CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: January 26, 2024
Expiration: January 25, 2025
J101 Trial of T-DXd: Antitumor Activity
We have seen an evolution in trials assessing the benefits of T-DXd, from initially showing very robust activity in patients with HER2-positive advanced breast cancer to now showing benefit even in patients with HER2-low (HER2 IHC 1+ or IHC 2+/ISH-) expression levels.
Initially, we saw data from the first-in-human phase I J101 trial of T-DXd in 54 heavily pretreated patients with HER2-low metastatic breast cancer who had received a median of 7.5 previous therapies.8 In this group of patients, the confirmed objective response rate (ORR) was approximately 40%, with a median duration of response of 10.4 months and a median progression-free survival (PFS) of 11 months. This clinical activity is very robust in a population of very heavily pretreated patients and suggested that T-DXd is beneficial to patients with pretreated HER2-low metastatic breast cancer which led to the development of DESTINY-Breast04.
DESTINY-Breast04: T-DXd vs Chemotherapy for Previously Treated HER2-Low ABC
The registrational DESTINY-Breast04 study is a multicenter, randomized, active-controlled phase III trial that enrolled patients with HER2-low unresectable or metastatic breast cancer who had received 1-2 previous lines of chemotherapy in the metastatic or recurrence setting.9,10 Patients were randomly assigned in a 2:1 fashion to receive T-DXd or chemotherapy of physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel). The primary endpoint was PFS by blinded independent central review in patients with hormone receptor (HR)–positive disease. Among 557 randomized patients, 494 had HR-positive disease and 63 had HR-negative disease. Since the study included a small exploratory cohort of patients with HR-negative disease, efficacy in the HR-negative patient population was one of the secondary endpoints.
DESTINY-Breast04: PFS (by Investigator)
In the HR-positive cohort, there was a dramatic improvement in PFS from 4.2 months with chemotherapy to 9.6 months with T-DXd in the primary analysis which was performed after a median follow-up of 18.4 months (hazard ratio: 0.37; 95% CI: 0.30-0.47).9 After a median follow-up of 32 months (updated analysis), the median PFS was consistent with results from the primary analysis (hazard ratio: 0.37; 95% CI: 0.34-0.46).9,10 These results demonstrate a PFS benefit with T-DXd that is greater than double that observed with chemotherapy. The same trend in PFS benefit with T-DXd over chemotherapy was observed in the overall patient population.
DESTINY-Breast04: OS
Of importance, significant improvement in overall survival (OS) was also observed in favor of T-DXd in the HR-positive population as well as the overall intent-to-treat population.9,10 In primary analysis of the HR-positive cohort, the median OS was 23.9 months with T-DXd vs 17.5 months with chemotherapy (hazard ratio: 0.64; 95%CI: 0.48-0.86). In the primary analysis of the overall patient population, the median OS was 23.4 months with T-DXd vs 16.8 months with chemotherapy (hazard ratio: 0.64; 95%CI: 0.49-0.84). The significant OS improvement seen with T-DXd over chemotherapy remain true even now with longer follow-up in the overall patient population (hazard ratio: 0.69; 95% CI: 0.55-0.86).
DESTINY-Breast04: ORR and Exploratory Analyses of PFS and OS in the HR-Negative Cohort
The investigators also performed exploratory analyses of PFS and OS in a small cohort of 58 patients with HR-negative disease.10 What was seen in the overall patients population both in the primary and updated analysis was similar to the results observed among patients with HR-negative disease. In the HR-negative cohort, updated analysis of the median investigator-assessed PFS showed an improvement from 2.9 months with chemotherapy to 6.3 months with T-DXd (hazard ratio: 0.29; 95% CI: 0.15-0.57). Regarding the median OS, significant benefit was seen with T-DXd vs chemotherapy (17.1 vs 8.3 months, respectively; hazard ratio: 0.58; 95% CI: 0.31-1.08). Of interest, the ORR in patients with either HR-positive or HR-negative disease was identical at approximately 50%, suggesting that, regardless of HR status, T-DXd is more effective than chemotherapy.9
DESTINY-Breast04: Subgroup Analysis of OS in All Patients
Of note, many of us in the field wondered whether patients with HER2 IHC 2+/ISH- disease would experience a longer and more durable benefit from T-DXd compared with those with IHC 1+ disease. However, the subgroup analysis of OS demonstrated no difference in OS based on the HER2-low subcategory.10 Regardless of whether the patient’s disease is classified as HER2 IHC 1+ or IHC 2+/ISH-, very similar benefit was achieved with T-DXd compared with chemotherapy.
A similar trend in OS benefit in favor of T-DXd was observed regardless of previous exposure to a CDK4/6 inhibitor, number of previous lines of therapy, age, race, geographic region, Eastern Cooperative Oncology Group performance status or whether the patients have visceral disease at baseline or not.
DESTINY-Breast04: Drug-Related TEAEs (≥20% of Patients)
The major drug-related adverse events associated with T-DXd include nausea, with an incidence of 78% in DESTINY-Breast04. Since the rate of nausea is high among patients receiving T-DXd, a 3-drug prophylaxis using a neurokinin 1 receptor antagonist, a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone is recommended on Day 1 of treatment.11
In the DESTINY-Breast04 study, fatigue (60%) and neutropenia (49%) were other notable adverse events seen with T-DXd. There was a 38% rate of alopecia with T-DXd, but in terms of patients becoming bald with complete hair loss, the incidence is lower.
DESTINY-Breast04: Adverse Events of Special Interest
There are also a couple of unique toxicities associated with T-DXd that we need to be aware of, including interstitial lung disease (ILD), which was experienced by 12% of patients who received T-DXd on DESTINY-Breast04. A major concern is that some deaths can occur because of ILD and, in DESTINY-Breast04, there were 4 deaths because of T-DXd, accounting for approximately 1% of patients.
However, the vast majority of T-DXd–related ILD was grade 1/2, which was experienced by 10% of patients enrolled on DESTINY-Breast04. ILD is an important adverse event associated with T-DXd that everyone needs to be cognizant of so that appropriate and careful monitoring is done for patients receiving T-DXd, especially because serious ILD can emerge without prompt recognition and management.
In addition, because T-DXd targets HER2, it is important to consider cardiac monitoring. T-DXd is associated with some risk of cardiac toxicity and approximately 5% of the patients who received T-DXd on the DESTINY-Breast04 study experienced decreased ejection fraction and approximately 1% experienced cardiac failure.
Appropriate monitoring for these adverse events of special interest on a routine basis for patients receiving T-DXd is recommended.
Management of ILD Associated With T-DXd: “Five S Rules”
With the potential for ILD in patients receiving T-DXd, it is important to think about specific management guidelines. Tarantino12 came up with this mnemonic of the “five S rules” for the management of ILD associated with T-DXd. The “five S rules” stand for screening, scan, synergy, suspend treatment, and steroids.
Screening is important at baseline and regularly during treatment. It is critical to ensure that the patient does not have any sign(s) or symptom(s) of ILD at baseline and ascertain that the patient has no known history of ILD based on the most recent treatments received and on the patient’s most recent scans. It is important that patients are monitored on a regular basis.
In my practice, we often obtain scans every 6-9 weeks when patients are receiving T-DXd. If a patient develops ILD, synergy with a multidisciplinary team helps to provide optimal care. For example, I make sure that the patient is assessed to rule out infectious causes before determining whether the patient has T-DXd–related ILD. I often involve my pulmonary colleagues to help with ILD management. On occasion, I request for pulmonary function tests to assess the significance of the impact of the changes that I am seeing radiographically to help me better understand how to monitor the patient.
Of most importance, if ILD is suspected, treatment with T-DXd should be interrupted. For asymptomatic ILD (grade 1), treatment with T-DXd can be resumed when the radiographic changes seen on imaging have resolved. For grade ≥2 ILD, T-DXd should be permanently discontinued.
Steroid use is recommended for patients with grade ≥2 ILD. For patients with grade 1 ILD, it is at the discretion of the physician to initiate steroids or not. Typically, I administer steroids for my patients with grade 1 ILD because I am hoping that steroid use will help the ILD resolve more rapidly, especially because my intention is to resume T-DXd in a timely fashion.
Remaining Questions About HER2-Low and HER2 IHC 0 BC
Based on the robust data seen with T-DXd on DESTINY-Breast04, T-DXd received FDA approval for the treatment of patients with unresectable or metastatic HER2-low breast cancer after previous chemotherapy for metastatic disease or for those who develop disease recurrence during or within 6 months of completing adjuvant chemotherapy.13 Of note, T-DXd is the first FDA-approved targeted therapy for patients with HER2-low advanced breast cancer.
Although T-DXd has now become a standard of care for patients with unresectable or metastatic HER2-low breast cancer, some questions remain. For instance, which method should be used to convincingly determine HER2-low status, and how do we optimally select patients for T-DXd?
Currently, HER2-low breast cancer is categorized as HER2 IHC 1+ or IHC 2+/ISH-. This categorization includes approximately 45% to 55% of patients with breast cancer.14 However, it is currently unclear if T-DXd may benefit a broader population of patients, perhaps even among patients whose disease is currently classified as HER2 0, where T-DXd has no approval. In all, we need more information and clarity regarding the optimal cutoff for assessing HER2-low status.
Another challenge is that HER2 expression changes over time. Given that HER2-low expression is dynamic and changes over time, the appropriate tissue collection time point to use to categorize a tumor as HER2-low is not clearly defined. This is, however, important to know to be able to confidently make the decision about the use of T-DXd.
DESTINY-Breast04: PFS by Tumor Characteristic
Despite the dynamic nature of HER2-low expression, most in the field have concluded that it would be appropriate to use HER2-low status determined at any timepoint. This is based on data from DESTINY-Breast04 indicating that PFS benefit with T-DXd compared with chemotherapy was observed regardless of the specimen collection date or whether the tissue specimen was collected from the primary or metastatic site.15 In fact, benefit was seen with T-DXd regardless of whether the specimen used for HER2-low status determination was from a biopsy, excision or resection, archived tissue or newly obtained tissue.
Assessment
J101 Phase I Trial of T-DXd: Antitumor Activity and ORR by Subgroup
Another question raised is whether the intensity of HER2 IHC staining for patients classified as HER2-low impacts efficacy. The initial phase I J101 trial demonstrated that T-DXd benefits patients with either HER2 IHC 1+ or HER2 IHC 2+.8 In that study, there was no difference in T-DXd activity between patients with disease classified as HER2 IHC 1+ or IHC 2+/ISH-. T-DXd elicited ORR regardless of HR status, previous exposure to HER2-directed therapy, Eastern Cooperative Oncology Group performance status or geographic location in J101.
DESTINY-Breast04: Antitumor Activity and PFS
DESTINY-Breast04 confirmed the results seen in the phase I J101 trial by demonstrating that regardless of the HER2 IHC status, T-DXd elicits similar benefits in patients in terms of ORR and PFS compared with chemotherapy.9 Also, T-DXd prolonged PFS vs chemotherapy regardless of previous exposure to a CDK4/6 inhibitor.
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