitis in patients receiving T-DXd cannot be overstated to ensure that on-time and appropriate management strategies are put in place for patients experiencing this TEAE.
ILD Risk Factors: Pooled Analysis from 9 Phase I/II Trials of T-DXd Monotherapy
In a pooled analysis of 1150 heavily pretreated patients with cancer who received monotherapy with T-DXd as a part of 9 phase I/II trials, the investigators retrospectively assessed ILD/pneumonitis events using an independent adjudication committee.16 The pooled analysis included patients with breast cancer (44.3%), gastric cancer (25.6%), lung cancer (17.7%), colorectal cancer (9.3%), and other cancers (3.0%). The majority of the patients experienced a first adjudicated drug-related ILD/pneumonitis event within ≤12 months of initiating treatment with T-DXd, with a plateau of events after the first 12 months. So, ILD tends to occur earlier on in the treatment course, emphasizing the need for early recognition, diagnosis, and management. In this retrospective study, 7 factors were identified as potential risk factors for the development of ILD/pneumonitis. These factors included age, trial enrolment in Japan, mild to moderate or severe decreases in renal function at baseline, >4 years since initial diagnosis, higher doses of T-DXd, oxygen saturation level at baseline, and the presence of lung comorbidities such as asthma, chronic obstructive pulmonary disease, or a history of pneumonitis or fibrosis.
To summarize the findings from this study, all patients who are receiving T-DXd require close monitoring and proactive management of treatment-induced ILD/pneumonitis.
Strategies to Manage ILD Associated With T-DXd
As previously stated, it is important to proactively monitor patients receiving T-DXd for signs and symptoms of ILD, as well as educate patients about what to look for while receiving therapy.2 Patients should be encouraged to immediately report fever and pulmonary symptoms such as cough and dyspnea.15 Once reported, these symptoms should be promptly investigated. If ILD is suspected, radiographic imaging assessments using high-resolution CT are warranted to confirm or rule out ILD. In my practice, we usually involve our pulmonary colleagues as soon as ILD is suspected and perform tests to rule out other causes of ILD, such as disease progression or infection.
Once diagnosed, all ILD events should be monitored until symptom resolution, even after drug discontinuation. For any grade 1 T-DXd‒emergent ILD, treatment should be held until symptom resolution to grade 0. Corticosteroid administration also should be considered, particularly for any patients who experience clinical deterioration. If grade 1 ILD resolves within 28 days of onset, the dose of T-DXd can be restarted at the same dose. However, if resolution occurs after 28 days of onset, T-DXd should be reduced by 1 dose level. For grade 2-4 T-DXd‒emergent ILD, treatment should be permanently discontinued, and a systemic corticosteroid should be promptly administered, for example, 1 mg/kg/day prednisolone for ≥14 days, followed by a taper for ≥4 weeks.
Occurrence of Left Ventricular Dysfunction: Summary of Events in Phase III Trials of T-DXd in Breast Cancer
Similar to other HER2-targeted agents, T-DXd also is associated with a risk of left ventricular ejection fraction (LVEF) declines, cardiomyopathy, or heart failure.2 In clinical trials of T-DXd, the rates of heart failure or LVEF decline were generally <5%. Of note, ADCs have not yet been studied in patients with LVEF <50% at baseline. In the DESTINY-Breast02, DESTINY-Breast03, and DESTINY-Breast04 phase III trials of T-DXd, all-grade left ventricular dysfunction occurred in patients who received T-DXd at an incidence of 2.7% to 4.9%, although the incidence of grade ≥3 left ventricular dysfunction was very low, ranging from none on the DESTINY-Breast03 trial to <1% on the DESTINY-Breast02 and DESTINY-Breast04 trials.4,12,17 It is not clear why there is a higher incidence of all-grade left ventricular dysfunction on DESTINY-Breast02 (4.5%) and DESTINY-Breast04 (4.9%) compared with DESTINY-breast03 (2.7%). We need additional data to better understand these differences.
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