Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer

Patients

Demographic and Baseline Clinical Characteristics.

Between July 20, 2018, and June 23, 2020, a total of 524 patients with HER2-positive metastatic breast cancer were enrolled at 169 centers in 15 countries. In total, 261 patients were randomly assigned to receive trastuzumab deruxtecan and 263 to receive trastuzumab emtansine (Fig. S1). Demographic and baseline disease characteristics were similar in the two groups and were largely representative of the overall HER2-positive breast cancer population (Table 1 and Table S2). A total of 130 patients (49.8%) in the trastuzumab deruxtecan group and 123 patients (46.8%) in the trastuzumab emtansine group had received one previous line of therapy (not including endocrine therapy) in the context of metastatic disease; 62.1% and 60.1% of the patients, respectively, had received pertuzumab therapy. Stable brain metastases were reported in 62 patients (23.8%) in the trastuzumab deruxtecan group and in 52 patients (19.8%) in the trastuzumab emtansine group. The median duration of follow-up was 16.2 months (range, 0 to 32.7) with trastuzumab deruxtecan and 15.3 months (range, 0 to 31.3) with trastuzumab emtansine.

Efficacy

Kaplan – Meier Analysis and Subgroup Analysis of Progression-free Survival.

Panel A shows the Kaplan – Meier estimates of progression-free survival, as assessed by blinded independent central review, in the intention-to-treat population (all randomly assigned patients), stratified according to hormone-receptor status, previous treatment with pertuzumab, and history of visceral disease. The median progression-free survival was not reached in the trastuzumab deruxtecan group and was 6.8 months in the trastuzumab emtansine group; the estimated percentage of patients who were alive without progression at 12 months was 75.8% (95% CI, 69.8 to 80.7) and 34.1% (95% CI, 27.7 to 40.5), respectively. The tick marks indicate censored data. Panel B shows hazard ratios and 95% confidence intervals for progression-free survival in subgroups defined according to hormone-receptor status, previous treatment with pertuzumab, baseline visceral disease, lines of previous therapy, and stable brain metastases (as defined by central documentation nervous system metastases in the patient’s medical history). The progression-free survival benefit of trastuzumab deruxtecan over trastuzumab emtansine was consistent across all the subgroups. Patients who had had rapid progression (ie, progression that had occurred within 6 months after receipt of neoadjuvant or adjuvant therapy or within 12 months after receipt of a neoadjuvant or adjuvant pertuzumab-containing regimen) were considered to have had one line of previous therapy. Lines of previous therapy did not include endocrine therapy. NE denotes could not be estimated, and NR not reached.

Treatment with trastuzumab deruxtecan showed a benefit over trastuzumab emtansine with respect to progression-free survival, as assessed by blinded independent central review. The median progression-free survival was not reached (95% CI, 18.5 to could not be estimated) in the trastuzumab deruxtecan group and was 6.8 months (95% CI, 5.6 to 8.2) in the trastuzumab emtansine group. At 12 months, the percentage of patients who were alive without disease progression, as assessed by blinded independent central review, was 75.8% (95% CI, 69.8 to 80.7) with trastuzumab deruxtecan as compared with 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine; the hazard ratio for disease progression or death from any cause was 0.28 (95% CI, 0.22 to 0.37; P <0.001) (FIG. 1A). Investigator-assessed median progression-free survival was 25.1 months (95% CI, 22.1 to could not be estimated) with trastuzumab deruxtecan as compared with 7.2 months (95% CI, 6.8 to 8.3) with trastuzumab emtansine (hazard ratio, 0.26; 95 % CI, 0.20 to 0.35; P <0.001) (Fig. S2). The subgroup analysis showed a benefit in progression-free survival (as assessed by blinded independent central review) with trastuzumab deruxtecan over trastuzumab emtansine across all the subgroups, including the subgroup defined according to the number of lines of previous treatment. The hazard ratio for disease progression or death from any cause was 0.33 among the patients who had received no lines or one line of previous therapy and 0.28 among those who had received two or more lines of previous therapy (FIG. 1B).

First Interim Analysis of Overall Survival.

Shown are Kaplan – Meier estimates of overall survival at 12 months in the intention-to-treat population, stratified according to hormone-receptor status, previous treatment with pertuzumab, and history of visceral disease. At the time of the data cutoff date of May 21, 2021, a total of 86 deaths had occurred; this analysis was performed on the basis of a progression-free survival benefit with trastuzumab deruxtecan. The median overall survival was not reached in either treatment group (hazard ratio, 0.55; 95% CI, 0.36 to 0.86; P = 0.007). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine. The tick marks indicate censored data.

At the time of data cutoff for the interim analysis, the percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (FIG. 2). The difference between the treatment groups did not reach the prespecified cutoff for significance (P <0.000265) (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; P = 0.007). A total of 33 of the 261 patients (12.6%) in the trastuzumab deruxtecan group and 53 of the 263 patients (20.2%) in the trastuzumab emtansine group had died as of the date of data cutoff.

Antitumor Activity.

Shown are the best percentage changes from baseline in the sum of the largest diameters of measurable tumors in patients for whom data from both baseline and postbaseline assessments of target lesions by independent central review were available: 245 of 261 patients who received trastuzumab deruxtecan (Panel A ) and 228 of 263 patients who received trastuzumab emtansine (Panel B). The upper dashed horizontal line indicates a 20% increase in tumor size in the patients who had disease progression, and the lower dashed line indicates a 30% decrease in tumor size (partial response).

An overall response occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan as compared with 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine (FIG. 3 and Table S3). A total of 42 patients (16.1%) in the trastuzumab deruxtecan group had a complete response as compared with 23 patients (8.7%) in the trastuzumab emtansine group. Progressive disease was the best overall response in 3 patients (1.1%) in the trastuzumab deruxtecan group and in 46 patients (17.5%) in the trastuzumab emtansine group; the percentage of patients who had disease control (defined as complete response, partial response, or stable disease) was 96.6% in the trastuzumab deruxtecan group and 76.8% in the trastuzumab emtansine group. After completion of the trial treatment, 78 patients in the trastuzumab deruxtecan group and 164 patients in the trastuzumab emtansine group received a new systemic anticancer treatment (Table S4). A total of 43 patients who had received trastuzumab deruxtecan during the trial began treatment with commercially available trastuzumab emtansine after completing the trial treatment, and 30 patients who had received trastuzumab emtansine during the trial began treatment with commercially available trastuzumab deruxtecan after completing the trial treatment.

Safety

The median duration of treatment was 14.3 months (range, 0.7 to 29.8) with trastuzumab deruxtecan and 6.9 months (range, 0.7 to 25.1) with trastuzumab emtansine. The incidence of adverse events after the start of treatment was similar in the trastuzumab deruxtecan group and the trastuzumab emtansine group (99.6% and 95.4%, respectively) (Table S5). Serious adverse events were reported in 49 of 257 patients (19.1%) in the trastuzumab deruxtecan group and in 47 of 261 patients (18.0%) in the trastuzumab emtansine group. The incidence of adverse events that resulted in the discontinuation of the trial treatment was higher with trastuzumab deruxtecan than with trastuzumab emtansine (13.6% vs. 7.3%). The incidence of adverse events of grade 3 or higher was similar in the two groups (52.1% and 48.3%, respectively).

Most Common Drug-Related Adverse Events and Adjudicated Drug-Related Interstitial Lung Disease or Pneumonitis.

The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. The most common drug-related adverse events of any grade that were reported in the trastuzumab deruxtecan group were nausea (in 72.8% of the patients), fatigue (in 44.7%), and vomiting (in 44.0%); the incidence of each of these events was lower in the trastuzumab emtansine group (27.6%, 29.5%, and 5.7%, respectively) (Table 2). Drug-related alopecia of any grade occurred in 36.2% of the patients in the trastuzumab deruxtecan group and in 2.3% of those in the trastuzumab emtansine group. The most common drug-related adverse events of grade 3 or 4 that occurred after the start of treatment in the trastuzumab deruxtecan group were neutropenia (in 19.1%), thrombocytopenia (in 7.0%), leukopenia (in 6.6%), and nausea ( in 6.6%); these events were reported in 3.1%, 24.9%, 0.4%, and 0.4%, respectively, of the patients in the trastuzumab emtansine group. No drug-related adverse events of grade 5 were reported with either treatment.

The independent adjudication committee that evaluated all potential cases of interstitial lung disease or pneumonitis identified drug-related events in 27 patients (10.5%) who received trastuzumab deruxtecan (7 patients had grade 1 events, 18 had grade 2 events, and 2 had grade 3 events) and in 5 patients (1.9%) who received trastuzumab emtansine (4 had grade 1 events and 1 had a grade 2 event) (Table 2). No such events of grade 4 or 5 occurred in either treatment group, and most of the patients recovered by the time of the data cutoff (Table S6). In the trastuzumab deruxtecan group, the median time to onset of interstitial lung disease or pneumonitis was 168 days (range, 33 to 507), and 3 patients had more than one event, as assessed by the adjudication committee (1 patient had two grade 2 events, 1 patient had three grade 2 events, and 1 patient had one grade 1 event and one grade 2 event). Discontinuation of the trial treatment owing to interstitial lung disease or pneumonitis occurred in 21 patients (8.2%) who received trastuzumab deruxtecan and in 3 patients (1.1%) who received trastuzumab emtansine.

A decrease in ejection fraction was reported in 6 patients (2.3%) in the trastuzumab deruxtecan group and in 1 patient (0.4%) in the trastuzumab emtansine group. All the events of ejection fraction decrease were reported as grade 2, and all resolved with no action taken, with the exception of the decrease in 1 patient in the trastuzumab deruxtecan group whose ejection fraction remained compromised. Left ventricular dysfunction (grade 1; resolved with no action taken) was reported in 1 additional patient who received trastuzumab deruxtecan. All the patients who had a decrease in ejection fraction or had left ventricular dysfunction were asymptomatic, with no reported cardiac failure.

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